rheumatic disease clinic

Rheum Dis Clin N Am 32 (2006) ix

Erratum

Erratum to ‘‘New Therapeutics in

Rheumatoid Arthritis’’

[Rheum Dis Clin N Am 32 (1) (2006) 57-74]

Christine Savage, MD, E. William St. Clair, MDT

Duke University Medical Center, Durham, NC, USA

In the February 2006 issue of Rheumatic Disease Clinics of North America,

an incorrect drug dosage was printed. On page 66 in the article ‘‘New Thera-

peutics in Rheumatoid Arthritis,’’ the correct dosage for rituximab should be

1000 mg intravenously once on days 1 and 15.

0889-857X/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.rdc.2006.05.009 rheumatic.theclinics.com

DOI of original article title 10.1016/j.rdc.2005.10.004.

* Corresponding author.

E-mail address: [email protected] (E.W. St. Clair).

http://rheumatic.theclinics.com

http://dx.doi.org/10.1016/j.rdc.2006.05.009

mailto:[email protected]

Rheum Dis Clin N Am 32 (2006) xi–xii

Preface

Gout

Hyon Choi, MD, DrPH, FRCPC

Guest Editor

Crystal deposition arthropathy continues to be one of the most common in-

flammatory rheumatic disorders that constitutes significant public health prob-

lems. These problems are anticipated to grow in scope in view of the growing

elderly population worldwide and increasing prevalence of risk factors for these

disorders. There have been many exciting recent developments in crystal ar-

thropathy research, and the current issue of Rheumatic Disease Clinics of North

America intends to summarize these data and put them into context.

First, recent epidemiologic data are reviewed, including the overall disease

burden and modifiable risk factors of gout, which have implications for the pre-

vention and management of this painful condition. An article discusses the ma-

jor chronic disorders associated with hyperuricemia or gout and acknowledges

the ongoing research and debate on their independent pathogenetic links. Recent

elucidation of molecular mechanisms of urate crystal–induced inflammation and

renal urate transport mechanisms is reviewed in two articles, both of which rep-

resent substantial advancement in our pathogenetic understanding with potential

therapeutic implications. Two articles review therapeutic approaches for crystal

deposition arthropathy: one for overall therapeutic modalities, including history

and recent advances, and the other for all relevant human clinical trials, including

trials of the new potent agents in development.

Specific to calcium deposition diseases, one article updates their overall patho-

genesis and clinical manifestations. Two separate articles review the potential

pathogenetic roles of calcium deposition on other major disorders in a balanced





prefacexii

manner: one for osteoarthritis and the other for nonrheumatic disorders. Finally,

another article reviews radiographic modalities that are used for crystal ar-

thropathy. Special thanks are owed to Anthony Reginato, MD, PhD, for assisting

reviews of these last four articles. It is hoped that putting these articles together

will help disseminate these important recent developments among clinicians and

researchers in the field and stimulate research that will elucidate further the

pathogenesis of these disorders and their associated conditions and lead to im-

proved methods of prevention, diagnosis, and treatment.

Hyon Choi, MD, DrPH, FRCPC

Division of Rheumatology

Vancouver General Hospital

The University of British Columbia

Arthritis Research Centre of Canada

Vancouver, BC, Canada

Channing Laboratory

Department of Medicine

Brigham and Women’s Hospital

Boston, MA, USA

E-mail address: [email protected]


Rheum Dis Clin N Am 32 (2006) 255–273

Epidemiology of Crystal Arthropathy

Hyon Choi, MD, DrPHa,b,TaDivision of Rheumatology, Vancouver General Hospital,

The University of British Columbia, Arthritis Research Centre of Canada, Suite 300,

895 West 10th Avenue, Vancouver, BC V5Z 1L7, CanadabChanning Laboratory, Department of Medicine, Brigham and Women’s Hospital,

181 Longwood Avenue, Boston, MA 02115, USA

Gout is an inflammatory arthritis mediated by the crystallization of uric acid

within the joints and often is associated with hyperuricemia. Epidemiologic data

suggest that the overall disease burden of gout remains substantial and may be

increasing. Identifying and characterizing important modifiable risk factors for

gout is a major step in the prevention and management of this painful condition.

As more scientific data on these modifiable risk factors and comorbidities of gout

become available, integration of these factors into gout prevention and care

strategies may become essential [1]. This article reviews the relevant epidemio-

logic data on gout, with a focus on recent progress and available data on other

crystal arthropathies, although existing data on the latter are limited.

Prevalence of gout

Definitive diagnosis of gout requires either the presence of monosodium urate

monohydrate crystals in joint fluid or a tophus [2]. In population surveys de-

signed to estimate the prevalence of gout, however, this method of identification

is impractical. For this reason, several criteria for gout case definition have been

developed, including the Rome criteria [3], the New York criteria [4], and the

American College of Rheumatology (ACR) criteria [2]. Although the ACR cri-



T Division of Rheumatology, Vancouver General Hospital, The University of British Co-

lumbia, Arthritis Research Centre of Canada, Suite 300, 895 West 10th Avenue, Vancouver,

BC V5Z 1L7, Canada.


http:\\www.cdc.gov\nchs\data\series\sr_10\sr10_200.pdf




choi256

teria are applicable in clinical and population-based research [2], the ACR sur-

vey criteria, in particular, have been used widely in recent epidemiologic studies

of gout [5,6].

The National Arthritis Data Workgroup reviewed earlier population-based

studies that estimated the prevalence of gout [7]—the Tecumseh Community

Health Study [8], the Framingham Heart Study [9], and the Sudbury study [10].

These data are summarized in Table 1. These studies were conducted in con-

fined geographic regions and were relatively small (total participants: 7207,

5127, and 4626, respectively). Furthermore, these studies were done before the

ACR criteria were developed [2]. Overall, the age distribution of the Framingham

study population was older, resulting in a higher prevalence than in the other two

(see Table 1).

The United States national prevalence of gout has been estimated using self-

reported data from various years of the National Health Interview Survey (NHIS)

and the Third National Health and Nutrition Examination Survey (NHANES III,

1988–1994). In the NHIS, the presence of gout during a 1-year period was

recorded if a respondent answered ‘‘yes’’ to the question, ‘‘Have you or any

member of your household had gout within the past year?’’ In contrast, during

the home interview of the NHANES, all subjects were asked, ‘‘Has a doctor ever

told you that you had gout?’’ Interviewers were instructed to emphasize the word,

doctor. If the respondent stated that it was another health professional who gave

the diagnosis of gout to him or her, then the answer was coded as ‘‘no’’ [11].

Although the accuracy of these self-reported data has not been studied spe-

cifically in these surveys, validation data from other studies may help understand

the general accuracy of self-reported gout. Data from the Sudbury study shows

that 44% of self-reported cases could be validated according to Rome or New

York criteria [10]. The validation rate from a physician cohort (Johns Hopkins

Precursor Study) was much higher, however—80% according to the ACR survey

criteria applied by mail and 100% by mail combined with medical record review

[6]. Similarly, the validation rate of self-reported gout in a recent large pro-

Table 1

Prevalence of gout in the United States in regional population studies

Source (year) Gout definition Age

Prevalence (per 1000)

Total Male Female

Tecumseh Community

Health Study (1960)

‘‘Rome’’a � 20 7.2 4.8

Framingham Heart

Study (1964)

Arbitraryb � 42 (mean, 58) 14.8 28.5 3.9

Sudbury study (1972) Romec and NYd � 15 3.7 6.6 1.0

a ‘‘Rome’’: ‘‘insofar as possible’’ on the Rome criteria.b Arbitrary: at least 2 of the following 3 features — a typical attack of arthritis, an attack of

arthritis with a prompt response to colchicine therapy, and hyperuricemia.c Rome: Rome criteria for gout.d NY: New York criteria for gout.

Table 2

Annual prevalence of gout per 1000 in the United States by age, sex, race, and income, 1996

Age, year

b 45 45–64 � 65

Sex

Male 3.4 33.5 46.4

Female 0.2 12.0 19.5

Race

White 1.9 21.0 31.0

Black 0.7 35.6 35.2

Income

b $10,000 — 54.9 36.6

$10,000–$19,999 — 23.9 34.9

$20,000–$34,999 1.4 29.8 21.5

� $35,000 2.8 18.3 28.5

epidemiology of crystal arthropathy 257

spective cohort of male health professionals (Health Professionals Follow-Up

Study [HPFS]) was approximately 70% according to the ACR survey criteria

assessed by a mailed survey [5]. The difference in the validation rate of self-

reported gout between these studies likely reflects differences in level of health

knowledge in the study populations, although the contribution of the differ-

ences in the criteria used cannot be eliminated.

The most recent available NHIS data on self-reported gout are from the 1996

survey (Table 2) [12]. The overall prevalence for the 1-year period was 9.4 cases

per 1000 persons in the United States. The prevalence increased with age, from

1.8 per 1000 in persons aged 18 to 44 to 33.5 per 1000 in persons aged 45 to 64,

and to 46.4 per 1000 in persons aged 65 and older. The prevalence was higher in

men at all ages and higher in blacks aged 45 and older than in whites in the same

age group (see Table 2) [12]. In addition, the prevalence tended to be higher with

lower family income levels (see Table 2).

In the NHANES III, the lifetime prevalence of gout was lowest (0.4%) in

subjects aged 20 to 29 and highest (8%) in those aged 70 to 79 (Table 3). Among

men, the prevalence of gout increased from 0.2% in subjects aged 20 to 29 to

Table 3

Life-time prevalence of gout per 1000 in the United States (Third National Health and Nutrition

Examination Survey, 1988–1994)T

Age, year Total Male Female

� 20 26 38 16

20–29 4 2 5

30–39 11 21 1

40–49 17 26 9

50–59 39 56 23

60–69 61 94 32

70–79 80 116 52

� 80 59 71 53

T Lifetime prevalence of gout obtained by the question, ‘‘Has a doctor ever told you that you

had gout?’’

Table 4

Annual prevalence of gout per 1000 in the United States by survey year (National Health Inter-

view Survey)T

Age group, year

All ages 17/18–44 45–64 � 65

1969 4.8 3.1 12.0 12.7

1976 7.8 3.8 18.4 24.1

1988 8.5 3.1 21.0 27.0

1996 9.4 1.8 22.4 30.8

T 1-Year prevalence of gout obtained by the question, ‘‘Have you or any member of your

household had gout within the past year?’’

choi258

11.6% in those aged 70 to 79. Although gout was reported more often in men

than in women overall, the prevalence in women approached that of men after

menopause (see Table 3). The prevalence of gout was 3.2% in women aged 60 to

69 and increased to 5.2% in women aged 70 to 79 and 5.3% in women 80 years

and older [11]. These national data suggest that the prevalence of gout is

approximately 2.7% in the United States. This corresponds to an estimated

5.9 million persons who have gout: 4.0 million men and 1.9 million women.

Despite the emphasis on physician diagnosis of gout, however, these estimates

may be overestimated, because they were based on self-reported data.

Available data suggest that the prevalence of gout is increasing. Prevalence

estimates derived from the NHIS over time can be compared directly (Table 4),

because the survey instrument has not changed. The prevalence more than

doubled, and the steepest increase occurred between 1969 and 1976 [13]. More

recent NHIS data from the 1992 to 1996 surveys suggest the increasing trend

seemed to slow substantially between 1992 and 1996 (8.4 and 9.4 per 1000) (see

Table 4). Similarly, a multicenter study of general practices in the United

Kingdom reports that the prevalence of gout in 1991 increased threefold com-

pared with the estimates from the 1970s [14]. An increasing trend between the

1960s and 1992 also was observed in Maori Indians and in European descendants

in New Zealand [15]. More recently, a study based on a United States managed

care population recently reported that the overall prevalence of gout or hyper-

uricemia requiring a gout or serum urate-lowering medication in 1999 increased

by 80% compared with that in 1990 [16]. A similar increasing trend was observed

in Chinese population surveys performed in the 1990s [17].

Incidence of gout

Data on the incidence of gout are limited. The Rochester Epidemiology

Project identified 39 new cases of acute gout meeting the ACR criteria [2] during

the 2-year interval, 1977 to 1978, resulting in an age- and sex-adjusted annual

incidence rate of 45.0 per 100,000 (95% confidence interval [CI], 30.7–59.3)

[18]. In comparison, for the interval 1995 to 1996, 81 cases were diagnosed,

Table 5

Annual incidence of gout per 1000 (Rochester County residents)

Age

(1977–1978) (1995–1996)

Male Female Male Female

20–29 0.2 0.0 0.1 0.0

30–39 0.6 0.0 0.8 0.1

40–49 1.1 0.2 1.0 0.1

50–59 1.6 0.4 1.6 0.0

60–69 1.3 0.5 2.5 0.6

70–79 2.3 0.6 4.6 1.3

� 80 2.6 0.9 3.4 1.6


providing an annual incidence rate of 62.3 per 100,000 (95% CI, 48.4–76.2).

These rates resulted in a greater than twofold increase in the rate of primary gout

(ie, no history of diuretic exposure) during the 20-year period. In contrast, the

incidence of secondary, diuretic-associated gout did not increase over time [18].

The age-specific incidence rates stratified by sex are summarized in Table 5.

The Johns Hopkins Precursor Study documents 60 cases of incident gout that

developed in 1216 male physicians during a median follow-up of 29 years

(34,729 person-years of observation) [19]. These figures indicated an annual inci-

dence rate of 1.7 per 1000 (95% CI, 1.3–2.2). Recently, the HPFS documented

a comparable incidence rate (1.5 per 1000).

Risk factors for gout

Demographic factors

Age

Prevalence and incidence of gout increase with age in men and women [5,7,

11,18]. Serum urate rate levels also tend to increase with aging in women, but

the trend is less clear in men [8]. For example, the Normative Aging Study finds

no independent association between normal aging and serum uric acid levels in

healthy men [20]. Age-associated risk factors for hyperuricemia and gout might

explain some portion of the increasing incidence of gout with older age, includ-

ing increased prevalence of chronic medical conditions and medication use and

deterioration of renal function.

Gender

Although the prevalence and incidence of gout are substantially higher in

men than in women before menopause, the disease burden in women tends to

approach that of men after menopause. For example, the prevalence of gout in

NHANES III (discussed previously) may be overestimated given that they were

based on self-reports of physician-diagnosed gout; however, even if the true age-

specific prevalences were 50% lower, they still would be substantial, with the

choi260

prevalence of gout in this population approaching that of rheumatoid arthritis

(2% in the NHANES III) [21]. Furthermore, the Rochester Epidemiology Proj-

ect data indicate that the incidence of primary gout has doubled in women during

the past 20 years [18].

Gender also may alter the magnitude of the effect of certain risk factors. For

example, case series of gout comparing distributions of risk factors between men

and women suggest that risk factors for gout in women may be different from

those for men [22,23]. A higher proportion of female than male patients who had

gout had hypertension and renal insufficiency and were treated with diuretics

[22–24]. Conversely, more males than female patients reported heavy lcohol in-

take (especially beer), suggesting that alcohol intake may not be a major factor

contributing to the development of gout in female patients [22–24]. Although

these data are intriguing, these differences may reflect the difference in back-

ground prevalence of these factors between men and women, and these hospital-

based case series are open to a referral bias. These data call for gender-specific

epidemiology studies to quantify the magnitudes of associations in the differ-

ent sexes.

Race

A study based on two cohorts of former medical students, 352 black men in

the Meharry Cohort Study and 571 white men in the Johns Hopkins Precursor

Study, showed that the relative risk (RR) for gout in the black men was 1.69 (95%

CI, 1.02–2.80) compared with the white men [25]. The excess risk for gout in

black men was explained by a greater risk for incident hypertension among

them [25].

Modifiable risk factors

Serum uric acid and gout

Although hyperuricemia is considered the precursor of gout, only a few

epidemiologic studies have prospectively investigated the relation between prior

uric acid levels and risk for incident gout in men [26,27]. The Normative Aging

Study evaluated incidence of gout stratified by prior uric acid levels [26]. Based

on 84 incident cases of gout during a 15-year period, the all-male study found

that annual incidence of gout was less than 0.1% for men who had serum uric

acid level less than 7.0 mg/dL, 0.4% for 7.0 to 7.9 mg/dL, 0.8% for 8.0 to

8.9 mg/dL, 4.3% for 9.0 to 9.9 mg/dL, and 7.0% for greater than 10.0 mg/dL.

A Chinese population study followed men who had hyperuricemia (defined by

� 7.0 mg/dL) during a 5-year period and documented 42 cases of incident gout

[27]. Annual incidence rates of gout in this study were 2.2% for 7.0 to 7.9 mg/dL,

5.5% for 8.0 to 8.9 mg/dL, and 12.2% for greater than or equal to 9.0 mg/dL

(Fig. 1) [27]. No data on the impact of prior uric acid levels on incident gout

specifically in women are available.

It remains unclear if dietary and other risk factors predict the risk for incident

gout independent of prior uric acid levels. The Normative Aging Study reported

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

<6 6-6.9 7-7.9 8-8.9 9-9.9 >10

Serum Uric Acid (mg/dL)

An

nu

al In

cid

ence

of

Go

ut

Fig. 1. Relation between prior serum uric acid levels and incidence of gout. Annual incidence of gout

was less than 0.1% for men who had serum uric acid level less than 7 mg/dL, 0.4% for 7 to 7.9 mg/dL,

0.8% for 8 to 8.9 mg/dL, 4.3% for 9 to 9.9 mg/dL, and 7.0% for greater than 10 mg/dL. Solid line

denotes these data points and dotted line shows an exponential projection of the data points. (From

Campion EW, Glynn RJ, De Labry LO. Asymptomatic hyperuricemia. Risks and consequences in

the Normative Aging Study. Am J Med 1987;82:421–6; with permission.)


that age, body mass index (BMI), and hypertension no longer were associated

significantly with the risk for incident gout after adjusting for baseline serum

uric acid levels [26]. The Chinese study, however, restricted to men who had

hyperuricemia, showed significant associations with obesity, alcohol consump-

tion, and diuretic use (for hypertension) independent of uric acid levels [27].

Furthermore, the same study found a significant interaction between persistent

alcohol consumption and baseline uric acid levels in the hyperuricemic range

[27]. These data suggest that certain risk factors may be associated more strongly

in men who have hyperuricemia. For example, because renal urate clearance

is impaired in those who have hyperuricemia (such as gouty patients), the ab-

sorption of dietary purines causes a steeper increase in the blood uric acid level

than do equivalent quantities in persons who have normouricemia [28,29].

Adiposity

Adiposity has been noted to be associated with serum uric acid levels and

proposed to increase the risk for gout. Several prospective cohort studies have

evaluated the association between obesity and gout [19,25,26,30]. The Johns

Hopkins Precursor Study reported that increased BMI at age 35, but not at

baseline (mean age, 22), was associated with the risk for gout (RR 1.12 for 1 unit

increase in BMI; P = .02) [19]. The Normative Aging Study showed BMI at

baseline (mean age, 52) significantly associated with hyperuricemia or gout, al-

though the study had similar limitations [26]. The Framingham study found a

choi262

significantly higher BMI in patients who had gout after adjusting for age [30].

In these studies, a small number of gout cases or the lack of data limited the

comprehensive adjustment of relevant covariates. Specifically, no prospective

information had been available about the relation between obesity and incident

gout after adjusting for dietary factors, which themselves may be risk factors for

gout and vary with adiposity.

In a recent prospective analysis in the HPFS, BMI and waist-to-hip ratio were

strongly associated with the risk for incident gout after adjusting for various

confounders including dietary factors [31]. Compared with men who had BMI

21 to 22.9 kg/m2, the multivariate RRs of gout were 1.95 (1.44–2.65) for men

who had BMI 25 to 29.9 kg/m2, 2.33 (1.62–3.36) for 30 to 34.9 kg/m2, and

2.97 (1.73–5.10) for greater than 35 kg/m2 (P for trend b .001) (Fig. 2). The multi-

variate RR for gout in men in the highest waist-to-hip ratio quintile (0.98–1.39)

compared with those in the lowest (0.70–0.88) was 1.82 (95% CI, 1.39–2.39;

P for trend b .001). The HPFS data showed a substantial attenuation of RR af-

ter adjustment for confounders, emphasizing the importance of multivariate

models. Further, compared with men who maintained their weight (�4 to +4 lb)

since age 21, the multivariate RR of gout for men who gained 30 pounds or

more was 1.99 (1.49–2.66). In contrast, the multivariate RR for men who lost

10 pounds or more since the study baseline was 0.61 (95% CI, 0.40–0.92) [31].

Increased adiposity may lead to hyperuricemia via increased production and de-

creased renal excretion of urate [32,33]. Factors not related to uric acid, such as

chronic joint trauma resulting from excess weight, are proposed as an additional

explanation for the association between obesity and gout [6,33].

The impact of adiposity on gout adds to the already substantial hazards asso-

ciated with the obesity epidemic in the United States. The 1999 to 2000 National

Health and Nutrition Examination Survey estimated that the age-adjusted preva-

lence of obesity (BMI N 30) in United States adults is 30.5% [34]. The prevalence

of class 3 obesity (BMI index � 40) in adults has more than doubled in 10 years,

P for trend = < 0.001

BMI (kg/m2)

<21 21-22.9 23-24.9 25-29.9 30-35 >=35

Mu

ltiv

aria

te R

elat

ive

Ris

k

0

1

2

3

4

5

6

Fig. 2. Relation between BMI and incidence of gout in men.


with an estimated prevalence of 2.2% in the year 2000 [35]. Obesity is associated

with at least as much morbidity as poverty, smoking, and problem drinking [36]

and leads to approximately 300,000 deaths per year in the United States [37]. For

example, weight gain is linked to increased risks of coronary heart disease (CHD)

[38,39], hypertension [40], type 2 diabetes [41,42], kidney stone [43], and gall-

stones [44]. A new Healthy Eating Pyramid strongly recommends daily exercise

and weight control, placing them at the foundation of the pyramid (Fig. 3) [1,45].

Comprehensive persistent efforts to reduce adiposity could contribute to reducing

the disease burden from gout and associated morbidities [46].

Diet

Purine-rich foods and high protein intake long had been believed risk factors

for gout [32,33]; however, the associations had not confirmed prospectively.

Metabolic experiments in animals and humans demonstrated the urate-raising

effect of artificial short-term loading of purified purine [47–50]. Small-scale case-

Fig. 3. Dietary influences on the risk for gout and their implications within the Healthy Eating

Pyramid. Data on the relationship between diet and the risk for gout are derived primarily from the

recent HPFS. Upward solid arrows denote an increased risk for gout, downward solid arrows denote a

decreased risk, and horizontal arrows denote no influence on risk. Broken arrows denote potential

effect but without prospective evidence for the outcome of gout. (Adapted from Choi HK, Mount DB,

Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499–516; with permission.)

choi264

control studies that assessed dietary intake retrospectively in confirmed cases of

gout and controls, however, failed to find an association between purine intake

and gout [51,52]. In addition, the possibility that the consumption of dairy

products has a role in protecting against gout has been raised by previous studies

[53,54]. In a recent study (HPFS), the relation between these purported dietary

risk factors and incident gout during a 12-year period in 47,150 male participants

(730 incident gout cases), who had no history of gout at baseline, was examined

prospectively [5]. Men in the highest quintile of meat intake had a 41% higher

risk for gout compared with those in the lowest quintile, and men in the highest

quintile of seafood intake had a 51% higher risk compared with the lowest

quintile (Fig. 4). Purine-rich vegetable consumption, however, was not associated

with an increased risk for gout. Further, men in the highest quintile of dairy intake

had a 44% lower risk for gout compared with those in the lowest and the inverse

association was limited to low-fat dairy consumption (Fig. 5). Although total and

animal protein intake were not associated significantly with risk for gout, men in

the highest quintile of vegetable protein had a 27% lower risk for gout compared

with those in the lowest quintile, and men in the highest quintile of dairy protein

intake had a 48% lower risk for gout compared with those in the lowest quintile.

Dairy protein may exert its urate-lowering effect without the concomitant purine

load contained in other animal protein sources, such as meat and seafood, given

that dairy products have a low purine content [54,55]. It also is possible, however,

that other factors in dairy products may be responsible for the inverse association.

The absence of the inverse association with high-fat dairy products could result

from the counteracting effect of saturated fats contained in high-fat dairy prod-

ucts. These fats are associated positively with insulin resistance [56,57], which

reduces renal excretion of urate, thus raising serum uric acid levels [46,58–60].

A recent Taiwanese case-control study (91 gout cases and 91 controls) suggested

P for trend = 0.016

Purine-rich Food Group Quintile (serving/d)

Q1 Q3 Q5 Q1 Q3 Q5 Q1 Q3 Q5

Mu

ltiv

aria

te R

elat

ive

Ris

k

0.0

0.5

1.0

1.5

2.0

P for trend = 0.016 P for trend = 0.779

Total Meat Seafood Purine-rich Vegetables

(0.6) (1.3) (2.3) (0.1) (0.3) (0.7) (0.2) (0.6) (1.4)

Fig. 4. Relative risk for incident gout according to intake of purine-rich food groups in men. The

reference group for comparisons is the men who have the lowest intake quintile in each food group.

Q1 to Q5 denote first quintile (lowest) to 5th quintile (highest).

P for trend = 0.648P for trend < 0.001

Dairy Intake Quintiles (serving/d)

Q1 Q2 Q3 Q4 Q5 Q1 Q2 Q3 Q4 Q5

Mu

ltiv

aria

te R

elat

ive

Ris

k

0.0

0.5

1.0

1.5 High-Fat Dairy IntakeLow-Fat Dairy Intake

(0.1) (0.4) (0.8) (1.2) (2.6) (0.2) (0.5) (0.8) (1.2) (2.5)

Fig. 5. Relative risk for incident gout according to dairy intake in men. The reference group for

comparisons is the men who have the lowest quintile of dairy intake. Q1 to Q5 denote first quintile

(lowest) to 5th quintile (highest).


a protective effect of folate and dietary fiber against gout (odds ratios, 0.43 and

0.37 between the extreme tertiles, respectively) [52]. These interesting findings

call for prospective confirmation.

Implications of these findings for dietary recommendation for patients who

have hyperuricemia or gout generally are consistent with the new Healthy Eating

Pyramid (see Fig. 3), except for fish intake [1]. The use of plant-derived omega-3

fatty acids or supplements of eicosapentaenoic acid and docosahexaenoic acid in

place of fish consumption could be considered to provide the benefit of these

fatty acids without increasing the risk for gout. Omega-3 fatty acids also may

have anti-inflammatory effect against gouty flares [1].

Alcohol

The association between alcohol consumption and risk for gout has been

suspected since ancient times; however, the association had not been confirmed

prospectively. Several cohort studies previously evaluated the association be-

tween alcohol intake and gout but were limited by small sample size and lack of

comprehensive adjustment of relevant variables [19,25,26,30,61] In the recent

HPFS, increasing alcohol intake was associated with increasing risk for gout

(a dose-response relationship) [62]. Compared with men who did not drink al-

cohol, the multivariate RR of gout increased from 1.25 (95% CI, 0.95–1.64) for

alcohol consumption (5 to 9.9 g per day) to 2.53 (1.73–3.70) (�50 g per day)

(P for trend b.001). This risk varied substantially according to type of alcoholic

beverage: beer conferred a larger risk than liquor, whereas moderate wine drink-

ing did not increase the risk (Fig. 6) [62]. These findings confirmed the long-

held belief of relation between alcohol intake and risk for gout. In addition, they

suggest that certain nonalcoholic components that vary among these alcoholic

beverages play a role in the incidence of gout. Beer is the only alcoholic beverage

P for trend < 0.001 P for trend = 0.01 P for trend = 0.68

Alcohol Types (serving/time)

< 1/m

Mu

ltiv

aria

te R

elat

ive

Ris

k

0

1

2

3

4

LiquorBeer Wine

5-7/w >1/d < 1/m 5-7/w >1/d < 1/m 5-7/w >1/d

Fig. 6. Relative risk for incident gout according to individual alcoholic beverage intake in men. The

reference group for comparisons in the lower panel is the men who have the lowest intake category,

less than 1 serving per month.

choi266

acknowledged to have a large purine content, which is predominantly guanosine,

a readily absorbable nucleoside [51,63]. The effect of ingested purine in beer on

blood uric acid may be sufficient to augment the hyperuricemic effect of alcohol

itself, producing a greater risk for gout than liquor or wine. It remains unclear

whether or not there are other nonalcoholic offending factors, particularly in beer,

or perhaps protective factors in wine mitigating the alcohol effect on the risk for

gout [62].

Medications, supplements, and toxins

Many medications and substances affect serum urate levels, potentially

affecting the risk for gout (Table 6). Among these, diuretics are shown to

independently increase the actual risk for gout in a prospective population-based

study [31]. During the HPFS 12 years of follow-up of men who had no previous

history of gout, diuretic use was associated independently with an increased risk

for incident gout independent of hypertension (RR 1.77; 95% CI, 1.42–2.20)

[31]. Because the indications for these urate-raising medications may pose an

increased risk for gout by themselves, it is important to adjust appropriately for

these indications in determining the independent impact of these medications.

Several studies suggest that high doses of vitamin C show a uricosuric effect

[64–68]. For example, ingestion of ascorbic acid (4 g) led to a twofold in-

crease in fractional clearance of uric acid up to 6 hours after the ingestion, and

ingestion of ascorbic acid (8 g for 3 to 7 days) reduced the serum uric acid by up

to 3.1 mg/dL as a result of a sustained uricosuria [67]. A recent trial showed that

supplementation with vitamin C (500 mg per day for 2 months) reduces serum

uric acid by 0.5 mg/dL [68]. Because vitamin C generally is considered safe, its

uricosuric effect may provide a useful option for the prevention and management

of hyperuricemia and gout.

Table 6

Substances affecting urate levels

Substances Implicated mechanisms and comments

Urate-raising agents

Diuretics zRenal tubular reabsorption associated with

volume depletion [71,72], may stimulate

URAT1 [73]

Salicylate (low dose) A Renal urate excretion [74]

b-blockers Unknown (no change in renal urate excretion [75]

Lactate, b-hydroxybutyrate, acetoacetate Trans-stimulation of URAT1 [73]

Pyrazinamide, nicotinate Trans-stimulation of URAT1 [73]

Ethambutol A Renal urate excretion

Cyclosporin, tacrolimus zRenal tubular reabsorption associated with

A glomerular filtration [76–80], hypertension [81],

interstitial nephropathy [82,83]

Insulin Higher insulin levels are known to reduce renal

excretion of urate [46,58–60]. May stimulate

URAT1 [73] or the Na+-dependent anion

cotransporter in brush border membranes of the

renal proximal tubule [1]

Lead A Renal urate excretion from chronic lead

nephropathy [84]

Urate-lowering agents

Probenecid, sulfinpyrazone, benzbromarone Inhibition of URAT1 [73]

Losartan Inhibition of URAT1 [73]

Salicylate (high dose) Inhibition of URAT1 [73]

Fenofibrate May inhibit URAT1

Amlodipine zRenal urate excretion [81]

Vitamin C Via uricosuric effect due to a competition for

renal reabsorption

via an anion-exchange transport system at the

proximal tubules

Allopurinol, febuxostat Inhibition of xanthine oxidase

Uricase Oxidation of urate to allantoin

Abbreviation: URAT1, urate transporter-1.


Although toxic levels of lead (ie, blood lead levels N60 mg/dL) clearly are

associated with gouty arthritis [69], no such relation was found with bone or

blood lead levels arising from community exposure in the Normative Aging

Study [61]. A clinical study based on 111 Taiwanese adults, including 27 who

had gout [70], however, suggested that chronic low-level environmental lead

exposure may inhibit urate excretion and that lead chelation therapy reduces this

inhibition [70]. Further research on large populations with variable lead exposure

levels would be helpful in determining the threshold for saturnine gout and the

importance of this variable in relation to other known risk factors for gout [61].

Associated medical conditions

Various medical conditions have been suspected of being associated with hy-

peruricemia and gout, including the metabolic syndrome, obesity, hypertension,

choi268

renal insufficiency, kidney stone, type 2 diabetes, and cardiovascular disorders.

Available data on the link between hyperuricemia and these disorders are re-

viewed in detail in the article by Becker and Meenakshi elsewhere in this issue;

this section discusses the relation with the risk for gout. Hypertension and renal

insufficiency have been shown in the HPFS to be associated independently with

the risk for incident gout (RR 2.31 [95% CI, 1.96–2.72] and 4.60; [1.88–11.25],

respectively) [31]. A history of kidney stone, however, was not associated with

the risk for incident gout (RR 1.05 [95% CI, 0.54–2.07]), whereas a confirmed

diagnosis of gout increased the risk for kidney stone (2.12 [1.22–3.68]) [85]. In

the Framingham study, gout was associated with a 60% increased risk for CHD in

men (95% CI, 1.1–2.2) [24]. The small number of women who had gout, how-

ever, limited a meaningful analysis (three cases of CHD in 19 women) [24]. The

potential independent link with other disorders remains to be clarified.

Calcium pyrophosphate dihydrate deposition and pseudogout

A definitive diagnosis of calcium pyrophosphate dihydrate (CPPD) deposition

disease would require unequivocal identification of CPPD crystals in joint fluid

or articular tissue [86,87]. It has been proposed that the presence of synovial fluid

crystal identification using polarized light microscopy and radiographic cal-

cification of the cartilage would make a definitive diagnosis and either one

would make a probable diagnosis [86,87]. Because joint aspiration or biopsy is

impractical in population studies, presence of radiographic chondrocalcinosis

often has been used in epidemiologic and clinical investigations to study CPPD

disease [86–91].

Studies have suggested that the prevalence of radiographic chondrocalcinosis

increases with age [88–90]. The Framingham Knee Osteoarthritis Study, based on

1402 elderly adults, reported that the prevalence of radiographic chondrocalci-

nosis in the knee joints increased from less than 4% in those under age 70 to 27%

in those over 85. The same study also reported a modest cross-sectional asso-

ciation between radiographic chondrocalcinosis and knee osteoarthritis (RR 1.52)

and females tending to have a slightly increased age-adjusted prevalence, although

the estimate was not statistically significant (RR 1.33 [95% CI, 0.93–1.92]). No

population epidemiologic data exist for pyrophosphate arthropathy or ‘‘pseudo-

gout’’ per se [87]. Most of available cases series suggest that mean age at

presentation of between seventh and eighth decades of life with a female pre-

dominance (2–3:1) [87,92].

Although many metabolic and endocrine diseases are reported to predispose to

CPPD deposition, the validity of many of these associations remains unclear [93].

A critical review reported that there were better evidences for the association with

hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia,

and hypothyroidism than with other suspected conditions [93].

Hereditary CPPD deposition diseases are reported in several ethnic popula-

tions, usually with autosomal dominance inheritance pattern [87,94,95]. Two


main clinical types are reported, the first characterized by early-onset, florid,

polyarticular chondrocalcinosis and the second by late-onset oligoarticular with

arthritis resembling sporadic pyrophospate arthropathy [87]. An abstract of a

Spanish familial study reported a comparison between 21 kindreds with definite

CPPD of ‘‘sporadic cases’’ and 15 kindreds of patients who had other rheumatic

disease (controls) [87,96]. The familial aggregation rate for chondrocalcinosis in

these kindreds was 38.8% compared with 0% in the controls.

Basic calcium phosphate deposition arthropathy

Basic calcium phosphate (BCP) crystal deposition is associated with several

clinical manifestations, ranging from asymptomatic status to destructive arthropa-

thy, called Milwaukee shoulder syndrome. Population data on these conditions

are scarce; there is only one large-scale study, reported in 1941 [97]. From 1937

through 1939, 6061 office workers and candidates underwent physical and fluo-

roscopic examination of both shoulders in connection with an insurance com-

pany. The prevalence of calcium deposition was 2.7% (3.6% in males and 2.5%

in females). Thirty-five percent of shoulders with calcium deposition were

associated with some degree of pain or discomfort before or during the time of

the study. Recent clinical studies indicate that the prevalence of intra-articular

BCP crystals in joints with osteoarthritis may be high (67%) [98]; these and

other related data are reviewed in detail in the article by Rosenthal elsewhere in

this issue.

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Hyperuricemia and Associated Diseases

Michael A. Becker, MDa,T, Meenakshi Jolly, MDb

aRheumatology Section, The University of Chicago Pritzker School of Medicine, Chicago, IL, USAbDepartment of Medicine, Rush University Medical Center, Chicago, IL, USA

In the years after introduction of effective urate-lowering therapy, many

persons who had hyperuricemia but no symptoms of gout were treated with

allopurinol or uricosuric agents in the belief that the previously demonstrated

association of gout with chronic structural and functional renal abnormalities

denoted a causal relationship. Epidemiologic studies in the late 1970s [1,2],

however, seemed to allay the concern that hyperuricemia and gout were in-

dependent risk factors for chronic kidney disease. These studies prompted the

current conservatism in the management of asymptomatic hyperuricemia. Never-

theless, the association of hyperuricemia and gout with other important disorders

continues to be documented and, combined with experimental data derived from

studies in rats, has led to reconsideration of a pathogenetic role for hyperurice-

mia independent of crystal deposition in hypertension, chronic kidney disease,

cardiovascular disease (coronary heart disease, stroke and peripheral artery dis-

ease, and congestive heart failure), and aberrant metabolic states, such as hyper-

triglyceridemia, obesity, insulin resistance, and metabolic syndrrome. Whether

or not hyperuricemia (or even ‘‘high normal’’ serum urate levels) plays a causal

role or simply is a marker arising in the course of each related disorder remains

unresolved. This article reviews the current status of the relationship between

hyperuricemia and associated disorders.



T Corresponding author. Rheumatology Section, MC 0930, University of Chicago Medical

Center, 5841 Maryland Avenue, Chicago, IL 60637.

E-mail address: [email protected] (M.A. Becker).




becker & jolly276

Definition of hyperuricemia

Physicochemical and population definitions of hyperuricemia exist [3]. The

physicochemical definition (serum urate concentration in excess of 6.8 mg/dL,

the limit of urate solubility in serum) is preferable in the context of gout, to stress

that the risk for crystal deposition disease imparted by urate supersaturation of

extracellular fluids begins at approximately this concentration and probably is

equivalent in comparably affected men and women. Hyperuricemia without

gout (asymptomatic hyperuricemia) is more common with this definition, with

prevalence rates of 5% to 8% in men in the United States [4–6] and up to 25% in

adult men of Polynesian derivation [7], than with a definition of hyperuricemia

based on serum urate values 2 standard deviations or more above the mean

population value.

With respect to the issue of crystal deposition and independent roles of

hyperuricemia, however, it is important to acknowledge the results of popu-

lation studies of serum urate, showing that values are higher in men than

in women before menopause and are more comparable thereafter. Furthermore,

children have lower serum urate levels, with adult male levels reached at the

time of puberty and female levels changing little before menopause. In fact, as

exemplified by the studies of juvenile-onset hypertension and cardiovascular

disease (discussed later), it may become necessary to frame new definitions

of ‘‘high’’ serum urate levels as distinct from physicochemical or population-

based hyperuricemia.

Hyperuricemia and hypertension

An association of hyperuricemia and hypertension [8–12] long has been rec-

ognized and is supported by the following observations:

1. Prevalences of hyperuricemia of approximately 20% to 40% in untreated

hypertensive patients and approximately 50% to 70% in treated or renally

impaired hypertensive patients

2. Gout prevalences of 2% to 12% in hypertensive patients

3. 25% to 50% hypertension prevalences in groups of patients who have

documented gout

4. Increasing prevalence of hyperuricemia with increasing blood pressure in

the general population

5. Increasing risk for development of hypertension with increasing baseline

serum urate levels

Despite these findings, conflicting results of epidemiologic studies and

the existence of multiple potentially confounding variables preclude establish-

hyperuricemia & associated diseases 277

ment of a cause-effect relationship in either direction. For example, the high

prevalence of hypertension in patients who have classical gout is related more

closely to obesity than to the duration of gout [13,14]. Moreover, only 1% of

blood pressure variation could be accounted for by serum urate values in

the Israel Ischemic Heart Disease Study of 10,000 men ages 40 or older [15].

These findings contrast with longitudinal studies in which the risk for future

hypertension is correlated with serum urate levels [9,10,12] and a trial of in-

dividuals, who initially were normotensive, in whom serum urate levels re-

mained positively and significantly associated with systolic and diastolic blood

pressures for 12 years and, when high, predicted the development of hyperten-

sion [8].

Because of difficulty in distinguishing epidemiologically between causal and

epiphenomenologic bases for the hyperuricemia-hypertension association, in-

creasing attention is devoted to mechanistic and experimental studies. Renal uric

acid clearances depend on tubular secretory and postsecretory reabsorption rates,

which are reported to be inappropriately low relative to glomerular filtration

rates in adult and childhood essential hypertension [3,16], and may be regu-

lated, in part, by renal blood flow. In fact, selectively increased renal vascular

resistance and total peripheral resistance are documented in subjects who have

essential hypertension and hyperuricemia, raising the possibility that hyper-

uricemia is a consequence of early nephrosclerosis in patients who have essential

hypertension [17]. A similar argument is made for the early appearance of

hyperuricemia in patients who have familial juvenile hyperuricemic nephropathy

(FJHN) [18].

In contrast, a causal role for hyperuricemia in hypertension is suggested by

the results of other experimental and clinical studies. Urate is reported to ac-

tivate critical proinflammatory pathways in vascular smooth muscle cells and,

hence, may have a role in the vascular changes associated with hypertension and

vascular disease [19,20]. Urate stimulates monocyte chemoattractant protein-1

production in vascular smooth muscle cells via mitogen-activated protein kinase

and cyclooxygenase 2. In Sprague-Dawley rats with serum urate levels raised

by oxonate inhibition of uricase activity, a direct correlation is observed between

serum urate level and the development of salt-resistant, allopurinol-reversible

high blood pressure [21]. Also demonstrated is increased juxtaglomerular renin

content and decreased macula densa neuronal nitric oxide synthase content,

implicating the respective mediator systems in the dysregulation of blood pres-

sure. Preglomerular arteriolopathy [22] accompanying these changes may ac-

count for the subsequent development of a salt-sensitive hypertensive state, not

reversible by lowering of serum urate levels [23]. Feig and Johnson recently

demonstrated a linear relationship between serum urate levels and systolic blood

pressure (r=0.8, Pb0.001) in adolescents who have new-onset hyperten-

sion [24]. Furthermore, in a pilot study of such individuals, allopurinol admin-

istration results in urate lowering and normalization of blood pressure [25].

Johnson and colleagues [26–29] review in detail the evidence for a role of urate in

human hypertension.

becker & jolly278

Hyperuricemia and chronic kidney disease

Despite the nearly invariable occurrence of hyperuricemia in chronic kidney

disease in humans and the high frequency of chronic renal impairment in patients

who have gout, evidence for a pathogenetic role of hyperuricemia in the initiation

or progression of chronic renal impairment comes mainly from animal studies

[30]. Mild oxonate-induced increases in serum urate levels in Sprague-Dawley

rats result in glomerular hypertension, hypertrophy, and, ultimately, sclerosis;

renin-dependent systemic hypertension and afferent arteriolosclerosis; and

interstitial renal inflammation, terminating in fibrosis [21,22,31–35]. All of these

changes occur at high but subsaturating urate levels and are independent of urate

crystal deposition. A role for increased urate levels in worsening structural and

functional renal disease also is demonstrated in the cyclosporine-induced [36]

and remnant kidney [33] models of chronic kidney disease in rats. Few studies in

humans are available to support the potential implications of the rat studies.

As discussed previously, earlier studies [1,2] in subjects who have gout and

hyperuricemia failed to corroborate a renal risk of hyperuricemia or gout, at least

at serum urate levels (b13 mg/dL in men; b10 mg/dL in women) commonly

encountered in clinical practice. Although a pathologically demonstrable in-

terstitial urate crystal deposition nephropathy (called urate nephropathy) does

exist, this entity only rarely is of clinical consequence [37]. The shift of in-

vestigative focus to crystal-unrelated effects of urate on the kidney holds more

promise for resolution of the question of a causal role of hyperuricemia in pro-

gressive renal disease.

FJHN is an autosomal dominantly inherited hyperuricemic disorder, commonly

progressing to end-stage renal disease, and allopurinol treatment is reported by

some investigators [38,39], but not all [18], to retard or prevent progression.

Although gout occurs in some patients who have FJHN, there is little evidence

for crystal deposition as a mediator of renal impairment [18], so that confirmation

of a benefical effect of allopurinol in this process is important in assessing the

role of hyperuricemia in the renal disease, for which alternative mechanisms are

proposed [40]. Most families who have the FJHN phenotype have mutations in

the UMOD gene encoding uromodulin (Tamm-Horsfall protein) [41], a fact that

should allow early identification of at-risk family members in whom the benefits

of early urate-lowering therapy can be assessed.

In epidemiologic studies, urate levels are reported to correlate with develop-

ment of chronic renal insufficiency in patients who have hypertension [42,43],

and patients who have impaired renal function have higher serum urate levels

[44–46]. Recently, a reciprocol relationship between serum urate levels and renal

vascular responsiveness to angiotensin II administration was reported [47], sug-

gesting that increased urate levels may, as in rats, activate the renin-angiotensin

system. Finally, the incidence of end-stage renal disease developing over 7 years

in Okinawan women who had serum urate levels greater than or equal to

6.0 mg/dL at baseline was significantly higher than in their counterparts who had

lower urate levels [48].


Hyperuricemia and cardiovascular disease

Coronary heart disease

The weight of recent evidence supports the view that hyperuricemia is an

important risk factor for ischemic heart disease and probably other forms of

cardiovascular disease [49,50]. Whether or not hyperuricemia is only a marker or

is a pathogenetic factor in cardiovascular diseases remains uncertain (Table 1),

and resolution of this issue will likely require large interventional trials assessing

the proposition that prevention or reversal of hyperuricemia has beneficial effects

on the course of cardiovascular disorders in at-risk patients.

The issue of hyperuricemia as an independent risk factor for atheroscle-

rotic cardiovascular disease is controversial [49]. Multivariate analysis of cardiac

risk factors in the original Framingham cohort did not identify an independent

predictive role for serum urate values in coronary heart disease [51] but did

show a 60% excess of coronary disease in gouty men never treated with di-

uretics [52]. Additional study of the Framingham cohort [53] supports the con-

tention that risk factors other than hyperuricemia are causal in atherosclerotic

heart disease. In 6763 subjects who had baseline serum urate levels established

from 1971 to 1976, hyperuricemia was not associated (by 1994) with an increased

risk for adverse outcome (coronary heart disease, death from cardiovascular

disease, or death from all causes) in men or, after adjustment for other cardiovas-

cular risk factors, in women. Similarly, Wannamethee and coworkers did not find

hyperuricemia a risk factor for coronary heart disease in men, independent of pre-

existing myocardial infarction, atherosclerosis, and the cluster of risk factors

associated with the insulin resistance syndrome [54]. Clustering of hyperuricemia

with cardiovascular risk factors also is reported by others [55].

Other published studies, however, favor a more direct role for hyperuricemia

in cardiovascular events or mortality [26,27,50,56–68]. In the National Health

and Nutrition Examination Survey (NHANES) I study, increasing serum urate

concentration was related to increasing cardiovascular mortality in both sexes and

in blacks and whites [56]. Death rates resulting from ischemic heart disease

increased in relation to serum urate quartile (relative risk 1.77 in men and 3.00 in

women), and cardiac and overall cardiovascular mortality risks of hyperuricemia

persisted even after adjustment for age, race, body mass index (BMI), smoking

status, alcohol intake, cholesterol, hypertension, and diabetes. In the NHANES III

study, serum urate levels greater than or equal to 6 mg/dL were found to be an

independent predictor of coronary heart disease [61]. Also, in two studies in-

cluding more than 2600 patients who had angiographically confirmed coronary

artery disease [57,62], overall mortality rates in patients either whose serum urate

was greater than 7.1 mg/dL (compared with those whose had serum urate was

b5.1) [57] or who were in the highest quintile for serum urate (N6.4 mg/dL) were

increased substantially and independently. Finally, the Losartan Intervention for

Endpoint Reduction in Hypertension (LIFE) study reported a significant

association between baseline serum urate level and risk for a morbid or fatal

Table

1

Studiesrelatingserum

urate

concentrationsandcardiovasculardisease

Author,year[ref.]

Subjects/studynam

eLongitudinal

study

Outcomevariables

Serum

urate

asindependent

predictorofCVD

Brand,1985[51]

Framingham

cohort

Yes

CHD

No

Culleton,1999[53]

Framingham

cohort

Yes

IncidentCHD,allcause

and

CVD

mortality

No

6763Participants

Wannam

ethee,1997[54]

7688Men,40–59years

Yes

Fatal/nonfatalCHD

events

No

Moriarity,

2000[63]

ARIC

cohort;13,504healthysubjects

Yes

CHD

events(fatal/nonfatal)

No

Lin,2004[139]

391Men

withhyperuricemia

Yes

CVD

Abbott,1988[52]

5209,Framingham

cohortwithgout

CHD

Yes,in

men

Freedman,1995[64]

5,421(N

HANES1)25–74years

Yes

Mortality(allcause,ischem

ic

heartdisease)

Yes,in

women

Alderman,1999[50]

7978Mild–moderateHTN

subjects

Yes

CVevents

Yes

Liese,1999[65]

MONICA

cohort,1044subjects,45–64years

Yes

CHD,allcause/CV

mortality

Yes

Fang,2000[56]

5926,Subjects25–74years

(NHANES1

follow-up)

Yes

CHD,allcause/CV

mortality

Yes

Franse,2000[66]

4327SystolicHTN

subjects�60years

(SHEP)

Yes

CVevents,allcause

mortality

Yes

Verdecchia,2000[67]

1720SubjectswithuntreatedHTN

Yes

CVevents,allcause/CV

mortality

Yes

Tuttle,2001[60]

277Patientsundergoingcardiaccatheterization

Yes

SUA

andCHD

Yes,in

women

Bickel,2002[57]

1,017CHD

(angiographic)

Yes

Mortality

Yes

Athyros,2004[71]

GREACEstudy,

1600withCHD

Yes

Allvascularevents

Yes

Niskanen,2004[68]

1423Middle-aged,healthyFinnishmen

Yes

CV/allcause

mortality

Yes

Hoieggen,2004[69]

9193Subjects,55–80years

old

withuntreated

HTN

andLVH

(LIFEstudy)

Yes

Fatal/nonfatalMI,CV

mortality,

fatal/nonfatalstroke

Yes

Tomita,

2000[45]

49,413HealthyJapanese25–60years

Yes

CHD

andstrokeevents,all

cause

mortality

Yes

Madsen,2005[62]

1,595Angiographically

defined

CAD

patients

Yes

Mortality

Yes

Abbreviations:

CAD,coronaryartery

disease;CHD,coronaryheartdisease;CV,cardiovascular;CVD,cardiovasculardisease;HTN,hypertension.

becker & jolly280


cardiovascular event (hazard ratio 1.024 per 10 mmol/L increment in baseline

serum urate) [69].

Data supporting a role for serum urate as a determinant of coronary heart

disease also have emerged from two cardiovascular disease interventional stud-

ies. In the LIFE study [69], which compares losartan-based and atenolol-based

therapy in high-risk hypertensive patients who had left ventricular hypertrophy,

losartan therapy is associated with lower rates of cardiovascular morbidity and

death [70]. Analysis of baseline and in-trial serum urate levels indicates that

29% of the cardiovascular benefit of losartan-based therapy could be ascribed

to the urate-lowering (uricosuric) effect of losartan (not shared by atenolol)

therapy, which prevented increases in serum urate levels during the 4.8 years

of the trial. Similarly, in the Greek Atorvastatin and Coronary-Heart-Disease

Evaluation (GREACE) study [71], patients who had coronary heart disease

treated with atorvastatin showed an in-trial 8.2% reduction in serum urate levels

compared with a 3.3% mean increase in urate in patients who were untreated. The

risks of recurrent coronary disease events were correlated significantly with the

serum urate levels, such that serum urate was regarded an independent predictor

of recurrent coronary heart disease events.

Mechanisms by which hyperuricemia may promote vascular occlusive dis-

ease are under study. A direct relationship between plasma homocysteine

and serum urate levels is reported in patients who have atherosclerosis [72]. A

mutation in the methyl tetrahydrofolate reductase (MTHFR) gene is correlated

with hyperuricemia and hyperhomocysteinemia, the latter a state associated with

thrombotic disease [73]. In a recent study [74], flow-mediated arterial dilation

(FMD) in healthy hyperuricemic and normouricemic control patients who hade

high cardiovascular risk was determined before and after 3 months of allopurinol

treatment. Allopurinol (300 mg daily) reduced serum urate levels in both groups

of subjects, and the significantly lower baseline FMD in the hyperuricemic

group was normalized, suggesting that restoration of normal serum urate levels

improved this measure of vascular function [74]. Other possible mechanisms

relating hyperuricemia and cardiovascular disease are reviewed by Gavin and

Struthers [75].

Stroke and peripheral artery disease

Uric acid administration is protective against experimental ischemic stroke in

rats [76]. In humans, however, there is only one report of a more favorable

outcome of stroke in individuals who are hyperuricemic [77]. In fact, higher

serum urate levels are associated with poorer outcomes in stroke, and serum urate

greater than or equal to 7 mg/dL is described as an independent risk factor for

stroke [61]. Lehto and coworkers [78] found hyperuricemia a predictor (hazard

ratio 1.93) of nonfatal and fatal stroke in a population-based study of middle

aged, non–insulin-dependent diabetics. Similar findings are reported by others

[79,80]. In the Cardiovascular Study in the Elderly (CASTEL) study [79], serum

becker & jolly282

urate also was an independent predictor of stroke mortality [79,59], poor out-

come, and subsequent vascular events, especially in diabetics [81]. Even though

levels of antioxidants, such as ascorbate, are reduced immediately after acute

ischemic stroke, patients who have the worst early outcome are those who have

higher plasma urate levels [82], raising the speculation that under circumstances

of alternative antioxidant depletion, urate may become prooxidant [82,83].

In patients in the LIFE study who were hyperuricemic [69], the cardiovascular

benefits of losartan extended to a reduced incidence of cerebrovascular events.

Whether or not the increased risk of stroke in individuals who are hyperuricemic

is mediated by increased predilection for the development of hypertension or

through a urate effect on the vascular endothelium is unclear, but these potential

mechanisms are under investigation [84].

Hyperuricemia also is a significant and independent risk factor for peripheral

arterial disease in Taiwanese men who have type 2 diabetes [84] and for carotid

artery atherosclerosis. Nieto and coworkers, in their prospective case control

study [85], find baseline serum urate levels associated significantly and in-

dependently with increased carotid artery atherosclerosis 13 years later. The

serum antioxidant capacity, however, was elevated unexpectedly in individuals

who had atherosclerosis, suggesting that hyperuricemia may be a compensatory

rather than a causative factor.

Congestive heart failure

Hyperuricemia is a common finding in congestive heart failure [86], and

higher serum urate levels are associated with increasing severity and poorer

outcomes in heart failure [87,88]. Anker and colleages [87] found high serum

urate levels an independent marker for impaired prognosis in patients who have

moderate to severe congestive heart failure. Urate also may contribute to more

severe heart failure via its role in hypertension [89]. Thus, there is evidence for

direct and indirect pathophysiologic roles of abnormal urate metabolism in con-

gestive heart failure [90].

In animal models, allopurinol decreases myocardial oxygen consumption [91]

and improves systolic function [92]. Endothelial damage resulting from local

xanthine oxidase-generated oxygen free radicals is proposed as a basis of cardiac

dysfunction in hyperuricemic states, and allopurinol inhibition of xanthine oxi-

dase is reported to improve endothelial dysfunction in patients who have heart

failure [86,93]. Ongoing interventional trials [89] assessing cardiovascular out-

comes resulting from inhibition of urate production with allopurinol and oxypuri-

nol should provide useful information relative to these proposed relationships.

Overall, a causal role for hyperuricemia in cardiovascular disease events and

mortality is not established unequivocally [26,58]. There seem to be more than

sufficient grounds, however, to support new clinical (interventional) and ex-

perimental initiatives for studying the potential causal mechanisms by which

hyperuricemia may promote cardiovascular disease [27].


Hyperuricemia, metabolic syndrome, and its components

Metabolic syndrome

Complexity in defining the role of hyperuricemia in chronic diseases, such

as hypertension and atherosclerotic cardiovascular disease, is underlined by

additional associations of hyperuricemia with the clinical and biochemical ab-

normalities of the metabolic syndrome: obesity, hyperlipidemia, and insulin re-

sistance. Included in the diagnostic criteria for the metabolic syndrome are waist

circumference, triglyceride levels, high-density lipoprotein (HDL) cholesterol

levels, blood pressure, and fasting blood glucose levels. Emmerson [94] has

reviewed evidence supporting inclusion of hyperuricemia resulting from impaired

renal uric acid clearance [95,96] as an intrinsic component of the metabolic

syndrome of hyperinsulinemia and resistance to insulin action [97]. The fact that

acute elevations of serum triglycerides, plasma free fatty acids, or serum insulin

do not effect serum urate levels in health volunteers supports this view [96].

Serum urate levels contribute significantly to levels of HDL cholesterol and

total cholesterol, BMI, and systolic blood pressure in children and adolescents

who are obese and may be a reliable marker of ‘‘premetabolic syndrome’’ [98].

The inverse correlation of serum urate and insulin sensitivity and the positive

correlation of urate and triglyceride levels may explain up to 50% of urate var-

iation [96]. It also is suggested that hyperuricemia may be used as a simple

marker of insulin resistance [96]. In addition, studies of weight loss-inducing

medications, such as sibutramine and orlistat, confirm reductions in BMI, fasting

and postprandial glucose levels, waist circumference, insulin resistance, blood

pressure, and serum levels of cholesterol, triglycerides, lipoprotein a, apolipo-

protein B, and urate uric acid [99] (ie, all the features of metabolic syndrome).

A corollary of these observations is that individuals who are hyperuricemic

and hyperlipidemic, in particular those who have abdominal obesity, may be a

high-risk group for the cardiovascular correlates of insulin resistance.

Obesity

Epidemiologic studies have established a strong positive correlation between

body weight and serum urate concentration, but the basis of the relationship is

complex and multifactorial [100–108]. Obesity is associated with decreased renal

uric acid clearance and increased urate production [109,110]. Direct and indi-

rect evidence for excessive body weight promoting hyperuricemia and gout is

presented in many studies [56,111–115], but a role of hyperuricemia influencing

development of obesity emerges from a few other studies (Table 2).

In interventional studies, weight reduction is associated with a modest low-

ering of serum urate concentration and a decrease in the rate of de novo pu-

rine synthesis [109]. In addition, the weight loss associated with moderate calorie

and carbohydrate restriction and increased proportional intake of protein and

unsaturated fat (as recommended for insulin-resistant states) is accompanied by a

Table

2

Characteristicsofselected

studiesonrelationship

ofhyperuricemia

andobesity

Author,year[ref.]

Studydesign

Subjects

Questionaddressed

Observations

Rem

arks

Loenen,1990[107]

Cross

sectional

460HealthyDutch

ages

65–79

Dem

ographic

correlates

ofobesity

Average7-kgdifference

betweenlowestandhighest

tertiles

ofSUA

formen,

and5kgforwomen

Anassociationbetweenbody

weightandSUA

present

Studyincluded

whites

only,

diabeticswereexcluded,and

30%

participantswereon

prescribed

dietary

restrictions

Fang,2000[56]

Longitudinal

5926Subjects

ages

25–74

Cardiovascularandall

cause

mortality

BMIandBPincreasedwith

increasingquartilesofSUA

in

men

andwomen

atbaseline

Independentrisk

factorstatus

notevaluated

Masuo,2003[114]

Longitudinal

433Young,nonobese,

norm

otensivemen

Relationbetweenserum

urate,weightgain,and

bloodpressure

elevation

SUA

predictssubsequent

weightgainandBPelevation

SUAwas

anindependentrisk

factorforweightgainandBP

Ogura,2004[113]

Longitudinal

17,155Students

SUA

andobesityor

relatedfactors

Serum

uricacid

levels

tightlyrelatedto

BMI

Independentassociation

betweenSUA

andBMInot

clear.Studyincluded

only

men

Abbreviations:

BMI,bodymassindex;BP,

bloodpressure;SUA,serum

urate.

becker & jolly284


decrease in serum urate levels and dyslipidemia in patients who have gout [116].

Furthermore, amelioration of insulin resistance by a low-energy diet decreases

serum urate levels in individuals who are overweight and hypertensive [117].

Finally, the weight-reduction agents, sibutramine and orlistat, lower serum urate

levels [99,118,119], and, in the prospective Swedish Obese Subjects Study [120],

2- and 10-year hyperuricemia and hypertriglyceridemia incidence rates were

lower in patients who had undergone bariatric surgery than in unoperated obese

control subjects.

Leptin, the hormone product of the obese (ob) gene, is expressed in adipo-

cytes and acts through the hypothalamus to regulate food intake and energy

expenditure. Most persons who are obese show leptin resistance, and increased

leptin levels are associated with insulin resistance in individuals who are non-

diabetic [121]. Insulin response, triglyceride levels, and BMI are associated in-

dependently and significantly with leptin concentrations [122].

Serum urate and leptin levels correlate in healthy male adolescents [123] and

in women who are moderately obese [124], and an independent relation between

serum leptin and urate was found in 822 Japanese women, even after adjust-

ing for BMI and percent body fat [125]. Women have a higher mean leptin

and lower mean urate and triglyceride concentrations than men even after adjust-

ment for BMI [126]. Similar findings are observed in children who are obese

[127]. Creatinine, leptin, insulin, and triglyceride levels account for significant

variability in serum urate in men and women [126]. These studies suggest that the

association of serum urate, obesity, and insulin resistance may be mediated, at

least in part, by leptin expression and that leptin levels may prove to be a link

between obesity and hyperuricemia.

Hyperlipidemia

The issue of hypertriglyceridemia and hyperuricemia is addressed in many

studies [56,98,128–131]. Hyperuricemia is observed in up to 80% of patients

who have hypertriglyceridemia. Furthermore, hypertriglyceridemia also may

be seen in 50% to 75% of patients who have gout. In humans, fasting serum

triglyceride levels may be the most important determinant of serum urate levels

[132]. Obesity and excessive alcohol intake confound these issues. Reductions in

serum HDL-C and HDL2-C concentrations also are observed in individuals who

are hyperuricemic [125,133]. By regression analysis, no association between

gout and HDL levels or BMI index was seen, suggesting that reduced HDL

levels are attributable to altered triglyceride metabolism [133]. Concentrations of

serum Lp(a) lipoprotein, triglycerides, and apolipoproteins AII, B, CII, CIII, and

E reportedly were increased, and HDL-C was decreased in patients who had gout

[134]. The prevalence of apolipoprotein E2 allele was greater in patients who had

gout, and its presence was associated with higher triglyceride levels in very low-

density and intermediate-density lipoproteins and with reduced renal uric acid

excretion [135].

becker & jolly286

In the prospective GREACE study, addition of atorvastatin to the standard

treatment of coronary heart disease patients resulted in serum urate reduction

averaging 8.2% compared with an average 3.3% increase in patients receiving

standard care without atorvastatin [71]. In the atorvastatin treatment group, tri-

glyceride levels fell by 31%, HDL-C rose by 7%, and the LDL-C/HDL-C ratio

decreased by 50%. Similarly, in another prospective study [120], lower 2- and

10-year incidence rates of hypertriglyceridemia and hyperuricemia were observed

in obese patients who underwent bariatric surgery.

Insulin resistance

The relationship between hyperuricemia and insulin resistance may be indi-

rect and mediated through increased fasting plasma triglyceride levels or BMI

[96,136]. In experimental animals, urate suppresses basal insulin release in iso-

lated rat pancreatic islets and inhibits glucose-stimulated insulin secretion [137].

In a study of the relationship of insulin-mediated glucose disposal and serum

urate in 36 healthy nondiabetic volunteers [95], renal uric acid clearance de-

creased in proportion to increased insulin resistance, resulting in increased se-

rum urate concentration. An association between hyperinsulinemia and decreased

renal uric acid clearance also is reported in another study [96].

Increased serum urate concentration is among the significant risk factors as-

sociated with non–insulin-dependent diabetes mellitus in Japanese Americans

living in Hawaii and Los Angeles [138]. Persistent hyperuricemia in postmeno-

pausal women in the Kinmen study also is associated with subsequent devel-

opment of diabetes [139,140]. In a longitudinal study of Japanese male office

workers, a strong association between serum urate and subsequent development

of hypertension or type 2 diabetes was found [141]. The relationship with dia-

betes was stronger in men who had BMI less than 24.2 kg/m2 compared with

higher BMI, but the absolute risk was greater in more men who were obese.

In another prospective study, however, hyperuricemia is associated with the

development of hypertension but not type 2 diabetes [10]. Finally, metformin

administration not only reduces postprandial and fasting blood glucose levels but

also serum urate levels [99].

Summary

It is the authors’ belief that the literature to date has not established a causal

link between hyperuricemia and the previously discussed disorders that justify

the use in clinical practice of urate-lowering treatment in aymptomatic hyper-

uricemia to avoid or modify the course of the associated diseases. Relationships

between hyperuricemia and each of these morbid states do, however, exist and

may, in one or more of these disorders, prove causal and, thus, exploitable by

urate-lowering intervention. Although experimental studies performed in animals


have limitations set by differences between humans and other mammals in purine

metabolism and in renal uric acid handling, and an entirely suitable mammalian

model for hyperuricemia remains to be created, additional experimental studies

and, especially, interventional clinical studies aimed at evaluating the effects of

urate-lowering on the courses of these disorders are warranted.

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[3] Wyngaarden JB, Kelley WN. Gout and hyperuricemia. New York7 Grune & Stratton; 1976.

[4] Gibson T, Waterworth R, Hatfield P, et al. Hyperuricemia, gout and kidney function in New

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Eur J Epidemiol 2003;18:523–30.


Gout: Update on Some Pathogenic and

Clinical Aspects

Frederic Liote, MD, PhDa,b,c,T, Hang-Korng Ea, MDa,b

aFederation de Rhumatologie, Pole Appareil Locomoteur (Centre Viggo Petersen),

Hopital Lariboisiere, Assistance Publique-Hopitaux de Paris (AP-HP), Paris, FrancebINSERM U606 (IFR139), Hopital Lariboisiere, Paris, FrancecUniversite Medecine Paris 7, Denis Diderot, Paris, France

Gout nowadays is under the scope of fame, thousands of years after its

description by Hippocrates. New pathogenic mechanisms (including autolimita-

tion of acute attacks), new clinical complications, new imaging aspects, and

(as described by Choi elsewhere in this issue) new epidemiologic insights and

therapeutic advances recently have been reported in the English literature. The

genetics of primary gout and hyperuricemia, however, a frequent metabolic

disorder, remain to be elucidated.

The pathogenesis of hyperuricemia is not addressed in this article, but

pathogenesis of gout inflammation is reviewed. New preliminary insights are

beginning to be available from MRI and ultrasound studies, providing possible

tools for evaluation of tophi in clinical trials.

Pathogenesis of urate crystal deposition and tophus

Uric acid is a weak acid (pKa 5,8) that is present mainly as urate, the ionized

form, at physiologic pH. As urate concentrations increase in physiologic fluids,

urate can crystallize as a monosodium salt in oversaturated tissues, mainly within

and around joints, but also in the skin or other structures, such as spinal ligaments



This work was supported by grants from the INSERM, the ARPS, and the ART.

T Corresponding author. Federation de Rhumatologie (Centre Viggo Petersen), Hopital Lari-

boisiere, AP-HP, 2, rue Ambroise Pare, F-75475 PARIS CEDEX 10, France.

E-mail address: [email protected] (F. Liote).




liotE & ea296

and fibrous tissues [1]. The physiochemical properties of monosodium urate

(MSU) cause crystals to precipitate in body fluids if the concentration is greater

than 6.8 mg/dL. The solubility of urate is modulated by temperature (lower

temperature at the foot), intra-articular fluid dehydration (onset at night), and

cation concentration. MSU crystallization is dependent on nucleating agents,

such as insoluble collagens, chondroitin sulfate, proteoglycans, cartilage frag-

ments, and other crystals [1].

Tophus can grow from urate crystals depending on urate sursaturation and on

increased promoters or loss of inhibitors of crystallization.

Pathogenesis of urate crystal-induced inf lammation

MSU crystals are capable of directly triggering, amplifying, and sustaining an

intense inflammatory response, a so-called ‘‘acute attack,’’ because of their abil-

ity to activate humoral and cellular inflammatory components. The pathogenic

inflammatory pathways of MSU crystal-induced inflammation recently have been

reviewed [1–3]. Sequential cellular activation is postulated from in vivo studies

focusing on tissue pathology analysis [4,5]: MSU crystals first are released in the

joint cavity, activating synovial lining cells, followed by the recruitment and

activation of mastocytes and peripheral blood monocytes through endothelial

cell activation. Neutrophils are recruited and egress into the joint cavity, leading

to further MSU crystal phagocytosis and cell activation. Autolimitation of

acute inflammation is driven by macrophages, neutrophil necrosis, and apopto-

sis, followed in some cases by low-grade residual synovitis or by restitution

ad integrum.

Initiation

As discussed recently by Liu-Bryan and Terkeltaub, free crystals or even

naked crystals with no protein coating are released from a remodelling tophus [6].

Once released within the joint cavity, under specific local and systemic circum-

stances (temperature, pH variations, local articular traumatism, infection, or sur-

gery), MSU crystals should interact with the synovial lining cells. These cells

are fibroblast-like synoviocytes and macrophage-derived cells, with phagocytic

properties. They can be opsonized by proteins and phagocytosed as particles,

triggering a typical phagocytic inflammatory response [7]. At the onset of crystal-

induced arthritis (CIA), however, synovial fluid contains low protein content,

especially regarding immunoglobulins.

The putative initial mechanism involves the physicochemical surface proper-

ties of MSU particles interacting directly within minutes [8] with membrane

proteins [6] and lipids, either physically or through electrostatic bounds, because

MSU crystals are negatively charged. This direct crystal-cell membrane inter-

action is reported in several studies: within minutes, the crystal contact can

trigger signal transduction, for instance in chondrocytes [6,8]. Recently, toll-like

pathogenic & clinical aspects of gout 297

receptors (TLR) 2 and 4 present at the cell surface have been implicated in

the chondrocyte and macrophage signaling, as shown in vivo using the air-

pouch model developed in TLR-2, TLR-4, and myeloid differentiation factor 88

(MyD88) knockout mice and in vitro in cultured cells [9,10]. In February 2006,

a new cell surface molecule was reported that triggering receptors expressed on

myeloid cells 1 (TREM-1), present on monocytes and neutrophils, which could

be induced rapidly on neutrophils and resident peritoneal macrophages by MSU

crystals in vivo [11]. Maximal expression of TREM-1 messenger RNA (mRNA)

and protein occurs early after MSU crystal exposure. In the murine air-pouch

model, MSU crystals also induce TREM-1 rapidly. It is speculated that cell

membrane modulation leads to cross-linking and clustering of membrane as an

initial event for activation of several and redundant signal signaling pathways,

including G proteins, phospholipase C and D, tyrosine kinases associated with

the FAK complex, and the three mitogen-activated protein kinases. Factors, such

as the myeloid related proteins [12] and the complement membrane attack

complex [13], recently have been identified as other mediators of acute MSU

crystal-induced inflammation.

Crystal-induced cellular activation and recruitment

Neutrophils are the hallmark of inflammatory cells recruited into the synovial

fluid (SF) in gouty attack, but several studies clearly show that other cells play a

central role in the early phase of CIA. Studies of cellular kinetics using animal

models of MSU crystal-induced inflammation demonstrate that monocytes re-

cruited from the blood and resident mastocytes are the first cells to infiltrate or

be activated [5]. Mast cells are proposed as playing a role in innate immunity [14]

and can be an important cell component of MSU CIA because they contain

preformed granules with cytokines and also histamine, an acute phase reagent

[15]. Histamine is well documented as having multiple effects leading to in-

creased vascular permeability and enhanced adhesion molecule expression, such

as upregulating P-selectin, which mediates neutrophil adhesion and recruitment.

Mast cell activation and histamine release are observed in CIA inflammation

model in vivo [5]. Other preformed and stored mastocyte mediators (eg, platelet

activating factor [PAF], vascular endothelial growth factor, tumor necrosis factor

[TNF]-a, and interleukin [IL]-1b) can activate endothelial cells, cell recruitment,

and increase vascular permeability. Finally, therapeutic issues can be raised,

because in MSU crystal-induced murine peritonitis, a role for endogenous mast

cells is suggested, as histamine1 antagonist and PAF antagonist reduce neutrophil

influx into the peritoneal cavity [16].

Monocytes also are implicated in the early onset of MSU CIA. They infiltrate

the tissues of animal models of MSU CIA at a rate 10 times higher than neutro-

phils [5]. As discussed earlier, rapid induction of TREM-1 can trigger inflam-

mation, because costimulation of peritoneal macrophages with MSU crystals and

an anti–TREM-1 agonist antibody increase the production of IL-1b and monocyte

chemotactic protein [11]. MSU crystals actually have the ability to trigger an

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inflammatory response by freshly isolated monocytes and THP-1 monocytic cells

[7,17–21], including TNF-a, IL-1b, IL-6, and IL-8 (but not IL-10) secretion,

which in turn promote endothelial cell E-selectin expression and secondary neu-

trophil adhesion under dynamic conditions. Similar results are achieved in MSU

crystal-induced rabbit arthritis [22,23]. Nishimura and colleagues show that

MSU CIA in rabbits is attenuated by a neutralizing antibody against IL-8 [24].

As a ‘‘newcomer,’’ IL-18, a member of IL-1 family, is reported to be increased

in plasma from patients who have gout arthritis and secreted by monocytes after

MSU crystal stimulation along with an activation of caspase-1, the processing

enzyme for IL-18 activation [25]. These cytokines and chemokines also are

able to activate endothelial cells and promote monocyte and neutrophil adhesion,

stimulate chemotaxis, and tissue infiltration. Reduced cytokine response by

monocytes to MSU crystals could be an explanation for reduced gout attack in

patients who have chronic renal failure [26].

Angiogenic factors also have cytokine properties and are expressed in gout.

For example, high levels of angiogenin, an angiogenic factor with anti-

inflammatory properties, are measured in SF from patients who have gout [27].

Monocytes play a central role in the regulation of acute attack, because they also

are implicated in the self-limitation of inflammation.

Amplification

Neutrophils are recruited into synovium and migrate within the synovial

cavity along with serum proteins. Their roles were distinguished early by

Schumacher and coworkers in gouty arthritis in dogs [4]. Activated endothelium

allows neutrophil adhesion dependent on E-selection and P-selectin upregulation

and migration into the synovium. This is supposed to be determined by effects of

cytokines (TNF-a and IL-1b) and chemokines (IL-8 and macrophage inflamma-

tory protein-1a) [22,28]. Neutrophils follow concentration gradients of chemo-

attractants, such as C5a and IL-8. IL-8 is a central player, as demonstrated in in

vivo models (air-pouch in mice and arthritis in rabbits) by Terkeltaub and col-

leagues [29] and Nishimura and colleagues [24], using knockout mice for IL-8

receptor, CXCR-2, or neutralizing anti–IL-8 antibody, respectively. By contrast,

IL-18 is not a player in neutrophil recruitment in in vivo MSU crystal-induced

inflammation model [25].

Spontaneous resolution of acute attack

In spite of the intensity and sudden onset of an acute bout of gout, the self-

limitation of joint inflammation that results in an apparent return of the joint

apparently ad integrum is puzzling. Crystal properties can be modified and

represent a first target: crystal size reduction and crystal clearance. Protein and

lipoprotein crystal-coating changes [30–32] have been discussed by several in-

vestigators, but these processes are not considered major players. Macrophages

(eg, resident and differentiated monocytes) could represent the major cell in this


regulatory process. Recently, Landis and Haskard have promoted the idea that the

mononuclear phagocyte may play a key role within the synovial compartment,

tipping the balance from the asymptomatic state to acute inflammation, or vice

versa, depending on the state of monocyte to macrophage differentiation [33].

They demonstrate that a switch from homologous monocytes to macrophages

leads to the loss of ability to produce proinflammatory cytokines (IL-1, Il-6, and

TNF-a) and, conversely, to stimulate anti-inflammatory cytokine secretion (IL-10

and transforming growth factor [TGF]-b1) when stimulated by phagocytosed

MSU crystals [34,35]. Under MSU crystal stimulation, macrophages produce

IL-10 and, mainly, TGF-b1, a pivotal cytokine in the anti-inflammatory process

[36]. TGF-b1 can lower endothelial activation, reduce monocyte and neutrophil

adhesion and recruitment [37], and reduce IL-1 expression and IL-1 receptor

expression. TGF-b1 secretion also can be triggered by ingestion of apoptotic

cells [38,39].

Other anti-inflammatory cytokines, such as IL-10, are shown to reduce in vivo

MSU crystal inflammation. Retrovirally transfected IL-10 cells injected in murine

air-pouch model significantly inhibited MSU crystal-induced cellular infiltration

and production of the mouse CXC chemokine KC. These findings are consistent

with results obtained by the injection of recombinant human IL-10 into air

pouches [40]. Relevance for humans is debated, however, because no IL-10 is

detected in any of the 17 sera tested from patients with gout [41], and lower IL-10

(and normal IL-4) mRNA levels are determined in SF mononuclears from pa-

tients who have gout compared with those who have rheumatoid arthritis [42].

This monocyte-macrophage switch and its ability to control inflammation is

a well-known mechanism not related specifically to MSU crystals. The intrinsic

mechanisms underlying the anti-inflammatory switch are understood poorly

but it seems, for example, that the production of pro- and anti-inflammatory

cytokines by phagocytic monocytes is regulated delicately during the ingestion of

apoptotic cells as part of an intrinsic mechanism to prevent inflammatory auto-

immune reactions [43].

Binding or phagocytosis of apoptotic cells, but not necrotic or lysed cells

[44,45], induces active anti-inflammatory or suppressive properties in human

macrophages [44]. It is observed in SF from various diseases, such as reactive

arthritis and CIA, but not rheumatoid arthritis [46]. Therefore, it is likely that

resolution of inflammation depends not only on the removal of apoptotic cells but

also on active suppression of inflammatory mediator production (Fig. 1).

Other anti-inflammatory compounds also are released by MSU crystal-

stimulated macrophages, namely nitric oxide (NO) and peroxisome proliferator-

activated receptor (PPAR)-g. NO synthase 2 or inducible NO synthase is induced

in vitro by freshly isolated human monocytes by MSU crystals [47]. NO also is

detected in vivo in rat air-pouch fluids after MSU crystal activation [2]. NO

donor can inhibit MSU-crystal inflammation when administered either before

or at the onset of acute inflammation in the rat air-pouch model. Conversely,

NO inhibition maintains the inflammatory cellular reaction evidenced in vivo

[2]. Therefore, in MSU-crystal inflammation, NO seems to act as an anti-

Fig. 1. Schematic representation of monocyte-macrophage switch in the installation and resolution

of acute MSU crystal-induced inflammation. (A) Monocytes are recruited from the blood, yet

immature macrophages (MAC) can be stimulated by MSU crystals. In turn, they produce various

cytokines and chemokines, leading to endothelium activation, leukocyte migration, and further cell

activation. Recruited neutrophils (PNN) migrate into the joint cavity and further phagocytize MSU

crystals and release mediators. They undergo various processes: death process from within, necrosis,

and apoptosis. (B) Differentiation of monocytes to MAC seems to be a paradigm in inflammation,

innate and adaptative immunity. A role for apoptotic neutrophil bodies to trigger the MAC ability to

secrete TGF-b1 is demonstrated in various situations but not yet in acute gout. TGF-b1 is a pivotal

anti-inflammatory cytokine, with the ability to block endothelial cell activation, leukocyte adhesion

and recruitment, reduce proinflammatory cytokine production, and increase IL-1ra production. MSU

crystals are unable to stimulate mature and differentiated MAC to produce proinflammatory cytokines.

Apoptotic bodies from neutrophils are demonstrated to enhance MAC differentiation and TGF-b1production, suggesting a regulatory mechanism for monocyte-MAC switch in acute gout attack.

liotE & ea300

inflammatory compound. PPAR-g is a member of the nuclear hormone super-

family, which can act as a transcriptional regulator of certain genes; it inhibits the

gene expression of cytokines, such as cyclooxygenase. Early PPAR-g stimula-

tion and production by adherent monocytes by MSU crystals is achieved in vitro.

Similarly, PPAR-g production is achieved in vivo in the rat air-pouch model as

early as 12 hours after crystal stimulation.

Neutrophil apotosis also is advocated as a possible mechanism for resolution.

In vitro experiments, however, suggest that MSU crystals can delay neutrophil

apoptosis [48,49], suggesting a direct role for crystals to avoid resolution of at-

tack. Conversely, apoptotic cell recognition and clearance, via exposure of phos-

phatidyl serine and ligation of its receptor, induce TGF-b1 secretion [38,39,45],

resulting in accelerated resolution of inflammation (Fig. 1).


Intercritical gout

Although MSU crystals are the hallmark of gouty arthritis, they can be found

even during the resolution phase but have lost their ability to stimulate further

inflammation, and also between attacks, because they remain in the joint. Two

studies from Pascual and coworkers [50,51] clearly identify MSU crystals in SF

taken from up to 70% of asymptomatic first metatarsal or knee joint of patients

who had proven gout during the so-called ‘‘intercritical period.’’ Treatment with

colchicine decreases white cell counts in synovial fluid of asymptomatic knees

that contain MSU crystals [52]. A preclinical phase of gout is ascertained, be-

cause MSU crystals also are detected in joints from some patients who had

asymptomatic hyperuricemia and hyperuricemic patients who had chronic renal

failure. Low-grade asymptomatic synovitis and associated intra-articular dormant

tophi can be postulated but await evidence.

Chronic tophaceous gout

After years of chronic and untreated hyperuricemia, gouty arthritis can de-

velop with its hallmark, intrarticular and periarticular tophi. Gout tophi are

characterized by foreign body granulomas consisting of mono- and multinu-

cleated macrophages surrounding deposits of MSU microcrystals. After primary

formation, granulomas grow associated with degradation of the extracellular

matrix. Once developed in situ in cartilage or in synovium, it is assumed that

MSU crystals may contribute to chronic synovitis and associated joint damage.

Tophi can grow at the cartilage surface and within the synovium, leading to low-

grade synovitis, even subsiding after clinical resolution of gout attacks or to

foreign body synovitis around crystals, as evidenced by histologic studies. Direct

cartilage-tophi contact is demonstrated by arthroscopy.

In contrast to acute inflammation, experimental studies related to tophi patho-

genesis are lacking. Immunohistochemistry studies performed on tophi show that

perivascular localized mononuclear cells are CD68+, S100A8+, S100A9+, and

25F9�, representing freshly migrated monocytes/macrophages. In contrast, al-

most all CD68+ mono- and multinucleated cells arranged within granulomas are

S100A8�, S100A9�, and 25F9+, representing mature (nonmigrating) macro-

phages. These macrophages coexpress TNF-a and matrix metalloproteinases

(MMPs) 2 and 9. In parallel, macrophages undergo apoptosis, a phenomenon that

may restrict the destructive potential of inflammatory macrophages [53]. Corti-

costeroids could enhance tophus formation, as shown in the air-pouch model by

Rull and colleagues [54] and in clinical reports.

In vitro chondrocytes can phagocytize particles, such as latex beads [55], and

in vitro nonadherent chondrocytes also can produce active MMPs after MSU

[8] or even calcium crystal stimulation [56]. Direct chondrocyte cell membrane

crystal can trigger cell activation, NO synthase expression and NO production,

IL-1b activation, and MMP expression [8], which can contribute to cartilage

degradation and further tophus breaking [6]. In addition, MSU crystals can con-

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tribute to bone lesions; Bouchard’s group shows that MSU crystals reduce

the activity of osteoblasts in vitro [57], thereby limiting the healing process

of erosions.

Based on the anti-inflammatory effects of macrophages triggered by either

MSU crystals or apoptotic cells, it can be speculated that a defect in anti-

inflammatory properties of macrophages, as observed in other chronic diseases

[58], could contribute to low-grade inflammation by residual MSU crystals.

Diagnosis of gout

Diagnosis of gout relies on the association of acute attacks, presence of

tophus, hyperuricemia, and, in some advanced diseases, chronic and destructive

arthropathies. Classification of gout is a different issue that is approached partly

with the (former) American Rheumatism Association preliminary criteria [59]. To

date, however, there are no diagnostic recommendations or evidenced-based

medicine recommendations for gout. This gap will be filled by a task force of

the European League Against Rheumatism (EULAR) Standing Committee on

International Clinical Studies Including Therapeutic Trials (ESCISIT), on gout

diagnosis and management. Preliminary diagnostic recommendations were re-

ported at the 2005 EULAR meeting in Vienna (Box 1) and currently are under

review [60]. Based on a systematic literature search and expert consensus

achieved through Delphi procedures, 10 recommendations have been sorted out

and validated. Only clinical issues are discussed briefly.

Clinical issues discussed by the EULAR task force relate mainly to the clini-

cal characteristics of crystal inflammation, namely rapid onset of severe pain,

joint swelling and local tenderness, and overlying erythema, with a peak in

symptoms occurring within 6 to 12 hours. This is typical for crystal acute attack

but can be related to another crystal type, such as calcium pyrophosphate or

apatite or other rarer inflammatory conditions.

Overall, there is a large consensus on the diagnostic value of MSU crystal iden-

tification in SF and tophus. This examination should be done routinely (but always

carefully), because MSU crystal detection can be considered a gold standard for

gout. Suspected tophus can be sampled carefully for MSU crystal to ascertain diag-

nosis. As discussed previously, a retrospective diagnosis of gout can be achieved

when asymptomatic metatarsophalangeal (MTP) or knee joints are tapped and

MSU crystals are detected easily at first look in the polarizing microscope, because

MSU crystals are strongly birefringent. Forty-three joints in gouty patients were

positive for MSU before any hypouricemic drug was started, and 34 out of 48

after treatment was begun [51]. Therefore, standard quality for crystal examination,

identification training should be better defined [61,62]. Before proper studies are

done, it should be recalled that proper conservation of SF has to be achieved,

because room temperature can modify crystals and cells can be lysed. Microscopic

analysis should be performed as soon as possible with a polarizing microscope, but

SF can be kept at �208C before analysis: in these conditions, there is a smaller risk

Box 1. Ten key recommendations for the diagnosis of gout from theEuropean League Against Rheumatism Standing Committee forInternational Clinical Studies Including Therapeutic Trials

1. In acute attacks, the rapid development of severe pain, swell-ing, and tenderness that reaches its maximumwithin just 6 to12hours, especiallywith overlying erythema, is highly sugges-tive of crystal inflammation, although not specific for gout.

2. For typical presentations of gout (such as recurrent podagrawith hyperuricemia), a clinical diagnosis alone is reasonablyaccurate but not definitive without crystal confirmation.

3. Demonstration of MSU crystals in synovial fluid or tophusaspirates permits a definitive diagnosis of gout.

4. A routine search forMSU crystals is recommended in all syno-vial fluid samples obtained from undiagnosed inflamed joints.

5. Gout and sepsis may coexist, so when septic arthritis issuspected, Gram’s stain and culture of synovial fluid stillshould be performed, even if MSU crystals are identified.

6. Identification of MSU crystals from asymptomatic jointsmay allow definite diagnosis in intercritical periods.

7. Although they are the most important risk factor for gout,serum uric acid levels do not confirm or exclude gout, be-cause many people who have hyperuricemia do not developgout, and serum levels may be normal during acute attacks.

8. Renal uric acid excretion should be determined in selected pa-tientswhohavegout, especially thosewhohave a family historyof young-onset gout, onset of goutunder age25,or renal calculi.

9. Although radiographs may be useful for differential diagno-sis and may show typical features in chronic gout, they arenot useful in confirming the diagnosis of early or acute gout.

10. Risk factors for gout and associated comorbidity should beassessed, including features of the metabolic syndrome(obesity, hyperglycemia, hyperlipidemia, and hypertension).

From Zhang WDM, Pascual E, et al. EULAR evidence based rec-ommendations for gout. Part I diagnosis. Report of a task forceof the standing committee for ESCISIT. Ann Rheum Dis 2006;in press; with permission.


for crystal dissolution, although cells usually are lysed. Microcrystals are identified

better when looking in the clot formed by fibrins and cell debris, eventually after

centrifuging the SF. Detection of MSU crystals has excellent value in the diagnosis

of symptomatic gout or even of asymptomatic gout (knee or first MTP joint),

allowing a definite diagnosis in intercritical periods [50,51].

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Unusual clinical involvement

Common clinical aspects

Acute gout attacks occur mainly in the lower extremities, starting at the foot

joint, as has been known for centuries. Podagra is located by definition in the first

MTP joint. As the disease progresses, other joints may be involved, including the

knee and hip joint or upper limb. Podagra is more common in men, and women

show a higher frequency of upper limb joint involvement [63]. The most common

diagnoses of arthritis in the first MTP joint are crystal-induced synovitis, septic

arthritis, traumatic conditions, psoriatic arthritis, and reactive arthritis. When

causes other than gout involve the first MTP joint, this frequently is referred to as

pseudopodagra. Therefore, radiographs can be suitable in some unusual settings,

such as those involving young patients, to rule out apatite calcification, calcium

pyrophosphate deposit, or necrosis of the sesamoid bone.

Skin involvement

Unusual sites for tophi are reported, but rheumatologists should be aware of

isolated skin involvement. Cutaneous tophi with inflammatory aspects, or at the

opposite indolent, are observed commonly in elderly women receiving diuretics

for hypertension [63] and more rarely in men. MSU deposits might be respon-

sible for unusual panniculitis [64]. Long-standing tophus could represent a risk

factor for angiosarcoma [65].

Spinal involvement

Tophus of various sizes can develop in any anatomic structure of the spine,

leading to nerve root, cord compression [2,66–68], or even lumbar spinal steno-

sis. Gout can represent a significant etiologic factor in the development of symp-

tomatic spinal stenosis associated with cyst formation from a facet joint. Cervical

cord compression by tophus [68] is rare compared with those associated with

calcium pyrophosphate dihydrate deposition (CPPD) deposits. When fever is

present, clinical features and even imaging can mimic epidural abcess or spondy-

lodiscitis [69]. Radiographs can show erosive and destructive changes in cervical

disks. Gout tophi by MRI studies yield homogeneous and hypointense masses

on T1- and T2-weighted images, with multiple hypointense speckles. Preopera-

tive diagnosis is uncommon but should be suggested when addressing patients

who have long-standing gout, chronic arthropathy, and tophi. In addition to stan-

dard histologic examination, material should be sent for examination under po-

larized light, which can reveal deposition of urate crystals in such cases. It is not

possible to diagnose gout of the spine by standard examination of a fixed speci-

men, because fixation in water dissolves MSU crystals; alcoholic conservative

should be used. In this setting, De Galantha staining allows direct visualization of

MSU crystals. Surgical decompression is mandatory and effective, because pre-


operative diagnosis of spinal gout rarely is evoked preoperatively; in rare cases,

regression of cord compression is achieved under urate-lowering agents [70].

Peripheral nerve root compression

Clinicians should be aware of the possibility of tophi causing nerve root com-

pression, such as carpal tunnel syndrome (CTS) and cubital compression. Preva-

lence of CTS was estimated at 0.6% in a large series of 2649 CTS releases,

occurring, as expected, mainly in men [71]. Imaging, including CT scan, MRI,

and ultrasound, provides confirmation [72]. Tophi can be found in the floor of

the carpal tunnel, carpal bones, radiocarpal joint, and extensor tendons or tendon

sheaths of the wrist. Surgical liberation usually is mandatory to avoid sequellae.

Gout and septic arthritis

Fever is a common feature of acute gout attack, mainly in polyarthritis. It is

necessary to rule out septic arthritis, and Gram’s stain and culture of SF are

mandatory, even if MSU crystals are identified readily, when diagnosis is

suspected. Several dozen such cases are published, including Yu and colleagues’

[73,74]. Organisms grew from SF taken from 73% of their 30 patients.

Infectious necrotizing fasciitis recently has been reported in gouty patients,

with a prevalence of 4.8% of fasciitis observed at a Taiwanese hospital [73].

The portal of entry clearly was related to skin changes or complications asso-

ciated with tophi in 60% of the patients. Therefore, fasciitis should be discussed

when facing tissue inflammation that resembles erysipelas or cellulitis, shortly

before bullae appears as a late manifestation of fasciitis. Again, the intensity

of pain is out of proportion to the physical findings. Septic shock, multiorgan

failure, and even death can occur. In these series, Staphylococcus aureus and

streptococcus and gram-negative bacterias are responsible for fasciitis in patients

who have gout. Outcome was poor in the Taiwan series and carried a 20% high

mortality rate in spite of surgical procedures, including amputation and antibio-

therapy. Aggressive treatment with antibiotics and surgical cleaning is mandatory.

Because the breakdown of the skin around tophi carries a high risk for infection,

it is of importance to get a local treatment to prevent extensive infection.

Imaging

Radiographs are not useful for the diagnosis of acute gout except for dif-

ferential diagnosis. A pseudopodagra can be observed in apatite or CPPD deposit.

Also, when young patients present with subacute or acute pain under the first

MTP after a walk, a sesamoid necrosis or fracture of the first MTP should be

discussed and a specific radiograph prescribed (Walter-Muller view).

Fig. 2. Radiographs of chronic gout arthropathy of the hands. Note the well-defined, punched-out

erosions with overhanging edges, asymmetric involvement, soft tissue swelling, and extension around

phalangeal bones.

liotE & ea306

In chronic disease evolving to destructive arthropathy, the radiologic hallmark

of tophus is well known (Fig. 2). Characteristic of gout is well-defined, punched-

out erosion with overhanging edges, with preservation of the joint space, lack of

periarticular osteopenia, asymmetric involvement, soft tissue nodules, and

extension around bone diaphysis (see Fig. 2) [75]. At the midfoot joint, a lateral

view can exhibit osteophytes on the dorsal part of the joint (Fig. 3). Tophi can

contribute to soft tissue swelling, with secondary calcium deposits in long-

standing disease. Anatomic distribution recently had been reviewed [76].

Modern imaging is still being evaluated. Ultrasound could be promising, and

MRI studies are of major interest in evaluating spinal involvement. To date,

various skin nodules have been imaged by comparing rheumatoid nodules, gout

tophus, sarcoid nodules, lipomas, and cysts. Tophi appear different from rheu-

matoid nodules: they are more heterogeneous, are more hypoechoic, can present

postacoustic shadow, and are more prone to be adjacent to bone erosions or at

Fig. 3. Radiographs of chronic gout arthropathy of the ankle and midfoot joints. Note the spikes of

the dorsum side of the midfoot and severe joint destruction and ankylosis.

Fig. 4. MRI study of the knee (A) T1-weighted sequence; (B) gadolinium T1-weighted sequence;

(C) T2-weighted sequence with fat sat sequence: lateral and axial views; and (D) lateral views.

Large tophi around the knee: large ovalar tophus at the posterior lower thigh (*), erosive prepatellar

and pretibial tophi (arrow).


least cortical irregularity [77]. Bursitis can occur. Hypoechoic areas might

decrease after aspiration of chalky material. Nodules can be measured readily but

reproducibility is ongoing. Diagnostic values of color Doppler technique remains

to be evaluated [78].

On MRI, tophi present as masses that usually have low or intermediate signal

intensity on T1-weighted images, low to intermediate T2-weighted images, and a

variable but characteristic enhancement pattern, especially for intra-articular tophi

(Fig. 4) [75]. Gadolinium can disclose an enhanced homogeneous or hetero-

genous rim signal around the tophus.

CT scan has been obtained in some cases. As described by Gerster and co-

workers [78], CT disclosed osteolytic lesions containing round or oval opacities,

with a mean density of approximately 160 Hounsfield units. Soft tissue tophi,

with dippled calcium deposits, can result in bone erosion clearly depicted at

CT scan [72].

Outcome and evaluation of gout

As new treatments are developed, there are no well-established outcome

measures or data on follow-up and outcome of gout cohorts, including patients

treated long-term, regarding chronic joint clinical and radiologic symptoms or

liotE & ea308

quality of life. The Outcome Measure in Rheumatoid Arthritis Clinical Trials

(OMERACT) has begun developing sets of outcome criteria that will be dis-

cussed at their meeting in Malta in May, 2006. Clinical issues remain as do imag-

ing aspects related to tophus detection by ultrasound examination or MRI

imaging, documented so far only in case reports.

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Renal Urate Transport

David B. Mount, MDa,b,c,T, Charles Y. Kwon, MDa,b,d,

Kambiz Zandi-Nejad, MDa,b

aHarvard Medical School, Boston, MA, USAbRenal Division, Brigham and Women’s Hospital, Boston, MA, USA

cDivision of General Internal Medicine, VA Boston Healthcare System, Boston, MA, USAdRenal Division, Children’s Hospital of Boston, MA, USA

Several recent developments have created a renaissance of sorts for uric

acid homeostasis. In particular, there have been major advances in the molecular

understanding of renal urate transport. These developments include the molecu-

lar characterization of urate transporter-1 (URAT1), the urate exchanger in

the proximal tubule that reabsorbs the bulk of filtered urate from the glomerular

ultrafiltrate [1]. More recently, two candidates have emerged for the sodium-

dependent anion transporters that collaborate with URAT1 in urate reabsorption

by the proximal tubule [2–5]. The physiologic relationships between these apical

transporters are relevant particularly for the pathogenesis of hyperuricemia and

gout. There also is an increasing interest in the role of uric acid in hypertension

[6] and progressive renal disease [7] (reviewed elsewhere) [6,8]. Novel, pro-

vocative roles for uric acid have also been proposed in inflammation [9,10],

cardiovascular disease [11], heart failure [12,13], and the metabolic syndrome

[14–16], such that urate homeostasis is of relevance to an increasing number of

disorders. This brief review focuses on recent developments in the molecular

physiology and genetics of urate homeostasis.



Work in the authors’ laboratory has been supported by RO1 DK-57708 from the National

Institutes of Health (DBM), an Advanced Research Career Development Award from the Veterans

Administration (DBM), a Pediatric Scientist Development Award from the National Institutes of

Health (CYK), and American Heart Association Postdoctoral Fellowship Award 0225706T (KZ).

T Corresponding author. Renal Division, BWH, Room 540, HIM Building, 4 Blackfan Circle,

Boston, MA 02115.

E-mail address: [email protected] (D.B. Mount).




mount et al314

Phylogeny and uric acid

In most mammalian species, uric acid generated from purine metabolism un-

dergoes oxidative degradation via the uricase enzyme to produce allantoin,

a more soluble metabolite. In humans, the uricase gene is crippled by two

mutations that introduce premature stop codons [17]. The absence of uricase,

combined with extensive reabsorption of filtered urate, results in urate levels in

human plasma that are approximately 10 times those of most other mammals

[18]. Whereas primates, such as the chimpanzee, share the same truncating

mutations in uricase, the existence of independent loss-of-function mutations in

the genome of gibbon apes suggests that this gene was subject to significant

negative pressure during the evolution of hominoids [19]. Highly speculative ad-

vantages conferred by the relative hyperuricemia in these species include reduced

oxidant stress and a decreased incidence of cancer [20], complexation of cir-

culating iron and inhibition of iron-catalyzed oxidation [21], an enhanced ability

to survive under conditions of low dietary salt [22], and even increased intel-

ligence [23]. The purported benefits of an increase in uric acid are offset in

part by the risk of gout [24] and nephrolithiasis [25], in addition to the host of

other disorders in which hyperuricemia is postulated to play a role. The risk

of hyperuricemia in humans is mitigated genetically by comparative repression

of the human xanthine oxidoreductase gene [26,27], the enzyme that mediates

the last two steps of purine metabolism [28]; transcription of this gene is con-

siderably more widespread and robust in mice [26,27]. This is a recurrent theme;

several other genes involved in urate homeostasis are differentially conserved or

preserved in various mammalian species, underlining the divergent evolutionary

pressure on these pathways.

Approximately one third of urate elimination occurs in the gastrointestinal

tract, with the remainder excreted in the urine [29]. In plasma, uric acid circu-

lates primarily as urate and is filtered freely by renal glomeruli. Subsequent

bidirectional transport along the nephron results either in net reabsorption

(humans, primates, rats, and dogs) or secretion (pigs and rabbits); pigs and

rabbits [30,31] seem to lack the apical urate-anion exchanger that is found

in all the ‘‘reabsorptive’’ species, presumably because of inactivation of the

SLC22A12 gene (Solute Carrier gene family 22, member 12) encoding URAT1

(discussed later). The fractional excretion of urate differs considerably in mam-

mals: 10% in humans versus approximately 40% in rats [32] and 200% in pig

[33]. Cebus monkeys also exhibit fractional excretion of approximately 10%

[34]; however, unlike other New World monkeys, Cebus monkeys possess an

active uricase enzyme and have uric acid levels that are approximately half

those of humans [35]. In contrast, chimpanzees lack uricase activity, exhibit

fractional excretion for urate of approximately 10%, and have circulating uric

acid levels that approximately are equal to those of humans [36]. Therefore, the

evolutionary loss of uricase and the development of highly efficient reabsorptive

mechanisms for urate seem to be separate, additive events that result in relative

hyperuricemia in humans and related hominoids.

renal urate transport 315

The four-component model

The dominant model of renal urate excretion has for decades consisted of four

steps: glomerular filtration, reabsorption from the glomerular ultrafiltrate, sub-

sequent secretion, and then ‘‘postsecretory reabsorption’’ [37]. Elements of this

four-component model appear in the current editions of leading physiology and

nephrology textbooks; however, the serious flaws in this model [29,38] neces-

sitate a brief review.

Regardless of the species studied, the bulk of urate transport occurs within the

proximal tubule, with minimal or nonexistent contributions from the distal

nephron [35]. Reabsorption and secretion can each be detected in reabsorptive

species, such as the dog [35]. The relative dominance of reabsorption or secre-

tion, however, can be influenced by pharmacologic manipulation or by genetic

background. Thus, in Dalmatian dogs, the fractional excretion of urate can equal

100% or just above 100%, suggesting minimal reabsorption or modest secretion

[39]; Dalmatians exhibit significant hyperuricosuria and modest hyperuricemia

as a result of defective hepatic transport of urate that limits metabolism via uricase

[40]. In contrast, mongrel dogs exhibit a predominance of urate reabsorption,

with fractional reabsorption of approximately 50% [39]; however, bidirectional

transport can be detected in mongrels [41] and secretion can be induced by a

combination of urate loading and osmotic diuresis [42]. Renal urate secretion can

be unmasked in humans after treatment with mannitol and a uricosuric agent [43].

In addition, patients who have renal hypouricemia (discussed later) can have

fractional excretions of urate that are greater than unity, indicative of tubular

secretion [44,45].

The four-component model evolved in the 1960s and 1970s from an

interpretation of the competing effects of uricosuric and antiuricosuric agents.

The key assumption underlying this model is that the antiuricosuric agent

pyrazinamide inhibits proximal tubular urate secretion. In a typical pyrazinamide

suppression test [46], the oral administration of 2 to 3 g results in a marked de-

crease in the fractional excretion of urate; this effect is mediated by pyrazinoate

(PZA), the deamidated metabolite [47]. Dog experiments from the mid 1960s

revealed that pyrazinamide abolished the secretory peak of 14C-labeled urate

(14C-urate) injected into the renal artery; given that the initial urinary bolus of

radioactive urate preceded that of 14C-inulin, the primary source of this urinary14C-urate peak was believed to be tubular secretion rather than glomerular ultra-

filtration. By extension, the antiuricosuric effect of pyrazinamide was attributed

to an inhibition of urate secretion [48]. The pyrazinamide suppression test thus

was adopted as a pharmacologic method to quantify tubular urate secretion [46].

The three-component model of renal urate handling originally was proposed

by Gutman and Yu in 1961, encompassing glomerular filtration, probenecid-

sensitive tubular reabsorption, and pyrazinamide-sensitive tubular secretion [49].

The full four-component model subsequently evolved to explain the interactions

between pyrazinamide and uricosuric agents, including probenecid [37,50],

chlorothiazide [50], benzbromarone [51], and sulfinpyrazone [37]. When these

mount et al316

drugs are administered after pyrazinamide, there is a striking attenuation of their

uricosuric effect [29]. To explain this phenomenom, uricosuric agents were pos-

tulated to have a dominant effect on ‘‘postsecretory reabsorption,’’ given that

their ability to increase urate excretion was blunted when putative ‘‘upstream’’

secretion was inhibited with pyrazinamide. It follows that these processes occur

serially in anatomically separate segments of the proximal tubule; such a

progression is incorporated in current textbook models of renal urate transport.

Physiologic studies of reabsorptive species, however, typically indicate a co-

existence of reabsorption and secretion along the entire length of the proximal

tubule [35].

The alternative possibility, that PZA does not inhibit secretion but instead

stimulates urate reabsorption, was considered ‘‘rather awkward’’ [43] and ‘‘ex-

tremely unlikely’’ [46] during the initial formulation of the four-component

model. A seminal observation in 1985 by Guggino and Aronson, however, sug-

gested that PZA does indeed stimulate tubular reabsorption [38]; the same

investigators previously reported analogous data for lactate [30]. Using brush-

border membrane vesicles (BBMV) from renal cortex, it was demonstrated that

sodium-dependent uptake of PZA or lactate results in a marked stimulation of

vesicular urate uptake via the brush-border urate-anion exchanger (these and

subsequent insights discussed later).

Urate transporter-1 is the reabsorptive urate-anion exchanger

An apical urate-anion exchange activity was described first in nonprimate,

urate-reabsorbing species (ie, rats and dogs) [30,52–54]. This anion exchanger

accepts various monovalent organic anions, including urate, p-aminohippurate

(PAH), and lactate, in addition to chloride (Cl�) and hydroxyl (OH�); divalent

anions are not substrates [30]. Apical urate-anion exchange activity evidently is

absent in species with net urate secretion [30,55], although it is present and

highly sensitive to uricosuric agents in urate-reabsorbing species [52,53]; these

observations suggest a significant role for urate exchange in proximal reabsorp-

tion. A similar urate exchanger has been demonstrated in BBMV from human

kidneys, albeit with some important distinctions; notably, PAH and OH� are not

substrates for the human exchanger [56]. This is reflected in the modest effect

of PAH infusion on urate excretion in humans; PZA, furthermore, is without

effect on PAH homeostasis, suggesting that the absorptive mechanism for PAH

and urate are distinct in this species [57].

The recent molecular identification of URAT1 as the dominant apical urate

exchanger of human proximal tubule [1] was a landmark event in the physiology

of urate homeostasis. The URAT1 protein is encoded by the SLC22A12 gene, part

of the rapidly expanding SLC22 family of organic ion transporters. URAT1

primarily is homologous to members of the organic anion transporter (OAT)

branch of this gene family; other subgroups include organic cation transporters

and organic cation transporter novel type/carnitine transporters [58]. Although


not acknowledged initially [1], URAT1 is the human ortholog of renal-specific

transporter (RST), cloned from murine kidney several years ago [59]. URAT1/

RST is in point of fact not renal specific, with detectable transcript in lung and

brain (Zandi Nejad, unpublished data, 2004). Regardless, immunohistochemistry

reveals the URAT1 protein at the apical membrane of proximal tubules in human

[1] and mouse [60] kidney. Heterologous expression in Xenopus oocytes indi-

cates that human URAT1 is capable of urate transport (14C-urate uptake), with a

Michaelis constant (Km) of 371 F 28 mM. Uricosuric drugs, such as probenecid

and losartan [61], are potent inhibitors of URAT1; this indicates that their effect

on serum urate is mediated through inhibition of urate reabsorption rather than an

activation of renal secretion. URAT1 has the highest affinity for aromatic organic

anions, such as nicotinate and PZA, followed by lactate, b-hydroxybutyrate,acetoacetate, and inorganic anions, such as Cl� and nitrate. These relative affini-

ties are manifest by a marked activation (trans-stimulation) of 14C-urate uptake

in URAT1-expressing oocytes that have been microinjected individually with

PZA, nicotinate, and lactate (ie, in-trans to the 14C-urate); the relative response

fits with the trans-stimulation of urate exchange in human BBMV sodium-

dependent transport of these monovalent anions [62] (discussed later). The same

anions are capable of cis-inhibiting the uptake of 14C-urate when present in the

extracellular medium, another operative characteristic of the anion exchanger.

In their report describing the identification of URAT1, Enomoto and co-

workers provide unequivocal genetic proof that this anion exchanger is essential

for normal urate homeostasis: a handful of patients who had ‘‘renal hypo-

uricemia’’ (OMIM #220150) [63] were shown to carry loss-of-function mutations

in the human SLC22A12 gene encoding URAT1, indicating that this exchanger

is essential for the proximal tubular reabsorption of urate [1]. Patients who

have homozygous loss-of-function mutations in SLC22A12 do not respond to

pyrazinamide and benzbromarone loading with urate retention and uricosuria,

respectively (discussed later). A very modest response to probenecid suggests,

however, that anion transporters other than URAT1 may participate in the luminal

reabsorption of urate from the glomerular ultrafiltrate [45].

The secondary sodium dependency of urate reabsorption

As discussed previously, URAT1 reabsorbs urate from the glomerular

ultrafiltrate by exchanging luminal urate with monovalent intracellular anions,

such as PZA. The intracellular concentration of these anions is determined largely

by sodium-dependent absorption from the same glomerular ultrafiltrate; this

generates a secondary sodium dependency of urate reabsorption, because these

anions increase proximal urate reabsorption via subsequent anion exchange. The

nephron thus is primed for urate reabsorption by the sodium-dependent loading

of proximal tubule cells with antiuricosuric anions.

Independent, overlapping studies from several laboratories suggest that a sin-

gle cotransport activity in renal BBMV is responsible for the sodium-dependent

mount et al318

uptake of PZA, nicotinate, lactate, pyruvate, b-hydroxybutyrate, and acetoacetate

[64–66]; urate is not a direct substrate (ie, there is no evidence for direct sodium-

dependent urate uptake). These anions all are substrates for URAT1 and share

a tendency to increase serum uric acid in vivo. By extension from the BBMV

data [38,62], increased plasma concentrations of antiuricosuric anions result in

increased glomerular filtration, increased delivery to the proximal tubule, and

increased intracellular concentration in tubular epithelial cells. Increases in intra-

cellular activity of these anions in turn induce urate reabsorption and hyper-

uricemia, via trans-stimulation of URAT1 from inside the cell.

There are clear clinical consequences for this physiology. Hyperuricemia is a

well-recognized concomitant of the increased concentration of b-hydroxybutyrateand acetoacetate found in diabetic ketoacidosis [67,68]. Increases in lactic acid,

as seen in alcohol intoxication [69], result in hyperuricemia resulting from

increased urate reabsorption [70]; transient increases in lactate or keto acids may

contribute to the association between gout and alcohol [71]. The effects of keto-

acids and lactate do not appear to be secondary to the respective acidoses, given

that the experimental infusion or ingestion of these anions also can lead to urate

retention [66,72,73]. Hyperuricemia also is a long-appreciated complication of

high-fat diet [74] and of starvation ketosis [75]. Ketoacidosis is thought to be

necessary for the weight-reduction seen with low-carbohydrate diets, with the

recent report of a particularly severe case of diet-associated ketosis [76];

hyperuricemia is assumed to also occur in ketotic patients, on such a low-

carbohydrate, Atkins diet. Finally, the treatment of hypercholesterolemia with

nicotinic acid (niacin) can be complicated by hyperuricemia [77], as can the

treatment of tuberculosis with pyrazinamide [78,79].

Patients who have renal hypouricemia and loss-of-function mutations in

URAT1 are found to lack a response to pyrazinamide and uricosurics [45]. This

provides genetic confirmation of the linkage between PZA and urate reabsorp-

tion; as predicted by the model shown in Fig. 1, a functional urate exchanger

is necessary for the antiuricosuric effect of PZA. Furthermore, BBMV urate

exchange is not detectable in animal species that secrete urate in the absence of

significant reabsorption [30]; presumably, the SLC22A12 gene is inactivated in

these species, much as the uricase gene is inactivated in humans and other homi-

noids. Again, PZA has no effect on urate transport in species in which secre-

tion predominates [29]. These observations all tend to refute the four-component

model, showing that PZA requires a functioning reabsorptive transporter for its

antiuricosuric effect.

The molecular identity of the sodium-dependent anion� cotransporter(s) is not

as yet clear. A leading candidate gene, however, is SLC5A8, which encodes a

sodium-dependent lactate and butyrate cotransporter [3] expressed in the proxi-

mal tubule; the murine Slc5a8 protein can transport both PZA and nicotinate [4],

and preliminary data indicate that this transport can potentiate urate uptake in

cells that coexpress URAT1 [2]. More recently, the related cotransporter Slc5a12

was reported to transport nicotinate and other monocarboxylates [5]; intrarenal

localization of the Slc5a8 and Slc5a12 proteins indicate expression at the apical

Fig. 1. Urate transport mechanisms in the proximal tubule. Sodium-dependent entry of monovalent

anions, such as lactate and PZA, through the SLC5A8 and SLC5A12 cotransporters stimulates the

absorption of luminal urate via the anion exchanger URAT1. Apical secretion of urate may occur

through an ATP-driven efflux pathway (MRP4) or through voltage-sensitive electrogenic pathways

(OATv1 or UAT1). Basolateral entry of urate during urate secretion by the proximal tubule is

stimulated by sodium-dependent uptake of the divalent anion a-ketoglutarate via SLC13A3, leading

to urate-a-ketoglutarate exchange via OAT1 or OAT3. The identity of the exit pathways for urate

during urate reabsorption is not as yet known.


membrane of S2/S3 and S1 segments of the proximal tubule (Zandi-Nejad and

colleagues, submitted for publication, 2006), respectively, such that the two

cotransporters may contribute serially to sodium-dependent anion� transport

within the proximal nephron. Finally, there is a residual question of molecular

heterogeneity in proximal tubular sodium-anion� cotransport; prior evidence sug-

gests electrogenic [80] and electroneutral [64,81] modalities for BBMV sodium-

dependent monocarboxylate and/or nicotinate/PZA transport, whereas SLC5A8

[3] and Slc5a12 [5] appear to be electrogenic cotransporters.

Pharmacologic implications

The monovalent anions that interact with URAT1 have the dual potential to

increase urate absorption and urate excretion, because they can trans-stimulate

and cis-inhibit apical urate exchange. Thus, although urate retention is caused

by the low concentrations of circulating PZA generated in the typical pyrazin-

amide suppression test (approximately 80 mM, 10 mg/ml), higher concentrations

mount et al320

achievable in chimpanzees result in uricosuria [82]; dissenting opinions

notwithstanding [83], these observations remain consistent with the basic scheme

of apical urate transport in the proximal tubule (Fig. 1). Thus, although 0.1-mM

sodium-PZA stimulates urate uptake by dog BBMV preparations, because of

trans-stimulation of urate exchange, 5-mM PZA inhibits the exchanger via

extracellular cis-inhibition (see Fig. 2) [38]. In human BBMV, the stimulatory

effect of PZA persists at 5 mM [62], suggesting that there are species-specific

differences in the ability of PZA to induce uricosuria. Regardless, similar bi-

phasic effects on urate excretion (ie, antiuricosuria at low dose and uricosuria at

high dose) long have been appreciated for salicylate [84]. Salicylate inhibits

human BBMV urate exchange [85] and human URAT1 [1], providing an expla-

nation for the high-dose uricosuric effect; the antiuricosuric effect at low dose

conceivably is the result of a trans-stimulation by intracellular salicylate [85].

Finally, the historically important effect of PZA to inhibit pharmacologic

uricosuria in humans likely is the net result of partial inhibition of renal urate

reabsorption by uricosurics and the particularly high affinity of URAT1 for

intracellular PZA, such that the antiuricosuric effect of PZA is dominant [29].

Again, salicylate has a similar effect, markedly reducing the uricosuric effect of

probenecid at low dose but not at high dose [84].

Fig. 2. The antiuricosuric agent pyrazinoate (PZA), a metabolite of pyrazinamide, has dual effects on

urate transport by the proximal tubule. Urate uptake by brush border membrane vesicles isolated from

dog kidney cortex is shown, in the presence of 100 mM sodium (Na+) with either 0.1-mM PZA (E),

0 PZA (&), or 5-mM PZA (.). The low concentration results in sodium-dependent uptake of PZA

and a potentiation of urate uptake via URAT1; in contrast, the higher concentration cis-inhibits

URAT1, thus reducing urate uptake by the membrane vesicles. (From Guggino SE, Aronson PS.

Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus mem-

branes. J Clin Invest 1985;76:543–7; with permission.)


Regulation of renal urate transport

Classical clinical teaching asserts that the serum concentration of uric acid

parallels extracellular volume status and salt absorption by the kidney [83], such

that salt-avid states (eg, those induced by diuretics) are characterized by hyper-

uricemia and often complicated by gout [86]. Indeed, it has been reported that

patients who have essential hypertension have a decreased fractional excretion of

urate [84–89]. Indices of proximal salt absorption show a significant correla-

tion with serum urate, such that proximal hyperabsorption of sodium (decreased

lithium clearance) is associated with hyperuricemia [87]. In rats, volume deple-

tion stimulates a marked increase in proximal tubular reabsorption of urate [90];

however, the mechanisms involved in the regulation of urate reabsorption by

extracellular volume status are not yet known. Angiotensin II (AT-II) infusion

does, however, decrease fractional excretion of urate; conceivably this is the

result of either hemodynamic effects or direct stimulation of tubular reabsorption

[89,91]. This effect of AT-II is relevant particularly to the hyperuricemia of the

metabolic syndrome [14,15], in that crosstalk between AT-II and insulin may play

a significant role in insulin resistance [92,93]. Acute insulin infusion also is

reported to reduce urate excretion [94,95], such that hyperinsulinemia may have

a direct impact on renal urate transport. Other mediators with potential effects

on renal urate transport include adenosine [96,97] and parathyroid hormone [98].

The URAT1, SLC5A8, and SLC5A12 proteins end with C-terminal sequence

motifs capable of interacting with scaffolding proteins that contain PDZ do-

mains [99]. Biochemical [100,101] and functional [102] interactions already have

been reported between URAT1 and PDZK1, one of a family of four PDZ proteins

(PDZK1/2 and NHERF1/2) that play increasingly appreciated roles in the regu-

lation of proximal tubular ion transport [102,103]. The proposed tethering of

URAT1 to the sodium-anion cotransporters may have additional roles in the

coordinated regulation of renal urate reabsorption. Even in the absence of such a

direct interaction, however, it is intuitively obvious from the antiuricosuric effect

of PZA and other anions that hyperuricemia and gout could result from increases

in the activity of either sodium-anion cotransport (SLC5A8/12) or of urate-anion

exchange (URAT1).

Other urate transporters in the proximal tubule

Considerably less is known regarding the molecular physiology of renal urate

secretion. There is evidence, however, for a voltage-sensitive urate transport

pathway in apical BBMV preparations from humans, weakly sensitive to urico-

suric drugs and PZA [56,85]. The lumen-positive voltage of the apical membrane

of the proximal tubule is hypothesized to favor urate secretion by this mechanism

[56]. Molecular candidates for this electrogenic pathway include urate transporter/

channel-1 (UAT1) [104] and voltage-driven organic anion transporter-1 (OATV1)

[105]. The apical ATP-driven efflux pump multidrug resistance protein 4 (MRP4)

mount et al322

also is shown to mediate substantial urate efflux, suggesting a role in urate se-

cretion by the proximal tubule (see Fig. 1) [106].

At the basolateral membrane of proximal tubular cells, the entry of urate

from the surrounding interstitium appears to be driven by sodium-dependent

uptake of divalent anions, such as a-ketoglutarate, rather than monovalent car-

boxylates, such as PZA and lactate [107,108] (see Fig. 1). Candidate proteins for

this basolateral urate exchanger include OAT1 (SLC22A6) [109] and OAT3

(SLC22A8) [110,111], each of which functions as anion1�-dicarboxylate2� ex-

changers [111–113]. What currently is unknown is whether or not there are separate

pathways for urate exit at the basolateral membrane during urate reabsorption across

the proximal tubule or whether or not OAT1 or OAT3 functions in this capacity via

the exchange of intracellular urate with extracellular a-ketoglutarate. In this regard,

OAT1-deficient knockout mice exhibit a secretory defect for organic anions [114],

suggesting perhaps that basolateral transporters other than OAT1 or OAT3 function

in the reabsorption of urate.

Genetic influences on urate homeostasis

Although twin and family studies suggest a genetic influence on serum uric

acid levels, studies in most populations suggest a polygenic mode of inheritance

without a major gene effect [115]. A recent report from the Framingham Heart

Study reveals several potential loci that affect serum uric acid [116]. Perhaps the

strongest evidence for a genetic basis for gout and hyperuricemia is provided by

indigenous Pacific islanders [117–121]. Of particular interest, a recent study

implicates a major gene on chromosome 4q25 in the gout susceptibility of

Taiwanese aborigines, who share genetic ancestry with other Pacific islanders

[121]. Prior to molecular characterization of the predisposing gene, it is difficult

to speculate on the underlying pathophysiology of this association.

Two specific enzyme defects are shown to lead to overproduction of uric

acid. In addition to Lesch-Nyhan syndrome resulting from complete deficiency of

hypoxanthine hypoxanthine-guanine phosphoribosyltransferase (HPRT) (OMIM

#300322) [63], partial deficiency of this enzyme is a well-described cause of

hyperuricemia and gout (Kelley-Seegmiller syndrome) [122,123], (OMIM

#300323) [63]. Another X-linked cause is overactivity of the phosphoribosyl-

pyrophosphate synthetase (PRPS1) enzyme (OMIM #311850) [63] resulting from

a variety of point mutations or to increased PRPS1 transcription, the latter re-

ported in kindreds with structurally normal enzyme [124].

Several genetic causes of renal disease are associated with hyperuricemia

and gout. Most prominently, medullary cystic kidney disease type 2 (MCKD2)

(OMIM #603860) [63] and the allelic disorder, familial juvenile hyperuricemic

nephropathy (FJHN) (OMIM #603860 and #162,000) [63], are characterized by

a reduced fractional excretion of uric acid, progressive renal dysfunction,

frequent but variable hyperuricemia (92% hyperuricemia in one kindred [125]

and 0% in another [126,127]), and a high incidence of early-onset gout. This


disorder is caused primarily by mutations in uromodulin or Tamm-Horsfall gly-

coprotein [128], a glycosyl-phosphatidylinositol-anchored membrane protein

with restricted expression at the luminal membrane of the thick ascending limb

and distal convoluted tubule. Altered biosynthesis results in markedly reduced

uromodulin excretion and intracellular aggregation within the distal nephron

[129]. Although experimental [130] and genetic [123] forms of hyperuricemia

may lead to renal injury, the absence of hyperuricemia in some affected patients

suggests that the renal impairment in MCDK2 and FJHN is not a consequence of

hyperuricemia. Presumably, hyperuricemia in these patients is secondary to renal

tubular dysfunction, hypovolemia, and secondary neurohumoral activation of the

renin-angiotensin-aldosterone axis or other mediators. Indeed, hyperuricemia is

well described in other cellular and functional defects of the distal nephron,

including MCKD1 (chromosome 1q21), Bartter’s syndrome [131], and familial

hypomagnesemia [132]. Hyperuricemic renal disease also has been reported in a

kindred with mutations in the hepatocyte nuclear factor-1b (HNF-1b) transcrip-tion factor [133]. Mutations in HNF-1b are associated with a spectrum of cystic,

dysplastic, and developmental abnormalities of the kidney [134]. Although the

related transcription factor HNF-1a is likely to regulate the expression of URAT1

[135,136], it is not yet known how dysregulated transcription of this or related

transporters contributes to the renal phenotype or hyperuricemia in patients who

have HNF-1b mutations.

Finally, as discussed previously, loss-of-function mutations in URAT1 are

associated with renal hypouricemia (OMIM #220150). These patients typically

have serum uric acid levels of approximately 1 mg per day, with marked in-

creases in their fractional urate clearance [45]. Clinical manifestations include a

characteristic syndrome of exercise-associated acute renal failure, which can be

recurrent. The mechanism of this renal injury is not known. The majority of renal

biopsies in a recent series, however, demonstrated evidence of acute tubular ne-

crosis, without intratubular deposition of uric acid [137]. An attractive hypothesis

is that the reduction in circulating uric acid, a known antioxidant [20,138], re-

duces the ability to cope with the increase in free radicals associated with stren-

uous exercise [139].

The hyperuricosuria associated with URAT1 dysfunction, typically greater

than 900 mg per day, is associated with renal stones in approximately 10% of

affected patients [45,140–142]. When analyzed biochemically, these episodes of

nephrolithias have included calcium oxalate [142] and uric acid [140,140] stones.

Hyperuricosuria is a well-described risk factor for calcium-oxalate stones [143];

affected patients generally have a urine pH greater than 5.0, with urinary super-

saturation of sodium urate and calcium oxalate resulting from concomitant in-

creases in urinary calcium and sodium [143,144]. In contrast, the uric acid stones

in patients who have ‘‘gouty diathesis’’ typically occur in the context of hyper-

uricemia and reduced fractional excretion of urate, with urine pH approximately 5

[145,146]. Recent data indicate a role for systemic insulin resistance in reducing

urinary ammonium excretion, generating an acid urine, and subsequent uric acid

crystallization [147]. The lesser role of hyperuricosuria per se in uric acid stones

mount et al324

is underlined in renal hypouricemia; uric acid stones are not a universal problem

in this syndrome, despite the marked increase in urinary uric acid [45].

Although reduced urinary ammonium and a low urine pH is the most con-

sistent finding in idiopathic uric acid nephrolithiasis (UAN), the pathophysiology

underlying this defect is not completely clear. A novel gene, however, recently

was implicated in the high incidence of UAN observed in Talana, a genetically

isolated village in Sardinia [148,149]. Approximately 85% of the affected pa-

tients in this population have low urine pH, with hyperuricosuria (N700 mg/d)

in 35% [148]. The gene involved, denoted Talanin, is contained within a

67-kilobase ‘‘critical region’’ of 10q21-22 that is associated with severe UAN by

linkage-disequilibrium mapping. Talanin is encoded by one of at least four

alternative transcripts generated from within the larger ZNF36 gene; the Talanin

transcript shares coding exons with one of the other three major transcripts, with

transcriptional initiation at a unique TATA-box promoter just 5V of the criti-

cal region [149]. Although the function of Talanin is completely unknown, se-

quence analysis suggests that it might by an O-glycosylated transmembrane

protein. The open reading frame of the Talanin transcript is specific to humans;

there is no conservation of exon structure in this segment of the mouse and rat

ZNF36 gene, with inactivating mutations in the coding sequence of the Talanin

transcripts of Old World and New World monkeys [150]. Therefore, as in

other genes that have a role in uric acid homeostasis (uricase, xanthine oxidase,

and URAT1/SLC22A12), there seems to be differential evolutionary pressure

on ZNF36/Talanin.

Perspectives

Reduced renal excretion of urate [151] is the underlying pathophysiology in

the majority of gouty patients who have an underexcretor phenotype [152],

although more recent evidence suggests that patients who have higher levels of

uric acid excretion also have a diminished fractional excretion [88]. What is the

projected impact of the recent advances in molecular physiology on the under-

standing and management of gout? The immediate effect is conceptual, in that a

reconsideration of the relationship between sodium-anion cotransport (SLC5A8/

A12) and urate-anion exchange (URAT1) provides a framework to understand the

effect of uricosuric and antiuricosuric physiology. In particular, the loss of a PZA

response in patients lacking URAT1 [45], the major reabsorptive pathway for

urate, should lay to rest the concept that this drug has a dominant effect on urate

secretion rather than reabsorption; the durable four-component model should,

perhaps, have a similar fate. Moreover, if one extrapolates from the effect of

changes in circulating PZA/lactate/keto acids on serum urate, the possibility is

apparent that hyperuricemia might result from changes in the activity of URAT1,

SLC5A8/A12, or the scaffolding proteins that potentially bind them together

[101]. On a more practical level, the molecular characterization of proteins in this


‘‘metabolic pathway’’ of renal urate transport provides the requisite tools to begin

to study its regulation by AT-II, insulin, and other hormones. With respect to drug

targeting, development can be foreseen of compounds that modulate GPR109A

(G-protein receptor 109A, also known as PUMA-G or HM74A), the lipid-

lowering receptor for nicotinate/b-hydroxybutyrate [153,154], without interact-

ing with SLC5A8/A12 and URAT1 to cause hyperuricemia.

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Treatment of Crystal Arthropathy—History

and Advances

George Nuki, MB, FRCP, FRCPET

Queen’s Medical Research Institute, University of Edinburgh, Scotland, UK

The history of gout and the many distinguished historical figures who have

suffered the agonies of this crystal deposition disorder have claimed the attention

of medical historians like no other disease. Flavors of this rich and colorful story

are captured in a charming and scholarly set of historical essays by Copeman [1],

Rodnan’s beautiful collection of prints and illustrations [2], and an excellent

introductory chapter to their comprehensive monograph on gout by Wyngaarden

and Kelley [3].

Emerging recognition of crystal-associated arthropathy

The earliest recorded drawings of crystals taken from a tophus from a patient

who had gout (Fig. 1) are those of Antoni Van Leeuwenhoek, the pioneer Dutch

microscopist, in 1769 [4]. At the time he did not recognize that they were crystals

and was unaware of their chemical composition. A century later, the English

chemist, Wollaston, a nephew of William Heberden, was able to show that ma-

terial obtained from a tophus in his own ear was composed of sodium urate [5],

after the first chemical identification of uric acid (‘‘lithic acid’’), in urinary cal-

culi, by the Swedish apothecary, Scheele, who worked after hours in the kitchen

of his apotheke in Koping in 1776 [6].



T University of Edinburgh, Osteoarticular Research Group, The Queen’s Medical Research

Institute (C2.23), 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK.





Fig. 1. (A–D) Crystals of sodium urate from a gouty tophus drawn by Antoni van Leeuwenhoek,

the Dutch pioneer microscopist, in 1679.

nuki334

Elevated levels of uric acid in the serum of patients who had gout were

demonstrated by Sir Alfred Baring Garrod. He first reported his findings in the

Transactions of the Medical Chirurgical Society of Edinburgh in 1848 [7]. In

what is now widely believed to be a milestone in the development of the disci-

pline of clinical chemistry, he subsequently described his semiquantitative thread

test for the measurement of urate [8]. Crystals of uric acid, that subsequently

could be weighed, were seen to form along a linen fiber suspended for 18 to

48 hours in the acidified serum of patients who had gout (Fig. 2). It was in his

Fig. 2. Demonstration of Garrod’s thread test by the late Professor H. L. F. Currey at the London

Hospital. Crystals of sodium urate have formed along a linen thread suspended for 48 hours in

acidified serum from a patient who had gout and hyperuricaemia.

treatment of crystal arthropathy 335

book, however, The Nature and Treatment of Gout and Rheumatic Gout, first

published in 1859 [9], that Garrod first described clearly the roles of hyper-

uricemia and urate crystals in the pathogenesis of gout. Wyngaarden and Kelley

[3] have drawn attention to the remarkable prescience of Garrod’s propositions

(Box 1) [9,10]. Support for the fourth of these, ‘‘that the deposited urate of soda

may be looked upon as the cause, and not the effect, of the gouty inflammation,’’

and his subsequent proposal [11], that acute attacks of gout were triggered by the

precipitation of sodium urate crystals in the joint or neighboring tissues, were

provided by the experiments of Freudweiler, who was able to mimic acute attacks

of gout by the intra-articular injection of microcrystals of sodium urate [12], and

by the experimental work of His, who showed that subcutaneous injection of

urate crystals in rabbits was followed by the formation of nodules with the his-

tologic characteristics of tophi [13]. The historical importance of these obser-

vations came to light only after Faires and McCarty [14] and Seegmiller and

colleagues [15,16] rediscovered the capacity of microcystals of sodium urate

to induce inflammatory responses in joints, skin, and subcutaneous tissues in

the early 1960s. The renewed interest in the role of microcrystals at that time

followed key clinical observations by McCarty and Hollander. In a landmark

paper published in 1961 [17], they demonstrated the diagnostic value of detecting

negatively birefringent crystals of monosodium urate within synovial fluid

leucocytes by polarizing light microscopy during acute attacks of gouty arthritis.

The application of this diagnostic technique soon led to the identification

of positively birefringent crystals, confirmed by x-ray diffraction to be calcium

pyrophosphate dehydrate (CPPD) in some patients with acute synovitis and pseu-

dogout [18,19]. Although the demonstration that acute synovitis could be induced

by the experimental injection of microcrystals of CPPD into normal canine and

human joints seemed to confirm the pathogenic role of CPPD crystals in pa-

tients who have pseudogout [20,21], the extent to which they are pathogenic, or

an epiphenomenon, in the wide range of clinical settings subsequently described

and classified by McCarty as manifestations of CPPD deposition disease [22] re-

mains much less certain. Cadaver studies undertaken approximately 80 years ago

showed that meniscus calcification is a common age-related finding, even in indi-

viduals who are asymptomatic [23]. This is confirmed by radiographic surveys.

The prevalence of meniscal chondrocalcinosis was approximately 27% in people

more than 85 years of age in an elderly cohort [24] and in the population at large

in the Framingham community study [25].

Basic calcium phosphate (BCP) crystals, including partially carbonate-

substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate,

also have been associated with several age-related joint pathologies. These in-

clude calcific periarthritis [26], first demonstrated radiographically approximately

100 years ago [27]; a destructive form of apatite-associated arthritis [28], best

known as the Milwaukee shoulder syndrome [29] but probably the same condi-

tion previously described as l’epaule senile haemorrhagique [30]; and, most com-

monly, osteoarthritis (OA). BCP crystals are found in up to 70% of OA synovial

fluids, often in the absence of overt inflammation, although there is some evi-

Box 1. Garrod’s propositions relating to uric acid, urate of soda, and gout

� First, in true gout, uric acid, in the form of urate of soda, invariablyis present in the blood in abnormal quantities, before and at theperiod of the seizure, and is essential to its production, but thisacid occasionally may exist largely in the circulating fluid withoutthe development of inflammatory symptoms, as, for example, insome cases of lead poisoning and in a few other instances. Itsmere presence, therefore, does not explain the occurrence of thegouty paroxysm.� Second, the investigations recently made in the morbid anatomy ofgout prove incontestably that true gouty inflammation is alwaysaccompanied with a deposition of urate of soda in the inflamed part.a

� Third, the deposit is crystalline and interstitial, and when once thecartilage and ligamentous structures become infiltrated, such depo-sition remains for a lengthened time.� Fourth, the deposited urate of soda may be looked on as the cause,and not the effect, of the gouty inflammation.� Fifth, the inflammation that occurs in the gouty paroxysm tends tothe destruction of the urate of soda in the blood of the inflamed partand, consequently, of the system generally.� Sixth, the kidneys are implicated in gout, probably in its early, andcertainly in its chronic, stages, and renal affection, perhaps onlyfunctional at first, subsequently becomes structural; the urinarysecretion also is altered in composition.� Seventh, the impure state of the blood, arising principally from thepresence of urate of soda, is the probable cause of the disturbancethat precedes the seizure and many of the anomalous symptoms towhich gouty subjects are liable.� Eighth, the causes that predispose to gout, independent of thoseconnected with individual peculiarity are either those that produce anincreased formation of uric acid in the system or that lead to itsretention in the blood.� Ninth, the causes exciting a gouty fit are those that induce a lessalkaline condition of the blood or that greatly augment, for the time,the formation of uric acid, or such as temporarily check the elimi-nation power of the kidneys.� Tenth, in no disease but true gout is there a deposition of urate ofsoda in the inflamed tissues

a This fact I wish to impress forcibly on the minds of my readers,because in the constancy of such deposition lies the clue that has longbeen wanting: the occurrence of the deposit is perfectly pathognomonicand at once separates gout from other diseases that at first sight mayappear allied to it.From Garrod AB. The nature and treatment of gout and rheumatic gout.London: Walton and Maberly; 1859.

nuki336


dence to suggest that the presence of crystals in synovial fluid in OA may be

associated weakly with radiographic evidence of cartilage destruction [31].

Approaches to management

A bladder calculus recovered by Elliot Smith from an Egyptian mummy at

El Amrah in 1901 probably is the earliest physical evidence of a human disease

associated with crystal deposition. This dates back to 4800 bc, and lithotomy for

bladder stones may have been among the earliest treatments for a crystal

deposition disorder. Shushruta was removing vesical calculi in India, possibly as

early as the sixth century bc [32], and it is clear that lithotomists were active in

Ancient Greece at the time of Hippocrates. In the Hippocratic oath, lithotomy is

singled out as a practice not to be undertaken by his fellow physicians [33],

although Hippocrates often was bold in recommending other surgical procedures,

such as thoracotomy or trephining the skull [1]. ‘‘I will not cut persons labour-

ing under the stone, but leave this to be done by men who are practitioners of

this work’’ [33].

Hippocrates’ remarkable clinical observations on gout and its natural history

contained in his aphorisms [34] include some of the earliest references to the

management of this disease. Although he advocated the use of all empirically

proven remedies if used ‘‘in such a way as to do good, or at least do no harm’’

[1], his approach predominantly was dietary and conservative. Hippocrates

believed that gout developed after accumulation of bodily humors, such as

‘‘phlegm,’’ which resulted in the painful distension of joints after dietary and

sexual excess and a sedentary life. His dictums on diet include advice on the

preparation and the content of foods, and he recommended moderation, but not

abstinence, from wine, ‘‘whereby the humours may be kept in healthy balance

and disease obviated’’ [1]. Ptisan, a type of barley water, also was recommended.

Local approaches to treating painful joints

Hippocrates’ advice concerning local therapy is best known from his aphorism

X-25: ‘‘swellings and pains in the joints, without sores, whether from gout or

from sprains, in most cases are relieved by a copious affusion of cold water,

which reduces the swelling and removes the pain’’ [34]. But he also recom-

mended heat and counter irritation: ‘‘This is a long, painful, but not a mortal

illness; if the pain still continue, burn the veins above the joint with raw flax.’’

Uncertainty about the best approach to the local treatment of acute gout

persisted for the next 2500 years. In his De re Medicina [35], written in the first

century ad, the Roman writer, Celsus, advocated warm applications according to

the intensity of the inflammation but advised great caution with regard to cold,

believing that this could frustrate nature’s efforts to dispel the disease through the

medium of an acute attack [1]. Avicenna, the great Arabic Persian physician of

nuki338

the eleventh century, subscribed to this belief and recommended that intractable

joints could be cauterized lightly with a hot iron through a layer of salt and oil

[36]. Yet earlier, in the second century ad, Aretaeus, the Cappadochian from

Asia Minor, who worked in Rome and was the first to suggest that a specific toxic

product, or ‘‘peccant humor,’’ was the cause of gout, observed that local re-

frigeration was more helpful than warmth in patients who have ‘‘hot species’’ of

arthritis [37]. He advocated cold sea water baths followed by an inunction of the

joint with oil or a cold poultice of cucumber, lemon peel, plantain leaves, and

rose petals wrapped in the unscoured wool of a sheep to which a little rose oil or

wine was added periodically. Nevertheless, extreme heat and counter irritation

became fashionable for the treatment of acute gout in the seventeenth century

with the introduction of the new treatment with moxa, from the East Indies, by

the Dutch (Fig. 3). Moxa was a fluffy, cotton-like plant that was placed on the

inflamed joint and ignited. Sir William Temple, an English diplomat who wrote

the celebrated Essay on the Cure of the Gout, in 1681, based on his personal

experience, believed that he had succeeded in curing himself with ‘‘the moxa’’

[38]. Thomas Sydenham, in his Treatise on the Gout, published in 1683 [39],

however, which contains his most famous classical clinical description of an

acute attack of gout, based on his own and his patients’ experiences, was

skeptical about the value of all local applications: ‘‘to ease the pain in the joint I

know of none (though I have tried abundance in myself and others) beside

coolers and repellents which I have already shown to be unsafe...let them be used

(by the patient) in the beginning of a fit and he will soon be convinced of their

insignificancy’’ [39].

Spa therapy with natural mineral waters, which had been used by the Greeks,

the Romans, and throughout Europe in the Middle Ages (Fig. 4), enjoyed a

fashionable vogue in Britain in the eighteenth century. Hydrotherapy was rein-

troduced at spas, such as Bath and Buxton, predominantly for the treatment of

Fig. 3. ‘‘The new treatment’’ of burning with moxa (1629).

Fig. 4. Spa treatment for gout and arthritis at Plomieres (1553).


gout. Although the lifestyle modification that accompanied the waters no doubt

was of some, probably temporary, therapeutic value, spa therapy was not without

its contemporary critics. In his celebrated Commentaries [40], Heberden wrote:

I have not been able to observe any good in arthritic cases from the external use

of these waters, either when the distemper was present or in its absence; on the

contrary it is rather appeared to increase the weakness of the limbs; and sea

bathing has contributed for more to recover the strength of gouty persons.

More recently, local therapy with ice has been shown effective (Effect size

[ES] 1.15; confidence interval [CI], 0.15–2.12) in relieving pain in acute attacks

of gout in a small randomized controlled trial (RCT) in which it was used as an

adjunct to colchicine and prednisolone [41].

Intra-articular approaches to therapy

The treatment of acute attacks of gouty arthritis with intra-articular injections

of corticosteroids is a relatively recent recommended approach, although it

has been the treatment of choice for pseudogout associated with CPPD crystal

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deposition since McCarty first drew attention to pseudogout in 1961 [17]. The

use of intra-articular steroid injections for acute attacks of gout is not mentioned

in Wyngaarden and Kelley’s comprehensive monograph published in 1976 [3]. In

one uncontrolled trial, published in 1999 [42], of intra-articular triamcinolone

acetonide (10 mg) in 19 patients who had acute gouty arthritis, all patients had

complete pain relief within 48 hours.

Colchicine

The history of more targeted, more specific, pharmacologic therapy for crystal

arthropathies began with the use of colchicum for the treatment of ‘‘arthritis’’

approximately 4000 years ago. The use of a plant extract believed to be similar

to colchicine is recorded in the Ebers papyrus (1550 bc) [43]. In Ancient Greece,

colchicum or white Hellebore (Veratrum album) was used predominantly as a

purgative. Hippocrates advocated powerful purgation with white Hellebore for

intractable cases of chronic gout, as he believed ‘‘that the best natural relief for

this disease is an attack of dysentery’’ [1], but there is nothing to suggest that

he was aware that it might have more specific value in patients who had acute

attacks of gout. It was approximately 1000 years later, in the sixth century AD,

that the Byzantine Christian physician, Alexander of Tralles, used Hermodactyl

extracted from the corm of Colchicum variegate, a species similar to Colchicum

autumnale (autumn crocus or meadow saffron), as a more selective and specific

remedy [44]. Aetius of Amida, another Christian physician from Byzantium in

the sixth century AD, probably was the first to understand clearly that the thera-

peutic effects of Hermodactyl were distinct from its gastrointestinal (GI) side

effects [44].

Because of its narrow therapeutic margin and its powerful purgative effects,

the use of colchicine was diminished greatly for long periods in the twelfth and

thirteenth centuries, the seventeenth and early eighteenth centuries, and again in

more recent times. Colchicine use virtually was discontinued in continental

Europe in the Middle Ages after its use was forbidden by the influential Abbess

Hildegard of Bingen (1098–1179 ad): ‘‘It is a deadly poison and not a health

giving drug’’ [44].

Five hundred years later, Thomas Sydenham, often known as the English

Hippocrates, also rejected all medicines that were purgatives as too toxic to use.

Because of his considerable influence, colchicine was not used for the treatment

of gout for approximately 150 years until it was rediscovered by Baron Von

Stoerk in Vienna in the middle of the eighteenth century [45].

In more recent times physicians also have been deterred from using colchicine

because of reports of bone marrow suppression [46], myopathy, and neuropathy

[47], particularly in patients who have impaired renal function. Intravenous

administration no longer is recommended because of reports of several sudden

deaths [48]. Although colchicine has been shown to be symptomatically effective

in approximately 75% of patients who have acute gouty arthritis in one small,


short-term, placebo-controlled RCT [49] (SE for pain relief 0.87; CI, 0.25–1.50),

all patients who received colchicine (1 mg immediately followed by 0.5 mg every

2 hours) developed GI side effects (nausea, vomiting, or diarrhea), confirming

the age-old adage ‘‘that patients treated with colchicine often run before they

can walk.’’

Suggestions that use of colchicine in reduced doses (eg, 0.5 mg 3 times daily)

may have a more acceptable harm-to-benefit ratio [50] await substantiation with

controlled clinical trials. The effectiveness of prophylactic colchicine (0.5 mg

once a day for 6 months [51] or 0.6 mg twice a day for 3 months [52]) is dem-

onstrated in two placebo-controlled RCTs in patients commencing urate-lowering

drug therapy with probenecid (SE 0.74; CI, 0.08–1.40) [51] or allopurinol

(number needed to treat, 2; CI, 1–6) [52]. Diarrhea occurred in 38% of patients

receiving the higher dose of colchicine, but GI side effects were not increased in

those receiving only colchicine (0.5 mg daily).

A single study of colchicine prophylaxis in 10 patients who had recurrent

attacks of pseudogout, followed for a year before and after receiving colchicine

(0.6 mg twice a day), demonstrates a reduction from 3.2 to 1 attack per patient

per year [53]. Colchicine is used to treat patients who have refractory CPPD-

associated arthropathies [54] but good controlled trial data are lacking. Clinical

experience also suggests that BCP-associated arthropathies are managed best with

nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular therapies.

Nonsteroidal anti-inflammatory drugs

Fast-acting NSAIDs, used at maximum recommended doses, for short periods

have become the oral drugs of choice for the symptomatic treatment of acute

gouty arthritis [55] and pseudogout [56], provided there are no contraindications.

The evidence base for the use of NSAIDs is much stronger for acute gout [55,57]

than for pseudogout.

Indomethacin became the yardstick for comparing the efficacy of newer anti-

inflammatory drugs in patients who have acute gout after its efficacy was first

demonstrated in 1963 [58,59]. Initially, the high-dosage Emmerson regime

(indomethacin 100 mg every 4 hours until symptoms begin to resolve, followed

by a tapering protocol), was shown to be followed by pain relief in 82% of

patients within 4 hours of taking the first dose and seemed to be associated with

remarkably few adverse effects [60]. Others, however, soon reported a high

incidence of headaches, central nervous system symptoms, and GI side effects

[61,62], when such high doses were used, and subsequent recommendations were

for doses of 50 mg every 6 to 8 hours in the first 24 hours [63,64]. Over the years,

there have been many short-term comparative trials of newer NSAIDs using a

variety of trial designs and outcome measures in patients who have acute gout,

without any good evidence emerging to suggest that any particular NSAID has

superior efficacy or safety for treating acute gouty arthritis [55,57]. Even for

short-term treatment, NSAIDs are contraindicated in patients who have heart

failure, renal insufficiency, or a history of previous peptic ulceration, perforation,

nuki342

or hemorrhage, and great caution needs to be exercised when considering their

use in patients who are frail and elderly and who have multiple pathologies.

Current guidelines for gastroprotection are advised when their use is considered

in patients at increased risk for peptic ulcers, perforations, or bleeds [55,57]. In

one well-designed, double-blind RCT, the selective cyclooxygenase (COX)-2

inhibitor, etoricoxib (120 mg), and indomethacin (50 mg 3 times a day) gave

comparable rapid pain relief in patients who had acute gout [65]. Nevertheless, in

view of recent studies highlighting the potential cardiovascular toxicity of coxibs

[66,67] and the weak evidence of increased risk of cardiovascular thrombogenic

events (odds ratio 1.49; CI, 0.42–5.31) in a systematic review and meta-analysis

of placebo-controlled trials of etoricoxib [68], it probably is wise to avoid the use

of a selective COX-2 inhibitor for treating acute gout in patients who have

established cardiovascular or cerebrovascular (CVS) disease, pending the acqui-

sition of better data on the relative CVS/GI risks and benefits of these agents in

the treatment of patients who have gout. Cardiovascular risk assessment is an

important part of the management of patients who have gout and hyperuricemia

who frequently have, or develop, cardiovascular comorbidity [55,57].

Approaches to lowering blood and tissue urate

Four therapeutic approaches to lowering plasma urate and the tissue pool of

urate have been undertaken over the years:

� Dietary modification� Uricosuric drugs� Uricostatic drugs� Uricolytic drugs

Dietary modification

Dietary restriction was advocated as a treatment for gout long before the

importance of hyperuricemia and tissue accumulation of urate of soda first were

demonstrated in the middle of the nineteenth century by Garrod [7]. It already has

been emphasized that dietary advice was central to the recommendations for

treating gout made by Hippocrates [34]. Galen, Hippocrates’ most illustrious

follower, believed that tophi result from the local accumulation of ‘‘humours’’

and that they could be treated by a combination of dietary restriction and pro-

phylactic bleeding [69]. The basis for his dietary recommendations is not easy

to understand: ‘‘Barley bread is a very excellent thing, and a sausage in due

season; and a little cabbage half boiled, with a soup of mixed vegetables.’’ It is,

perhaps, particularly disappointing that he recommended ‘‘sea foods,’’ such as

oyster, limpet, and sea urchin soup; ‘‘such fishes as inhabit rocky places’’; and

meats, such as ‘‘mutton, goat, hares and wild boar,’’ in view of recent studies that

confirm the association of gout with diets rich in shellfish and red meat [70].


In the sixteenth century, the French surgeon, Ambroise Pare, himself a suf-

ferer of gout, seems to have been more in tune with current medical teaching

when he wrote [71], ‘‘Such gouty persons as remain intemperate and given to

gluttony...may hope for no health by the use of medicines’’ and ‘‘There have

been, as I know, not a few rich and riotous persons, who having spent their

estaites, have therewith changed their health together with their fortune and their

diet, and so have been freed from the goutte.’’ Although he advocated chicken,

he suggested that, ‘‘capon and suchlike birds are not good, being themselves

subject to goute in their feet’’ [1]. Physiologic studies undertaken in the 1970s on

chickens with an inherited susceptibility to dietary induction of gout and tophi

show this to be the result of impaired renal clearance of uric acid [72,73].

The relationship between gout, and diets rich in meat and alcohol were well

recognized in eighteenth-century England. ‘‘The people of distinction and

opulence indulge themselves...eating the most rich and luscious fleshes in great

quantity, and drink large amounts of generous wines. By this means Nature is

rendered incapable of managing the large quantity of blood, and carrying off the

secretions which ought to be made from it,’’ wrote Bernadino Rammazzini of

Padua in his De Morbus Artificiam (English translation, 1746) [1]. Sydenham

recommended a light but adequate diet but also was aware that ‘‘fasting and

actual abstinence is not good’’ [1].

Gout reached almost epidemic proportions in early nineteenth-century

England when ‘‘tophi like crocuses were bursting every where’’ [74]. There is

some reason to suppose that this was at least in part attributable to the prodigious

consumption of wine and port at this time. Analysis of fortified wines from

1770 to 1820, however, reveal significant contamination with lead [75], suggest-

ing that lead poisoning (saturnine gout), as well as alcohol, may have contributed.

Alcohol raises the serum urate by enhancing urate production and by reducing

renal clearance. Acetate conversion to acetyl coenzyme A in the metabolism

of alcohol [76] leads to degradation of adenine nucleotides and accelerated

urate production [77]. More importantly, the metabolism of alcohol to lactic acid

results in inhibition of uric acid secretion and a reduction in the fractional

clearance of uric acid by the kidney [78]. The purine content of beer also may

contribute [79]. Recent studies of a large cohort of male health professionals fol-

lowed for 12 years confirmed, for the first time, the long-held perception that

alcohol consumption is an important risk factor for the development of gout

[80]. Modest beer intake was associated with greater risk than spirits, despite

lower alcohol content, and regular consumption of two glasses of wine was

not associated with increased risk [80], contradicting, to some extent, the popu-

lar nineteenth-century stereotype of the gout sufferer as a portly wine drinker

(Fig. 5).

It has been known for decades that high protein diets may increase urinary uric

acid excretion [81] and milk proteins, in particular, may be protective. In a

subgroup of a male professionals cohort, whose diet contained a high intake of

dairy products, the relative risk (RR) of developing gout was reduced sig-

nificantly (RR 0.56; CI, 0.42–0.74) [82]. Consumption of milk proteins is shown

Fig. 5. Origin of the gout. Eighteenth-century print by Henry William Bunbury (1750–1811).

nuki344

to result in a fall in serum urate levels [83], and serum urate levels rose sig-

nificantly in a RCT 4 weeks after starting a dairy-free diet [84].

Admiral Nelson, who began to have frequent attacks of gout when stationed in

Malta, ceased to be troubled with gout some months after abstaining from all

animal food and adopting a diet of milk, vegetables, and water [1].

The Rev. Sydney Smith, known as the witty canon of St Paul’s, and a notable

nineteenth-century sufferer of gout, wrote of the need for ‘‘stomatic monasti-

cism’’: ‘‘The sufferer must also enter into a solemn compact with his stomach to

relinquish all serious flirting with the sirens of the kitchen and the houris of the

wine cellar’’ [85].

Observational studies in small numbers of obese patients who had gout have

shown that gradual weight reduction by restriction of carbohydrate intake can be

associated with decreases in serum urate [86,87], although restricting the intake

of purine-rich foods has a greater effect.

At the turn of the twentieth century, after Miescher’s demonstration that

nucleoproteins were the main constituents of cell nuclei [88] and Nobel laureate

Emil Fischer’s landmark discovery that uric acid could be derived from purine

bases, such as xanthine and hypoxanthine [89], interest began to stir into the role

of dietary purines and endogeous purine metabolism in the synthesis of uric acid.

In Britain, Alexander Haig (1853–1924), a physician at St Bartholomew’s Hos-

pital, became obsessed with the notion that uric acid plays a role in the causation

of many diseases, including his own headaches, hypertension, and depression.

Much of this is related in his book, Uric Acid as a Factor in the Causation of

Disease, first published in 1892. Haig was among the first people to undertake

detailed analyses of the purine content (uric acid and xanthine) of various dietary


constituents. He also spent much of his professional career promoting a low-

purine diet after undertaking a series of physiologic studies on himself in which

he demonstrated that serum urate levels and urinary uric acid excretion could be

reduced by a diet from which he excluded all fish and animal proteins, tea, coffee,

and cocoa (Fig. 6). In the course of his experiments, he also came to understand

that uric acid in the body was derived from both endogenous synthesis and the

intake of purine-containing food and beverages [90]:

Fig. 6

1897

(From

1908

I have had in my experimental work the most absolute proof that a sufficient

supply of nitrogen is the prime necessity of nutrition. For before I became aware

that the uric acid which poisoned me was being poured in ready formed in flesh

foods, tea, coffee, etc., I believed that the only way to reduce uric acid was to

reduce total nitrogen, and this I proceeded to do, with the unfortunate result of

reducing myself to a condition of extreme debility and asthenia.

But when I found out in 1893, that all uric acid and xanthin swallowed appeared

in the blood, and eventually in the urine, I saw that I could take as much nitrogen

as was necessary for nutrition as long as I avoided substances containing much

uric acid or xanthin.

The considerable magnitude of the contribution of dietary purines to serum

urate and urinary uric acid excretion were demonstrated clearly 70 years later in

physiologic studies in which healthy volunteers were fed isocaloric, purine-free

formula diets [91].

Current guidelines for the treatment of gout emphasize the importance of

advice about lifestyle modification. Recommendations include weight reduction

. Dr. Alexander Haig’s chart of his own urine uric acid, urea and acid excretion from 1893 to

. The sharp fall in uric acid excretion in 1895 illustrates the effect of his purine-free diet.

Haig A. Uric acid as a factor in the causation of disease. 7th edition. London: J&A Churchill;

. p. 799.)

nuki346

to ideal body weight, restriction of alcohol (especially beer) intake, and limited

consumption of foods with high purine contents (especially offal, red meat, and

shellfish) [55,57].

Uricosuric drugs

Many analgesic and anti-inflammatory drugs also increase renal excretion of

uric acid. The uricosuric effects of the quinoline analgesic, cinchophen, were

recognized approximately 100 years ago [92] and the drug continued to be used

for the treatment of gout in Europe, but not in the United States, for decades

despite reports of agranulocytosis and liver toxicity [93,94]. It also had been

known for 50 years that salicylates have sufficiently potent uricosuric properties

to control hyperuricemia in patients who have gout, when given in doses of 4 to

6 g daily [95]. Few patients can tolerate such a regime, and aspirin, paradoxi-

cally, is antiuricosuric when administered in lower doses [96]. It was with the

introduction of treatment with probenecid in 1951 [97], sulphinpyrazone in 1957

[98], and benzbromarone in 1965 [99] that physicians first were provided with

agents that could be used to control hyperuricemia and gout safely and effec-

tively in the majority of patients for long periods of time. The effectiveness of

probenecid is illustrated in one of Talbott’s case reports (Fig. 7) [100]. Mobili-

zation of tophi after long-term treatment with probenecid was demonstrated first

Fig. 7. Early case chart demonstrating the effect of probenecid on serum urate and time lost from work

because of recurrent episodes of acute gouty arthritis. (From Talbott JH. Gout. New York: Grune &

Stratton; 1967; with permission.)


by Yu and Gutman in 1951 [101]. Sulphinpyrazone (200–400 mg/day) is more

potent than probenecid (1–2 g/day), but neither is effective in patients who have

renal insufficiency (creatinine clearance less than 30 mL/min) [102], and in

approximately 25% of patients who have gout, adequate control of hyperuricemia

cannot be achieved [103,104]. Benzbromarone (100–200 mg/day) is a more

potent uricosuric, can be effective in patients who have moderate renal insuffi-

ciency, and can be useful particularly for patients who cannot tolerate allopurinol

and for managing transplant patients when allopurinol is contraindicated [105].

Because of a small number of reports of hepatic toxicity and failure, however, the

use of benzbromarone recently has been restricted in several European countries

[106], and it never has been licensed for use in the United States.

All uricosuric agents now are contraindicated in patients who have a history of

urolithiasis, and in patients who are receiving them, care needs to be taken to

ensure that a high fluid intake and urine output are maintained [63].

Azapropazone (1200–1800 mg/day) is a NSAID shown to have moderate

uricosuric potency [107] and efficacy in acute gouty arthritis [108] and in

reducing the frequency of attacks of gout during the intercritical period compared

with indomethacin plus allopurinol [109]. After examination of the United King-

dom General Practice database demonstrated that its use in general practice

was associated with a relatively high risk of upper GI bleeds and perforations

(RR 23.4; CI, 6.9–79.5 compared with RR 7.0; CI, 5.2–9.6 for high-dose ibu-

profen, diclofenac, naproxen, indomethacin, and ketoprofen) [110], however, use

of this uricosuric NSAID largely was discontinued in the United Kingdom, and

it never has been licensed for use in the United States.

Uricostatic drugs

The development of allopurinol in the late 1950s by scientists at the Burroughs

Wellcome research laboratories led to the most important advance in the treat-

ment of gout and the control of uric acid production. The work leading to this dis-

covery was a brilliant example of Gertrude Elion and George Hitchings’ targeted

approach to developing analogs of purine metabolites that selectively inhibited key

steps in cellular metabolic pathways and DNA synthesis. Elion and Hitchings

shared the 1988 Nobel Prize in Physiology or Medicine with Sir James Black

for ‘‘discoveries of important principles for drug treatment’’ [111]. Initially devel-

oped as a putative, but not promising, cancer chemotherapeutic agent, it was used

to inhibit the degradation of 6-mercaptopurine [112] and found to be an inhibitor

of xanthine oxidase [113]. Serum and urinary uric acid were reduced dramatically

when allopurinol was used first as an adjunct in a trial of 6-thiopurine in patients

who had leukemia and, subsequently, in patients who had gout [114]. Serum urate

levels begin to fall 1 to 2 days after starting allopurinol with maximal decrements

in 1 week [115]. Gradual resolution of tophi can be observed if the serum urate

level is maintained below 6 to 6.2 mg/dL (360–370 mmol/L) [116,117]. The

number of acute attacks of gout was diminished from 4.4 per year to 0.06 per year

in a cohort of 60 patients followed longitudinally [118]. A case chart from one of

nuki348

Rundles’ early patients, illustrating many of these improvements, is shown in

Fig. 8. The reduction in urine uric acid excretion is not replaced stoichiometri-

cally by excretion of oxypurines (xanthine and hypoxanthine), as allopurinol has

an additional effect of inhibiting de novo purine synthesis, except in rare patients

who have primary purine overproduction associated with mutations of the purine

salvage enzyme, hypoxanthine guanine phosphoribosyltransferase [119].

Although it previously was suggested that doses of 300 mg of allopurinol

reduce serum urate to normal levels in 85% of patients and that in some patients

doses of 100 or 200 mg are adequate [120], more recent studies suggest that

frequently this is not the case. In one open comparison of allopurinol (300 mg

daily) and benzbromarone (100 mg daily), the plasma urate fell to 6 mg/dL

(360 mmol/L) in all patients treated with benzbromarone but only in 53% of those

receiving allopurinol in this dose [121]. Also, in a recent study of 762 patients

who had gout where the effects of allopurinol (300 mg daily) were compared

with a new xanthine oxidase inhibitor, febuxostat (80 mg and 120 mg daily),

the primary endpoint (serum urate measurements less than 6 mg/dL at the final

3 monthly measurements) was achieved in only 21% of the patients receiving

allopurinol compared with 53% of those receiving febuxostat (80 mg) and 62%

of those receiving 120 mg per day [122]. Although clearly this suggests that

Fig. 8. Serum urate and urine uric acid and oxypurine values in a 58-year-old man treated with

allopurinol in 1963. HPP, 4-hydroxypyrazolo(3,4-d)pyrimidine (allopurinol). (From Rundles RW,

Wyngaarden JB, Hitchings GH, et al. Effects of a xanthine oxidase inhibitor on thiopurine metabo-

lism, hyperuricaemia and gout. Trans Assoc Am Physicians 1963;76:126–40; with permission.)


allopurinol doses should be adjusted upwardly in many patients who have gout

and are being treated with this agent, studies are required to confirm that such a

strategy will result in optimal control of hyperuricemia in patients who have gout

without adverse effects. Care should be taken to reduce the dose of allopurinol

according to renal function in all patients who have a reduction in estimated

glomerular filtration rate [55,63], as there is evidence that adverse events, espe-

cially rashes, are more frequent in patients who have impaired renal function

[123]. This may be associated with raised plasma concentrations of the allopu-

rinol metabolite, oxipurinol, which is eliminated by the kidney [124].

Febuxostat (80 mg and 120 mg per day) has been shown, in phase II studies,

to be safe and effective in lowering serum uric acid levels in patients who have

gout and hyperuricemia [125], safe and more effective than allopurinol (300 mg

per day) in maintaining serum urate levels less than 6 mg/dL [122], and more

effective in reducing the size of tophi during 12 months [126] in phase III com-

parisons. It is not yet approved for the treatment of gout in the United States

or Europe.

Combining uricosuric and uricostatic drugs

Combining allopurinol treatment with probenecid or sulphinpyrazone for pa-

tients who have extensive tophaceous deposits and adequate renal function was

shown to result in increased elimination of urinary uric acid shortly after the

introduction of allopurinol therapy [127,128]. More recently, this also has

been demonstrated when allopurinol is combined with benzbromarone [121,129].

These combinations are effective despite the fact that uricosuric drugs increase

the clearance of the active allopurinol metabolite, oxypurinol [130–132].

Uricolytic agents

Humans are susceptible to developing gout because they lack the enzyme,

urate oxidase (uricase), which metabolizes uric acid to allantoin in most mam-

malian species.

Transient reduction of serum urate after infusion of purified uricase was re-

ported first in a paper in Science in 1957 (Fig. 9) [133]. More recently, repeated

injection of urate oxidase purified from Aspergillus fumigatus (uricozyme) and

the recombinant enzyme expressed in Strep Mitis (rasburicase) have been used to

prevent the development of the tumor lysis syndrome in patients undergoing

chemotherapy for malignancies [134,135]. Although currently not approved for

the management of gout, rasburicase has been given by repeated intravenous

injection with good effect in isolated cases of tophaceous gout in transplant re-

cipients [136] and patients who have tophaceous gout resistant to combined

treatment with allopurinol and benzbromarone [137]. Although this approach

currently is limited by the need for repeated intravenous infusions, the cost, and

concerns about the development of antibodies, rasburicase has been administered

monthly for more than a year without significant immune reactions [138]. In the

Fig. 9. Serum uric acid and urine allantoin before and after IV administration of purified uricase in

1957. (From London M, Hudson PB. Uricolytic activity of purified uricase in two human beings.

Science 1957;125:937–8; with permission.)

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United States, a polyethylene glycol (PEG)–modified mammalian urate oxidase

is undergoing orphan drug development. Single subcutaneous injections were

followed by prolonged reduction of serum urate in 13 patients who had severe

refractory gout in an open phase I trial, but there was some evidence of devel-

opment of antibodies to the PEG [139]. In a phase II open study where multiple

intravenous injections of PEG-uricase were given to a similar cohort of 41 severe

refractory gout patients, sustained and substantial reduction of serum urate was

confirmed [140]. Rapid resolution of tophi was observed within 3 months in two

patients [141], and no serious immunologic side effects were observed [140].

Calcium pyrophosphate dehydrate– and basic calcium phosphate–associated

arthropathies

The history of therapy for pseudogout, chronic CPPD- and BCP-associated

crystal arthropathies, and crystal-associated periarthritis has been less exciting

than the history of the treatment of gout. Symptomatic therapy with NSAIDs,

joint aspirations, intra-articular steroids, and nonpharmacologic support have been

the core approach to management, but there are few controlled clinical trials.

Historical approaches to inhibiting pathologic calcification have included admin-

istration of bisphosphonates to try and prevent heterotopic bone formation after

hip surgery [142] and the administration of warfarin in low dosage, based on the

premise that it depresses the synthesis of the vitamin K–dependent Gla protein,

which may be involved in the process of ectopic calcification [143]. After the

demonstration that probenecid could block the production or release of pyro-


phosphate by chondrocytes in vitro in response to transforming growth factor b[144], probenecid was used to treat patients who had refractory CPPD-associated

arthritis with some success in an uncontrolled trial [145]. Cheung proposed the

use of phosphocitrate as a potential therapeutic strategy for calcium crystal de-

position disorders [146], as this naturally occurring pyrophosphate analog can

inhibit calcium crystal nucleation and several crystal-induced inflammatory me-

diators (reviewed in [147]) and has been shown to inhibit disease progression in

murine progressive ankylosis [148].

In 1967, the key discovery that primary purine overproduction and severe

premature gout in boys who had Lesch-Nyhan syndrome resulted from an inher-

ited deficiency of the purine salvage enzyme, hypoxanthine guanine phospho-

ribosyltransferase [149], led to an explosion of knowledge about the regulation of

purine metabolism in humans and the pathogenesis of gout that rapidly led to the

development of rational and effective treatment and prevention of this disease.

This was characterized as the ‘‘purine revolution’’ [150], and the treatment of

gout with uric acid–lowering drugs became a paradigm for the successful treat-

ment and prevention of a chronic rheumatic disease.

There now are indications that we may be on the brink of an analogous

breakthrough in understanding how extracellular pyrophosphate promotes CPPD

deposition and inhibits the formation of apatite crystals in crystal-associated

disorders [151]. This, hopefully, will lead to new therapeutic approaches for

controlling CPPD and BCP crystal deposition. As in gout, some of the clues are

emerging from examining the consequences of critical gene mutations. In mice,

mutations of the pyrophosphate-generating ectoenzyme, nucleoside triphospate

pyrophosphohydrolase isoenzyme PC-1 (NTP-PPH PC1) [152], and the ANK

gene [153], which codes for a transmembrane channel protein involved in pyro-

phosphate extrusion from cells, are associated with phenotypes that include

progressive ankylosis and matrix calcification with BCP. Paradoxically, however,

in humans, familial [154] and sporadic [155] forms of CPPD disease are asso-

ciated with mutations in ANKH, the human homolog of the ANK gene.

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Clinical Trials in Crystal Arthropathy

Nancy Joseph-Ridge, MDa,T,Susan Cazzetta, BS Pharm, PharmD Candidatea,b,

Patricia MacDonald, BSN, NPa

aTAP Pharmaceutical Products, Inc., Lake Forest, IL, USAbUniversity of Florida College of Pharmacy, Gainesville, FL, USA

A literature search was conducted in the MEDLINE, EMBASE, Derwent

Drug File, Current Contents, BIOSIS, and International Pharmaceutical Abstracts

databases using various combinations of search terms, including apatite,

hydroxyapatite, basic calcium phosphate, crystal arthropathy, crystal arthritis,

crystal deposition, calcium pyrophosphate dihydrate, gout, hyperuricemia, mono-

sodium urate, pseudogout, and clinical trial. In addition, a manual search of

review articles was conducted to identify other studies. The abstracts of the

identified articles were reviewed, and if relevant, the full text was evaluated.

Clinical trials in the management of acute crystal arthropathy

The initial management of acute arthritis resulting from crystal arthropathy, re-

gardless of the type of crystal, is symptomatic therapy, including selective

and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and colchi-

cine [1–7].



The manuscript preparation was supported by a grant from TAP Pharmaceutical Products, Inc.

(Lake Forest, Illinois).

T Corresponding author. TAP Pharmaceutical Products, 675 Field Drive, Lake Forest, IL 60045.

E-mail address: [email protected] (N. Joseph-Ridge).




Table

1

Selectedclinical

studiesofnonsteroidal

anti-inflam

matory

drugsin

thetreatm

entofgout

Reference

NSAID

sstudied

No.of

patients

Regim

enDiagnosis

Outcomes

Garciadela

Torre,

1987[23]

Tenoxicam

(T)versus

placebo(P)

30

T:40mgonce

daily

Acute

goutof

knee,ankle,

wrist,big

toe,

orelbow

Pain:im

proved

by�50%

(10/15,67%)with

TversusP(4/15,26%);Pb.05

Tenderness:im

proved

by�50%

(6/15,40%)

withTversusP(1/15,7%);Pb.05

Schumacher,

2002[27]

Indomethacin

(I)versus

etoricoxib

(E)

150men

I:50mg3times

daily

Acute

goutfor

b24hours

Pain:nodifference

after2to

5daysusing

5-pointLikertscale(difference

+0.11,95%

confidence

interval�0.14to

+0.35)

E:120mgonce

daily

Fraser,

1987[19]

Indomethacin

(I)versus

azapropazone(A

)

93

I:200mg/d

individed

dosesfollowed

bya

reducingregim

enfor

28days

Acute

gout

Nostatisticallysignificantdifference

inthe

proportionofpatientswhoreported

that

the

treatm

ent‘‘suited

them

’’after4days(I,35/47

[74%]versusA,40/46[87%]).

A:600mg3times

daily

for4daysfollowed

by

600mgtwicedaily

for

28days

Maccagno,

1991[31]

Etodolac(E)versus

naproxen

(N)

61

E:300mgtwicedaily

Acute

gout

Painscore:nosignificantdifference

in0to

5painscore

(higher

score

indicatingworse

pain)after2,4,or7days(m

eanpainscore

joseph-ridge et al360

N:500mgtwicedaily

at2days:2.6

withEversus2.8

withN;

meanpainscore

at4days:1.8

withE

versus2.0

withN)

Painscore

meanim

provem

ent:nosignificant

difference

betweenE(1.4

atday

8)versus

N(1.4)

Lederman,

1990[30]

Etodolac(E)versus

naproxen

(N)

60

E:300mgtwicedaily

Acute

gout

Pain:nosignfiicantdifference

after1,2,4,

and7days

N:500mgtwicedaily

Altman,

1988[18]

Indomethacin

(I)versus

ketoprofen(K

)

59

I:upto

225mgfor1day

individed

dosesfollowed

by50mg3times

daily

Acute

goutfor

b48hours

Painscores:nosignificantdifference

after2,

5,or8daysusing0-to

3-pointscale(higher

score

indicatinggreater

pain).Meanscoresat

days2,5,and8were0.9,0.8,and0.3

for

Iversus1.1,1.3,and0.4

forK,respectively

K:450mgin

divided

dosesfor1day

followed

by100mg3times

daily

Lomen,

1986[17]

Indomethacin

(I)versus

flurbiprofen(F)

29

I:50mg4times

daily

for

4daysfollowed

by25mg

4times

daily

for5days

Acute

gout

Improved

pain:nosignfiicantdifference

betweenIandFin

theproportionofpatients

whohad

improved

painat

restafter2days

(I,11/12[92%]versusF,11/12[92%])

F:100mg4times

daily

for

1day

followed

by50mg

4times

daily

for5days

clinical trials in crystal arthropathy 361


Clinical studies comparing the various NSAIDs find similar pain relief effi-

cacy and tolerability profiles, with these agents generally considered first-line

therapy for those who have gout or pseudogout (Table 1) [8–10]. Until 1990,

NSAID studies involved acemethacin [11], ibuprofen [12,13], indomethacin

[11,14–20], oxamethacin [15], phenylbutazone [14,21], azapropazone [19], pro-

quazone [16], fenoprofen [21,22], flurbiprofen [17], tenoxicam [23], meclophe-

namate [20], ketoprofen [18], and sulindac [24]. No significant differences in

pain relief were found between the various NSAIDs.

In more recent studies, diclofenac, eterocoxib, rofecoxib, and ketorolac have

been investigated. Cheng and colleagues studied [25] the effect of rofecoxib,

diclofenac, and meloxicam on 62 patients experiencing an acute attack of gout.

Subjects (n = 62) received rofecoxib (50 mg), diclofenac sodium (150 mg sus-

tained release), or meloxicam (15 mg), each administered once daily for 7 days in

a single-blind, randomized controlled trial. There was no statistically significant

difference between patient-rated responses for rofecoxib and diclofenac. Inves-

tigator ratings were similar and by day 8, there were no statistical differences

among the three treatment groups.

Two studies investigated the effect of eterocoxib versus indomethacin in acute

gout [26,27]. In both double-blind studies, a total of 349 subjects were ran-

domized to eterocoxib (120 mg daily) or indomethacin (50 mg 3 times daily) for

8 days. Both trials showed similar efficacy between treatment arms at all points

of the trials.

Shrestha and colleagues [28] studied the effects of intramuscular ketorolac

(60 mg) in nine patients presenting to an emergency department with attacks of

acute gout. All patients were satisfied with ketorolac treatment. This study was

followed by a randomized, double-blind study examining the efficacy of intra-

muscular ketorolac (60 mg) versus oral indomethacin (50 mg) in 20 patients

presenting to an emergency department with acute gout [29]. Pain scores de-

creased similarly in both groups during the first 120 minutes of the study, with

some rebound of pain in ketorolac patients after 6 hours.

Two small, randomized double-blind trials [30,31] evaluated the use of

etodolac (300 mg) twice daily (n = 29, 31) versus naproxen (500 mg) two or three

times daily (n = 31, 29) for between 3 and 7 days for the treatment of acute gout

attacks. Improvement by the end of treatment occurred in 87% to 97% of subjects

in each treatment arm. There were no significant differences between the treat-

ment groups at any visit or at the final evaluation.

Colchicine is considered the classic treatment for acute crystal arthropathy

management; however, it is less effective in those who have pseudogout than

those who have gout [8,32]. One small (n = 43), randomized, placebo-controlled

trial finds colchicine associated with pain improvement after 48 hours. Colchicine

also is associated with diarrhea or vomiting within the first 24 hours [33].

Therefore, colchicine for an acute attack of arthropathy often is reserved for those

who cannot take or tolerate NSAIDs [34].

Corticosteroids, via oral, intravenous, intra-articular, or intramuscular routes,

are used in patients who have acute attacks of gout, pseudogout, and basic cal-


cium phosphate (BCP) deposition, although studies are limited, with an absence

of systematic reviews or randomized controlled trials to confirm their efficacy

[5,34–39]. There is general agreement that corticosteroids should be reserved

for those who cannot be treated with NSAIDs or colchicine [8,10]. One pro-

spective trial [40] investigated the use of oral prednisone and intravenous

methylprednisolone for acute gout attacks in 13 patients during a 12-month

period. Oral prednisone dosages varied from an initial dose of 20 mg to 50 mg

per day (range 30 mg to 160 mg), with dosages tapered during a mean of 11 days.

Two patients received parenteral methylprednisolone at doses ranging from

30 mg to 160 mg, with conversion to oral prednisone as soon as possible. Com-

plete resolution of symptoms occurred within 7 to 10 days. A more recent

prospective, open-label study [41] evaluated the use of one dose of intra-articular

betamethasone (7 mg; n = 10) or intravenous methylprednisolone (125 mg; n = 7)

in patients who had contraindications to NSAIDs versus diclofenac (150 mg daily

for 3 days titrated to 75 mg daily for 3 additional days; n = 10). Patient-reported

improvement and severity of joint swelling improved promptly in all three

groups. Roane and coworkers [42] prospectively investigated the use of triam-

cinolone acetonide (60 mg intramuscularly) in 14 patients who had pseudogout

and conclude that it was safe, well tolerated, and effective. Alloway and col-

leagues [43] conducted a prospective, open-label study in which patients

experiencing acute gout attacks were assigned randomly to indomethacin

(50 mg 3 times daily; n = 10) or triamcinolone acetonide (60 mg intramuscularly;

n = 10) plus acetaminophen plus codeine as needed. There was no statistically

significant difference in the number of days to resolution of all symptoms at

each evaluation period.

Adrenocorticotropic hormone or corticotropin has been studied in patients

who have acute gout or pseudogout [44–50]. Although it was effective in re-

lieving pain, in one study quicker than indomethacin [44], its clinical usefulness

is limited by the need to administer multiple injections [8,10,51]. Like that of

corticosteroids, the use of corticotropin generally is reserved for those who

cannot tolerate NSAIDs or colchicine treatment [8].

Recently, there have been case reports regarding the use of the tumor necrosis

factor (TNF) inhibitors, etanercept and infliximab, in the treatment of patients

who have acute pain and inflammation who are unable to use NSAIDs or

colchicine [52,53]. Etanercept was injected subcutaneously twice weekly in a

53-year-old man who had frequent recurrent attacks of gout and who was taking

probenecid and urine alkalizers [52]. The intensity and frequency of the attacks

decreased after four injections, and inflammation decreased although serum

urate values remained similar. Fiehn and colleagues [53] describe a 44-year-old

man who had chronic gouty tophi, painful flares, and significant joint inflam-

mation who was given infliximab (400 mg intravenously [5 mg/kg] at weeks 0,

2, and 6). The patient experienced fast relief from pain and inflammation.

After experiencing a flare 6 weeks after the third injection, infliximab was

administered (400 mg intravenously every 6 weeks) with good response. These

case reports are difficult to assess because of the multiple medications that the


patients were taking. Randomized controlled clinical trials are needed to confirm

the safety and efficacy in gout patients. The overall expense of these agents may

preclude their use in gout.

Clinical trials in the prophylaxis of recurrent crystal arthropathy

Preventative measures or prophylaxis may be required to reduce the fre-

quency and severity of acute crystal arthropathy episodes or gout flares. Mul-

tiple retrospective studies postulate that colchicine prophylaxis is an effective

means of preventing acute gout [54–56]. Few randomized controlled trials for

preventing acute gout attacks have been conducted. In a 6-month, randomized,

double-blind study [57], 51 subjects were treated with probenecid (1.5-gm

daily) and either colchicine (1.5-mg daily) or placebo. The investigators analyzed

only 38 subjects who were assessed as compliant with probenecid, based on a

reduction in serum urate, and found that colchicine reduced the frequency of

acute attacks significantly. Borstad [58] conducted a randomized, double-blind,

prospective, 6-month clinical trial using colchicine as prophylaxis when initiat-

ing therapy with allopurinol. Forty-three subjects initiating allopurinol therapy

received colchicine (0.6 mg; n=21) or placebo (n=22) twice daily. Allopurinol

was initiated (100 mg per day) with the dose titrated to serum urate less than

6.5 mg/dL in 100-mg increments (mean dose 265 mg per day). When targeted

serum urate was reached and maintained, subjects reported fewer gout flares

after 6 months. Acute gout flares occurred in 14% of the colchicine group and

63% in the placebo group (P =0.008). Subjects treated with colchicine had

fewer gout flares in the first 3 months of treatment and fewer flares in the 3- to

6-month treatment period. Because inflammation in osteoarthritis often is

secondary to the presence of calcium-containing crystals, Das and coworkers

[59] investigated whether or not colchicine would prevent crystal-induced acute

inflammatory flares in patients who have osteoarthritis. A randomized, double-

blind, placebo-controlled study was conducted in which colchicine (0.5 mg

twice daily) or placebo was added to NSAID treatment in 36 patients who had

osteoarthritis. Improvement was higher by 30% after 20 weeks in the col-

chicine group compared with the placebo-treated group. The investigators con-

clude that further evaluation of colchicine’s role in osteoarthritis is needed to

determine if the effect seen is the result of crystal-induced inflammation or to

other mechanisms.

Clinical studies of a new nonpurine selective inhibitor of xanthine oxidase

(XO), febuxostat, also include prophylaxis with either colchicine (0.6 mg once

or twice daily) or naproxen (250 mg twice daily) [60–62]. In phase II studies,

gout flares during colchicine prophylaxis occurred in approximately 10% of

subjects and increased to 40% to 53% of subjects when prophylaxis was with-

drawn after the mandated 2- to 4-week period [60]. In phase III studies, an

increase in acute gout flares also was noted after discontinuation of prophylaxis

after 8 weeks [62].


Clinical trials in management of chronic crystal arthropathy

Pseudogout and basic calcium phosphate

Strategies for the chronic management of those who have crystal arthropathy

depend on causative crystal identification and underlying or associated disease

states. In those who have pseudogout, underlying conditions that are associated

with this disorder, such as hyperparathyroidism, haemochromatosis, hypophos-

phatasia, hypomagnesaemia, and Wilson’s disease, should be ruled out and, if

identified, treated. The cause of BCP arthropathy is less clear but is known to

occur with degenerative joint disease. A prospective, self-controlled trial shows

that chronic long-term treatment with colchicine (0.6 mg twice daily) reduces the

number of recurrences of pseudogout [32]. Given the low frequency of recurrent

attacks of pseudogout or BCP arthropathy, however, the benefits of long-term

colchicine need to be weighed against the risks for side effects [2]. To date, no

effective chronic, long-term treatment exists for those who have calcium pyro-

phosphate dihydrate deposition (CPPD) or BCP crystal deposition disease [4].

Gout

Chronic management of gout is defined based on correction of hyperuricemia,

the underlying cause of this disease. In contrast to other crystal arthropathies,

gout recurrence is high. An observational study notes that after the initial

presentation of acute gout, there is a 62% recurrence rate within 1 year, 78% by

year 2, and 89% by year 5 [54]. Another study notes that the frequency of

recurrence of acute gouty arthritis also increases after withdrawal of long-term

urate-lowering treatment [63–65]. Long-term symptomatic treatment with an

NSAID or colchicine may provide some benefit; however, neither addresses the

hyperuricemic etiology of gout. A reasonable pharmacologic therapeutic target is

to reduce serum urate to subsaturation levels of 6.0 mg/dL or less [3,56,66–68].

This may be attained with a uricosuric that increases uric acid excretion or phar-

macologic agents that inhibit the enzyme XO, which reduces uric acid pro-

duction. Currently, the most commonly used agents are probenecid, a uricosuric,

and allopurinol, a purine analog and the only XO inhibitor available. Each of

these agents has clinical advantages and limitations, with the latter generally

resulting from dosing or tolerability and safety profiles (Table 2).

Clinical trials of agents in the treatment of gout

There have been few advances in the management of chronic gout in the past

40 years. Although probenecid and allopurinol remain the antihyperuricemic

agents prescribed most frequently, recent studies find promising results with new

Table 2

Summary of advantages and disadvantages of current and investigational agents used in the treatment

of hyperuricemia and gout

Drug

Mechanism of action

and advantages Disadvantages

Allopurinol Widely used XO inhibitor May be associated with acute gout

flare on initiationOnce-daily administration

Adverse events are common and may be

severe and serious (ie, hypersensitivity

syndrome, liver and renal toxicity) and

occur with greater frequency in those

receiving concomitant diuretic agents

or ampicillin

Effective in underexcretors

and overproducers

Must modify dose in those who have

renal impairment

Can be used (with dosage

modification) in those who

have renal impairment

Associated with drug-drug interactions

(ie, oral anticoagulants, theophylline,

azathioprine)

Probenecid Uricosuric agent that

reduces uric acid in

underexcretors and those

who have normal renal

function without renal

stones or massive tophi

May be associated with acute gout flare

on initiation

Ineffective in those who have

diminished renal function

(creatinine clearance b50 mL/min)

Diminished efficacy in those treated

with acetylsalicylates

Adverse events include rash,

gastrointestinal symptoms, headache,

and serious events, such as nephrotic

syndrome and blood dyscrasias

Drug-drug interactions (ie, increased

plasma levels of concurrent agent)

may occur resulting from interference

with urinary excretion of other agents

(eg, NSAIDs or captopril)

Benzbromarone Uricosuric agent that

effectively lowers serum

uric acid in underexcretors

and overproducers

Available in Europe, limited availability

in United States

May precipitate acute gout flare on

initiation

Concerns regarding hepatotoxicity

Oxypurinol Like its parent compound,

a good inhibitor of

xanthine oxidase

Patients who are intolerant of

allopurinol may exhibit toxicity to

oxypurinol

May be useful in patients

who are allopurinol

intolerant


initiation

Febuxostat Nonpurine selective

inhibitor of XO


initiation

Effectively lowers serum

urate in underexcretors and

overproducers

Administered orally and

once daily

Most common side effects are liver func-

tion abnormalities, diarrhea, headache,

and joint-related signs and symptoms

(continued on next page)


Table 2 (continued )

Drug

Mechanism of action


Febuxostat May be used without

dosage adjustment in those

who have renal insufficiency

or hepatic impairment

Found safe and effective in

large, long-term clinical trials

Rasburicase Potent recombinant uric acid

oxidase compound that

catalyzes enzymatic oxidation

of uric acid

Parenteral route of administration

Useful in patients who have

tumor lysis syndrome

Rapid reduction of serum urate may pre-

cipitate acute gout flare on initiation

May administer only one course of rasbu-

ricase during patient’s lifetime because of

potential for antibody formation

Potential for anaphylactoid reactions

Carries black box warning for anaphylac-

toid reactions and for hemolysis and

methemoglobinemia, especially in those

who have glucose-6-phosphate dehydro-

genase deficiency

Long-term safety is unknown

PEG-uricase

(Puricase)/

uricase-PEG20

Effective recombinant porcine

urate oxidase compound that

produces rapid and profound

decrease in serum urate

Administered intramuscularly

Potentially useful in patients

who have tumor lysis

syndrome and possibly those

who have refractory gout

May precipitate acute gout flare

PEG strands may reduce the

risk for immunogenicity

compared with rasburicase

Potential for allergic reactions from

foreign protein

Well-described safety and efficacy data

not yet published

Fenofibrate Hypolipidemic agent that

increases clearance of purine

bases including uric acid

Effects of fenofibrate on serum urate are

modest compared with allopurinol or

febuxostat

Orally administered useful

adjunct to hyperuricemic

therapy in patients who have

concurrent hypertriglyceridemia

Hypouricemic efficacy not yet determined

in long-term studies

Losartan Orally administered angiotensin

II receptor antagonist that

interferes with urate reabsorption

Effects of losartan are modest compared

with other uricosurics, such as probenecid

Useful adjunct to hyperuricemic

therapy in patients who have

concurrent hypertension

E3040 Member of a new class of anti-

inflammatory agents found to

reduce plasma urate levels.

Agent in early stages of investigation

Efficacy and safety data still evolving

(continued on next page)


Table 2 (continued)

Drug

Mechanism of action


Y-700 XO inhibitor shown more potent

than allopurinol

Agent in early stages of investigation

May be safe in those who have

renal impairment


Scopoletin Agent with weak uricolytic and

potent uricosuric activity

In early stages of investigation



agents designed specifically for the treatment of hyperuricemia and those

designed for other indications but are found also to lower serum urate levels.

Probenecid

Probenecid is the uricosuric prescribed most commonly in the United States

[4]. It is effective in lowering serum urate in patients who have hyperuricemia

resulting from underexcretion and normal renal function without renal stones or

massive tophi [10]. Uricosurics in general, however, are ineffective in those who

have reduced renal function and efficacy may be diminished in those taking

salicylates [4,51].

There is insufficient evidence from systematic reviews or randomized trials

on the effects of probenecid to prevent gout attacks [69] and the clinical use-

fulness of probenecid is limited by its tolerability profile. One study of 37 male

patients assigned to treatment based on the last digit of their hospital number

[70] finds no significant difference between treatment with allopurinol (300 to

600 mg per day) and probenecid (1 to 2 g per day) in reducing acute gout

recurrence. After a mean follow-up period of 18.6 months, 45% (9/20) of those

treated with allopurinol and 47% (8/17) of those treated with uricosurics were

recurrence free. The results of this trial are difficult to interpret because of the

randomization treatment allocation and because of the five patients who

were allocated to probenecid but were switched to sulphinpyrazone because of

adverse events.

Probenecid is associated with rash, gastrointestinal symptoms, headache,

drug-drug interactions, and rare but serious reactions, such as nephrotic syndrome

and blood dyscrasias [71]. Caution is advised in patients who have a history of

peptic ulcer disease and those taking NSAIDs or captopril, as plasma levels of

these agents may be increased with concurrent probenecid use [72].

Benzbromarone

Benzbromarone, a uricosuric agent, is available for the treatment of gout in

select European countries but is not available in the United States. Clinical trials

show it to be an effective uricosuric and more effective than allopurinol

[66,67,73–75]. Benzbromarone is effective in those who have reduced renal


function [67]. Although effective, there is concern that benzbromarone is

hepatotoxic [76–78].

Allopurinol

Allopurinol is a purine analog that inhibits XO along with other enzymes in

the purine and pyrimidine pathway. At doses ranging from 100 to 900 mg per

day, with the most commonly prescribed dose 300 mg per day, it produces a dose-

dependent reduction in serum urate. This agent has been available for more than

40 years and historically is the urate-lowering agent prescribed most commonly

[10,79].

Although allopurinol has been available for a long time, there is insufficient

evidence from randomized controlled clinical trials on the ability of this agent to

prevent gout attacks. Some nonrandomized studies report that allopurinol reduces

acute gout attacks over time [80–82] and is comparable to probenecid [70] in

reducing the frequency of gout attacks. A prospective study by Perez-Ruiz and

colleagues [67] evaluates the efficacy of allopurinol in reducing serum urate.

Allopurinol is compared with benzbromarone in 86 male patients who have

primary chronic gout. Allopurinol-treated patients (300 mg per day) exhibited a

mean reduction of plasma urate of 2.75 mg/dL (from 8.6 to 5.85 mg/dL) in

normal excretors and of 3.34 mg/dL (from 9.10 to 5.76 mg/dL) in underexcretors.

Only 53% of patients, however, achieved the targeted serum urate concentration

of less than 6.0 mg/dL. This result was similar to that of other studies that

found the majority of patients who have gout who were treated with allopurinol

(300 mg per day) fail to attain serum urate targets of less than or equal to 6 mg/dL

[83–85].

Allopurinol is excreted mainly through the kidneys; therefore, dosage adjust-

ments are necessary in patients who have renal impairment. Although a dose of

300 mg per day is standard in those who have normal renal function, it is recom-

mended that the dose be reduced in those who have impaired renal function. In

addition, there are several clinically relevant drug-drug interactions that may

occur when allopurinol is given to patients receiving oral anticoagulants, theo-

phylline, and azathioprine, with these agents often requiring dose adjustment [72].

Up to 5% of patients are unable to tolerate allopurinol because of adverse

events, including headache and gastrointestinal irritation [10]. Less common but

more severe adverse events, such as bone marrow suppression and hyper-

sensitivity syndrome, are described. Allopurinol hypersensitivity syndrome can

range from a severe skin rash to a life-threatening illness, in which patients

develop toxic epidermal necrolysis, fever, hepatitis, eosinophilia, and worsening

renal function [86,87]. This syndrome occurs more frequently in those who have

renal insufficiency or those taking concomitant diuretic agents or ampicillin

[88–91]. It is postulated that clinicians often undertreat gout patients on a long-

term basis with allopurinol in an attempt to lessen the small risk of major

allopurinol sensitivity [92]. Desensitization to allopurinol is attempted in patients

who have minor hypersensitivity reactions with some success [93].


Oxypurinol

Oxypurinol is the primary metabolite of allopurinol and, like its parent com-

pound, is a good inhibitor of XO. Oxypurinol’s half-life is 9 to 15 times longer

than that of allopurinol and is shown to be effective in at least 50% of patients

who are allergic to allopurinol. Evidence of toxicity identical to that observed

with allopurinol, however, is seen in 30% to 50% of treated patients [94–96].

Oxypurinol compassionate-use protocols, in subjects intolerant or allergic to

allopurinol, have been conducted since 1966. One safety study conducted in

99 allopurinol-naive subjects, receiving 384 mg per day of oxypurinol for

14 days, reports 3% of subjects having related adverse events and concludes that

only approximately one half of patients who are allopurinol hypersensitive

can tolerate oxypurinol [95]. In a phase II, randomized, double-blind trial of

oxypurinol, the primary endpoint is the reduction in serum urate of 2.0 mg/dL

between baseline and week 14. The 77 enrolled subjects achieved a mean serum

urate decrease of 1.90 mg/dL (baseline mean 10.11 mg/dL; post-baseline mean

7.96 mg/dL). In another phase II trial, serum urate was lowered by 2.87 mg/dL

in 190 (of 533) compassionate-use patients in a 1-year treatment period [95].

Therefore, its usefulness in the treatment of gout may be limited given the ad-

vent of newer antihyperuricemic agents.

Febuxostat

Febuxostat, a new orally administered, potent nonurine selective inhibitor of

the oxidized and reduced forms of XO, currently is in late-stage development for

the treatment of hyperuricemia and gout [97–101]. Febuxostat is specific for

inhibition of XO and, unlike allopurinol, does not inhibit other enzymes involved

in purine or pyrimidine metabolism [98,102–104]. Pharmacokinetic clinical

studies indicate that febuxostat does not require dosage adjustment in those who

have renal insufficiency or those who have mild to moderate hepatic dysfunction

[105–107].

Several placebo- and comparator-controlled clinical trials performed in North

America and Japan have been conducted and confirm the efficacy and safety of

febuxostat in patients who have hyperuricemia and gout. A phase II, placebo-

controlled, 4-week, randomized, multicenter, double-blind study performed in the

United States evaluated the dose-response efficacy of febuxostat (40 mg, 80 mg,

and 120 mg once daily) in 153 patients who had hyperuricemia (baseline serum

urate �8.0 mg/dL) and gout [60]. Significantly greater proportions of subjects

who were febuxostat treated than those who were placebo treated (febuxostat,

40 mg [56%], 80 mg [76%], 120 mg [94%], placebo [0%]) achieved a serum

urate less than or equal to 6.0 mg/dL at the end of the study (day 28). A similar

response was seen at each weekly visit.

The phase II study has an ongoing open-label extension study, which, in a

2-year interim analysis, demonstrates that febuxostat has sustained urate-

lowering effects [108]. One hundred and sixteen subjects who had gout were


given febuxostat (80 mg once daily, titrated to 40 mg or 120 mg per day based

on serum urate and adverse events). The effects of febuxostat were sustainable,

with between 74% and 81% of subjects obtaining serum urate values less than

6.0 mg/dL at each visit during the 2-year analysis period [108].

In a phase III North American trial (United States and Canada), the serum

urate lowering efficacy and safety of febuxostat was compared with those of

allopurinol [62]. A total of 760 patients (96% men) was randomized to 52 weeks

of treatment with febuxostat (80 mg; n =256), febuxostat (120 mg; n =251), or

allopurinol (300 mg once daily; n = 253). The primary efficacy endpoint was the

percentage of patients reaching a serum urate level of less than 6.0 mg/dL at

the last 3 monthly visits. Significantly greater percentages of patients treated

with febuxostat (80 mg or 120 mg once daily) attained this primary endpoint

and maintained their last three serum urate levels of less than 6.0 mg/dL (53%

and 62%, respectively) compared with patients treated with allopurinol (21%)

(P b.001 for each febuxostat group versus allopurinol). A post hoc analysis of

the effect of serum urate levels on gout flare incidence shows that subjects who

achieved an average post-baseline serum urate level of less than 6.0 mg/dL had

fewer gout flares requiring treatment (6% versus 14%) and a greater median

reduction in tophus area (75% versus 50%) at week 52 compared with those who

did not, regardless of therapy. The most frequent treatment-related adverse

events with febuxostat were liver function abnormalities, diarrhea, headaches,

and joint-related or musculoskeletal and connective tissue signs and symptoms.

In another phase III study of febuxostat, 1067 subjects who had gout and

serum urate levels greater than or equal to 8.0 mg/dL were randomized in a

1:2:2:1:2 ratio to once-daily fixed dose of placebo, febuxostat (80 mg, 120 mg, or

240 mg), or allopurinol (100 mg per day for subjects who had renal impairment

or 300 mg per day for subjects who had normal renal function) for 28 weeks

[109]. At the end of the 28-week study, the percentages of subjects who met the

primary endpoint of last three serum urate values less than 6.0 mg/dL were 0%

among those treated with placebo, 48% in those treated with febuxostat (80 mg),

65% in those treated with febuxostat (120 mg), 69% in those treated with febu-

xostat (240 mg), and 22% in those treated with allopurinol. These percentages

were significantly higher in all febuxostat dose groups compared with placebo

or allopurinol (Pb.05). There were 40 subjects in this study who had moderate

to mild renal impairment. Between 44% and 60% of these subjects treated with

febuxostat achieved serum urate less than 6.0 mg/dL at each of the last three

visits compared with 0% treated with placebo or allopurinol. The rate of adverse

events was low and similar between those who had normal renal function and

those who had moderate impairment. The most frequent treatment-related adverse

events were similar to those in the previously reviewed phase III study [62].

There are three double-blind, multicenter, placebo- or allopurinol-controlled

trials conducted in Japan evaluating the efficacy and safety of febuxostat in

subjects who had gout or hyperuricemia (baseline serum urate �8.0 mg/dL)

[110–112]. These clinical trials used lower doses of febuxostat (10 mg, 20 mg,

and 40 mg) and were of shorter duration than the North American trials. The


dose of allopurinol also was lower, as the treatment regimen used 100 mg once or

twice daily. These studies show similar results to the North American trials,

with febuxostat having significantly greater reduction in serum urate compared

with placebo or allopurinol.

Rasburicase

Uric acid oxidase, or uricase, is an enzyme found in most mammals, but not

humans, that catalyzes the enzymatic oxidation of uric acid into the more

(10 times) water-soluble allantoin, which then is excreted easily. Rasburicase is a

recombinant uric acid oxidase made from Aspergillus flavus with a terminal

half-life of approximately 17 hours [113]. An intravenous formulation of rasbu-

ricase recently was approved by the United States Food and Drug Administration

for the initial management of plasma urate levels in pediatric patients who have

leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer

therapy expected to result in tumor lysis and subsequent elevation of plasma

urate [114].

The profound effects of rasburicase on serum urate suggest that it may be a

useful agent in the management of patients who have gout [92] and, as such, the

agent currently is under evaluation in gout clinical trials in the United States.

A recently published case [115] involving a 33-year-old allopurinol-intolerant

female patient who had an 8-year history of hyperuricemia, 8 to 12 acute attacks

of gout per year, and severe tophi reports that rasburicase (0.15 mg/kg), ad-

ministered intravenously every 2 weeks for 2 months and monthly thereafter,

decreased serum urate levels, eliminated gout recurrence, and decreased tophi

size substantially. Serum urate levels decreased from approximately 850 mmol

(1.43 mg/dL) at baseline to less than 50 mmol (0.08 mg/dL) during the first week

after therapy and increased steadily during the subsequent weeks to levels before

therapy during the first 6-month treatment period. Thereafter, and for the rest of

the 3 years of monthly rasburicase therapy, serum urate decreased from 850 mmol

(1.43 mg/dL) to 658 mmol (1.11 mg/dL). Rasburicase was well tolerated with the

patient having mild inflammation of multiple joints (symmetrically fingers,

knees, and feet) during the first 2 months and no side effects during the follow-

ing 3 years of treatment.

The viability of rasburicase as a therapeutic treatment option for those who

have gout likely is limited [10]. In addition to its limitation of only one course per

lifetime, its parenteral route of administration is an undesirable treatment mode,

especially given the options for oral agents. The profound and rapid effects that it

has on serum urate may be associated with an increased risk for acute gout flare.

Furthermore, because rasburicase is a foreign protein, there is a significant risk

for anaphylactoid reactions [113]. Despite the exclusion of patients who have a

history of significant atopic allergy or bronchial asthma in clinical studies,

antibodies to uricase still occurred in 7% to 14% of patients treated [116–118].

Cases of anaphylactoid reactions also are reported, resulting in the product

carrying a black box warning to that effect and for hemolysis and methemo-


globinemia, especially for patients who have glucose-6-phosphate dehydro-

genase deficiency.

Polyethylene glycol–uricase/uricase–polyethylene glycol 20

In an attempt to neutralize the immunogenicity issues associated with rasbu-

ricase, polyethylene glycol (PEG) has been added to the uricase compound [119].

PEG-uricase is described as a recombinant porcine urate oxidase to which mul-

tiple strands of PEG of average molecular weight of 10,000 are attached. In

addition to reducing the immunogenicity, the attachment of PEG greatly prolongs

the circulating half-life of the compound. This mammalian PEG-uricase is re-

ported to be nonimmunogenic and effective in preventing urate nephropathy in a

uricase-deficient strain of mice [120]; however, some subjects entered in a phase I

trial exhibited antibodies [121].

PEG-uricase is found effective in treating tumor lysis by maintaining a plasma

urate of 9.0 mg/dL in a patient who has non-Hodgkin’s lymphoma without

producing antibodies [122] and shows promise in the treatment of patients who

have hyperuricemia and gout [123]. As a result, PEG-uricase has received orphan

drug designation for the treatment of refractory gout by the FDA Office of

Orphan Products Development, and the developing company recently announced

completion of patient dosing in a phase II clinical trial [124]. In this phase II

study, subjects who have refractory gout are administered PEG-uricase (8 mg

by intravenous infusion) once every 3 weeks for a total of five infusions. The

primary measure of efficacy is a reduction in plasma urate to less than 6.0 mg/dL

and a reduction in the ratio of urate to creatinine in urine to less than 0.2. The

ability of PEG-uricase to lower the total urate pool size (measured using a method

involving an infusion of uric acid labeled with N15, a stable nonradioactive

isotope of nitrogen) will be evaluated in a subset of subjects [121].

Clinical trials of other agents with antihyperuricemic effect

Fenofibrate

Fenofibrate is a hypolipidemic fibric acid derivative used commonly that in-

creases the clearance of purine bases hypoxanthine, xanthine, and uric acid. The

results of several studies suggest that fenofibrate may be a useful adjuvant with

traditional antihyperuricemic therapy in selected patients who have gout (ie, those

who have hypertriglyceridemia), with its uricosuric effect independent of its

lipid-lowering efficacy. Case reports suggest that the reductions in serum urate

seen with fenofibrate range between 15% and 35% [10,125].

In a study of five healthy subjects, fenofibrate was administered (150 mg

three times daily for 3 days) with allopurinol (300 mg) given 4 hours after the

last dose [126]. A significant 46% (P b.05) reduction in urate from baseline

was observed. Takahashi and coworkers [127] assessed the effect of fenofibrate


(300 mg once daily; n=27) or losartan (50 mg once daily; n=25) in patients who

had gout receiving treatment with benzbromarone or allopurinol. After 2 months,

the addition of fenofibrate resulted in a statistically significant drop in serum

urate, although the effects were modest (approximately 15%) and less than that

observed in other studies. Feher and colleagues report that fenofibrate has a rapid

and reversible urate-lowering effect in patients who have hyperuricemia and

gout currently receiving allopurinol therapy [128]. Ten men ranging in age from

38 to 74 who had chronic tophaceous or recurrent gout were treated with allo-

purinol (300 to 900 mg daily) for at least 3 months and were given open-label

fenofibrate (200 mg) once daily for 3 weeks. At the 3- week visit, a significant

(P =0.004) 19% decrease in serum urate was observed (0.37 F 0.04 to 0.30 F0.02). Fenofibrate also produced a 36% increase in urate clearance (7.2 F 0.9 to

11.4 F 1.6; P =0.006) with no change in creatinine clearance. The effect on

serum urate was reversible, with levels returning to baseline within 3 weeks of

fenofibrate discontinuation.

Fenofibrate offers a modest decrease in serum urate compared with several

other agents; nonetheless, it may be considered a useful agent for patients who

have hyperlipidemia and gout. Its hypouricemic efficacy needs to be confirmed in

larger and longer-term studies [10,129].

Losartan

Losartan is an angiotensin II receptor antagonist that interferes with urate

reabsorption in the proximal tubule, thereby lowering serum urate. Like feno-

fibrate, the maximal serum urate-lowering effects of losartan (7% to 15%) seem

to be less than the effect achievable with standard dosing regimens of primary

uricosuric drugs, such as probenecid [92,130–132].

Two studies performed in patients post renal [132] or heart [133] transplan-

tation report significant reductions in serum urate. As discussed previously, the

use of losartan in combination with antihyperuricemic patients who have gout

may offer a modest additional decrease in serum urate in addition to its effects on

hypertension [127]. In the Losartan Intervention For Endpoint (LIFE) reduction

in hypertension study [134], the effect of losartan is compared with atenolol

(a b-blocker with no known effect on serum urate concentration) in patients who

were not hyperuricemic (mean serum urate of 5.5 mg/dL). The investigators note

that baseline serum urate is associated significantly with an increased rate of the

composite outcome of cardiovascular death, fatal or nonfatal myocardial in-

farction, fatal or nonfatal stroke in the entire study population (hazard ratio 1.024

[1.017–1.032] per 10 mmol/L [0.168 mg/dL]; P b.0001). The baseline-to-end-of-

study increase in serum urate was significantly greater in those treated with

atenolol versus those treated with losartan (44.4 mmol/L [0.075 mg/dL] versus

17.0 mmol/L [0.286 mg/dL]; P b.0001). Serum urate as a time-varying covariate

was associated strongly with cardiovascular events in the entire population

(P b.0001), and the contribution of serum urate to the treatment effect of losartan

on cardiovascular events was 29%. This finding suggests attenuating serum urate


not only may reduce gout recurrence but also, perhaps more importantly, may

reduce cardiovascular events in a population already at high risk [135–137].

Other early investigational antihyperuricemic agents

E3040, a new class of anti-inflammatory agents, was found to reduce the

plasma urate level in phase I clinical studies. Yamada and colleagues [138]

assessed the fractional excretion of urate in an animal model of hyperuricemia

and found E3040 to have uricosuric activity in the proximal tubules.

A series of 1-phenylpyrazoles demonstrate XO inhibitory activity in vitro

and in a rat model of hyperuricemia [139]. Of these, the compound 1-(3-cyano-

4-neopentyloxyphenyl)pyrazole-4-carboxylic acid (Y-700) has the most potent

enzyme inhibition. In a rat model of hyperuricemia, Y-700 shows a more potent

and longer-lasting hypouricemic action than allopurinol [140]. A single oral dose

of Y-700 (5 mg, 20 mg, or 80 mg) in healthy, male Japanese volunteers caused a

dose-dependent reduction of serum urate levels [140]. In a pharmacokinetic

analysis that also enrolled healthy, male Japanese volunteers [141], Y-700 was

absorbed orally rapidly and was eliminated with a half-life of between 23.5 and

40.2 hours. Urinary excretion was less than 1.5% at doses of 0.5 to 80 mg. This

suggests that Y-700 may be safe in patients who have renal failure. Higher

(120 mg) and repetitive doses (once daily for 10 days) also have been assessed

in male volunteers [142]. No serious adverse events are reported, although ab-

dominal cramps, abdominal pain, and flatulence occurred.

Intraperitoneal administration of scopoletin, an agent with uricolytic and

uricosuric effects, was found in a study of hyperuricemic mice to be a potent

uricosuric (at doses of 100 and 200 mg) and a weak uricolytic (at doses of 50,

100, and 200 mg) [143].

Summary

There are few clinical trials evaluating crystal arthropathy. These clinical trials

demonstrate, however, effective management of acute arthritis. Crystal arthrop-

athy requires identification of the crystal (monosodium urate monohydrate

[MSU], CPPD, or BCP) and the underlying cause for appropriate management.

For acute arthritis, therapies include NSAIDs, colchicine, or corticosteroids. Of

the three types of crystal arthropathies, only that of gout, or MSU deposition, has

effective therapies aimed at reversing the underlying cause of hyperuricemia.

Clinical trials in gout demonstrate effective urate-lowering therapies, including

the uricosuric, probenecid, and XO inhibitor, allopurinol. These clinical trials

indicate that XO inhibitors are the most effective in reducing serum urate in

chronic treatment of gout and work well in patients who are overproducers or

underexcretors of uric acid. Uricosuric agents are not as effective in patients who

have renal impairment. Newer agents, such as febuxostat, a nonpurine selective


inhibitor of XO, demonstrate effectiveness in reducing serum urate. In addition,

clinical trials indicate that other agents with antihyperuricemic effects, such as

fenofibrate and losartan, may be useful as adjuvant urate-lowering therapies in

those who have comorbid conditions of hypertriglyceridemia and hypertension,

respectively. Among the newer agents investigated, recombinant urate oxidase

and PEG-uricase work well for the management of hyperuricemia associated with

tumor lysis. Further studies are needed, however, to assess the risk of antigenicity

and their efficacy in the treatment of those who have hyperuricemia and gout.

Acknowledgments

The authors thank Susan Ruffalo, PharmD, of MedWrite (Newport Coast,

California), for her editorial support and consolidating and incorporating the

authors’ comments.

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Calcium Crystal Deposition Diseases:

Update on Pathogenesis and Manifestations

E.S. Molloy, MBa,T, G.M. McCarthy, MDb,c

aDepartment of Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation,

9500 Euclid Avenue, A50 Cleveland, OH 44195, USAbDepartment of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland,

123 St Stephen’s Green, Dublin 2, IrelandcDepartment of Rheumatology, Mater Misericordiae University Hospital, Eccles Street,

Dublin 7, Ireland

Basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPPD)

crystals are associated with several human diseases, especially various forms of

acute and chronic joint inflammation and joint degeneration. This article reviews

recent work that has advanced knowledge of the clinical syndromes associated

with calcium crystal deposition and the underlying mechanisms that may

contribute to these pathologic manifestations.

Basic calcium phosphate crystals

BCP crystals are composed predominantly of partially carbonate-substituted

hydroxyapatite and include octacalcium phosphate (OCP), tricalcium phosphate,

and magnesium whitlockite. BCP crystals are associated with several rheu-

matic syndromes, including acute calcific periarthritis, soft tissue calcification,

osteoarthritis (OA), and other degenerative arthropathies, such as Milwaukee

shoulder syndrome (MSS). Recently, they also have been linked to breast cancer

and atherosclerosis.

The key mechanisms whereby BCP crystals may cause tissue damage are (1)

induction of mitogenesis; (2) upregulation of matrix metalloproteinase (MMP)



T Corresponding author. Cleveland Clinic Foundation, Department of Rheumatic and Immuno-

logic Diseases, 9500 Euclid Avenue, A50, Cleveland, OH 44195.

E-mail address: [email protected] (E.S. Molloy).




molloy & mccarthy384

production; (3) stimulation of cyclooxygenase (COX) 1 and 2 and prostaglandin

E2 (PGE2) production; (4) stimulation of cytokine production, in particular

interleukin (IL) 1b; and (5) induction of nitric oxide (NO) production.

Pathogenesis

The degree of damage that can occur in apatite-associated destructive ar-

thropathies is marked. The basis of cartilage damage by calcium-containing

crystals still is somewhat speculative. Theoretically, crystals in cartilage may

injure chondrocytes directly. BCP crystals are shown to stimulate production of

MMP-1 and -13 from porcine chondrocytes [1] and NO production from bovine

chondrocytes [2], making in vivo pathologic interaction between these crystals

and chondrocytes feasible. In pathologic specimens, however, crystals rarely are

seen in immediate contact with chondrocytes and found engulfed by chondro-

cytes even less frequently. A significant contribution to BCP crystal-associated

cartilage damage ultimately may be derived from effects of these crystals on

synoviocytes (discussed later).

Basic calcium phosphate crystal-cell interaction

One of the earliest cellular effects of BCP crystals is a bimodal increase in

intracellular calcium ([Ca2+]i). Using the photoactive dye, fura-2, in a human

fibroblast model, Halverson and colleagues demonstrated that BCP crystals in-

duce a rapid tenfold increase in [Ca2+]i within seconds, returning to baseline

within 8 minutes [3]. As this increase was not apparent when BCP crystals were

added in calcium-free media, this immediate rise in [Ca2+]i was the result of

an influx predominantly of calcium from the extracellular space, not a release

of calcium from intracellular stores. A second increment in [Ca2+]i started at

60 minutes and continued to increase up to at least 3 hours after stimulation.

In contrast, epidermal growth factor induced the early transient rise of [Ca2+]ibut not the later sustained release. Increasing phagolysosomal pH by pretreat-

ment with ammonium chloride prevented crystal dissolution and abolished

the second rise in [Ca2+]i but had no effect on the early transient peak [3].

More recent work has further elucidated the mechanisms by which BCP crystals

can interact with cells [4]. Sun and coworkers evaluated the hypothesis that BCP

crystals could stimulate the influx of other molecules, such as DNA fragments and

small peptides from the extracellular space, and thus modulate normal molecular

signaling. Luciferase activity was enhanced greatly (500–1000-fold) in a dose-

dependent manner in cancer cell lines treated with a BCP crystal-cytomegalovirus

promoter (pCMV) luciferase plasmid mixture. The time course of luciferase

activity followed a pattern similar to the first, rapid, transient rise in [Ca2+]i that

occurs in response to BCP crystals. These effects of BCP crystals were inhibited by

several anticalcification agents, including etidronate and, in particular, phos-

phocitrate [4]. These results suggest that BCP crystals may stimulate the endo-

cytosis of various extracellular molecules, such as DNA fragments, nucleotides, or

calcium crystal deposition diseases 385

small peptides, that might exert important but as yet uncharacterized effects,

potentially contributing to the pathogenesis of BCP crystal-associated diseases.

Induction of mitogenesis

BCP crystals demonstrate a mitogenic effect in vitro in fibroblast cell lines and

osteoarthritic synovial fibroblasts [1,5], which may explain the synovial pro-

liferation seen in BCP crystal-associated degenerative arthropathies. Increased

cellularity in the synovial lining enhances the capacity for secretion of MMPs

and cytokines, which may promote chondrolysis. BCP crystals also enhance

survival of and induce DNA synthesis in murine macrophages in vitro [6].

Enhanced local macrophage survival or proliferation in the synovium also could

contribute to the synovial hypertrophy seen in association with BCP crystals.

It has been established that the mitogenic response to BCP crystals requires

endocytosis and intracellular crystal dissolution [7]. BCP crystals increase phos-

pholipase C (PLC) activity in synovial fibroblasts [8], which should result in

accumulation of diacylglycerol and enhanced protein kinase C (PKC) activity.

Mitchell and colleagues show that downregulation of PKC is associated with

inhibition of crystal-induced mitogenesis in Balb/c-3T3 fibroblasts [9]. Further

investigation of the molecular mechanisms behind the mitogenic response to BCP

crystals indicates a role for nuclear factor kB (NF-kB), PKC, and activator

protein 1 (AP-1) induction [10]. The PKC inhibitor, staurosporine, prevents BCP

crystal-induced NF-kB and c-fos messenger RNA (mRNA) expression and

mitogenesis but not c-jun mRNA upregulation. Although high-affinity receptor

protein tyrosine kinases with resultant recruitment and activation of phosphati-

dylinositol 3-kinase (PI3K) mediate the mitogenic response to other stimuli,

neither is required for BCP crystal-induced cell proliferation [10]. BCP crystals

activate extracellular signal-regulated kinase 1 and 2 (ERK1/2) but not the p38

mitogen-activated protein kinase (MAPK) pathway in human foreskin fibroblasts

(HFF) [11]. BCP crystals also cause phosphorylation of cyclic adenosine

monophosphate response element-binding protein (CREB) on serine 133, a step

critical to CREB’s activity as a nuclear transcription factor. C-fos activation is

believed to occur by a mechanism involving CREB phosphorylation. PD98059,

an inhibitor of MEK1, an upstream activator of the MAPK pathway, and U0126,

an inhibitor of MEK1/2, significantly inhibited crystal activation of p42/44

MAPK, CREB serine 133 phosphorylation, c-fos, and cell proliferation in a dose-

dependent fashion [11]. Zeng and colleagues describe the induction of early

growth response gene (Egr) 2 by BCP crystals, which could stimulate the

activities of several transcription factors that are associated with cell proliferation,

such as c-fos, serum response factor (SRF), and c-myc [12]. This upregulation of

Egr-2 is abrogated by U0126, a specific p44/p42 MAPK inhibitor, and TMB8, a

calcium chelator, but not by p38 MAPK or PKC inhibitors. BCP crystals also

may induce fibroblast mitogenesis via induction of Egr-1. Zeng and colleagues

demonstrate by reverse transcription polymerase chain reaction (RT-PCR) and

Egr-1 promoter analysis that BCP crystals induce Egr-1 transcription via a PKC-


a–dependent ERK1/2 MAPK pathway. Overexpression of Egr-1 stimulates

mitogenesis in a human fibroblast cell line [13].

Induction of matrix metalloproteinases production

MMPs are proteases that accelerate the degradation of cartilage matrix com-

ponents, such as type II collagen, fibronectin, laminin, and proteoglycan. BCP

crystals are shown to upregulate MMP-1, -3, -8, and -9 production from human

fibroblasts [14–17] and MMP-1 and -13 from porcine chondrocytes [1]. These

observations correlate with the detection of collagenase and neutral protease

activities in synovial fluid from patients who have MSS [18]. BCP crystals also

can downregulate the synthesis of tissue inhibitor of metalloproteinases (TIMP)

1 and 2 [19], which are capable of inhibiting the activities of all known MMPs.

This shifts the balance of MMP/TIMP activity further in favor of excess pro-

tease activity. It previously has been postulated that loss of coordinated regula-

tion of MMP/TIMP underlies the cartilage degradation in OA [20,21].

Although crystal endocytosis is necessary for BCP crystals to induce MMP-1

and MMP-3 synthesis, intralysosomal crystal dissolution is not, in contrast to the

requirement for both events to occur to obtain the maximal mitogenic response to

BCP crystals [22]. The collagenase subfamily of the MMPs includes MMP-1

(collagenase 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3). The col-

lagenase promoter contains a 12-O-tetradecanoyl-phorbol-13-acetate (TPA) re-

sponse element, the transcriptional activity of which depends on AP-1. AP-1 is a

heterodimer of the c-fos and c-jun proteins, which are known to be induced by

BCP crystals [16]. It also previously has been demonstrated that the ERK1/2

MAPK pathway is a key signal transduction pathway involved in crystal-induced

MMP-1 and -3 expression [23].

Recent studies have further characterized the molecular mechanisms involved in

BCP crystal induction of MMP production. Sun and coworkers [24] report that

human MMP-1 induction by BCP crystals is Ras dependent and involves multiple

elements, including AP-1 and polyomavirus enhancer activator 3 (PEA-3). AP-1

and PEA-3 are implicated in MMP-1 induction by phorbol ester, and their coop-

eration also is reported for other promoters. By transfecting canine synovial fibro-

blasts with human MMP-1 luciferase reporter plasmids, it is demonstrated that

the induction of MMP-1 promoter by BCP crystals is mediated largely through

the �72AP-1 element. Elimination of either the �72AP-1 or the �88PEA-3elements abolishes the hMMP-1 promoter activity in response to BCP crystals. It

also is shown that cotransfection of plasmids encoding dominant negative Ras,

Raf, and MEK1/2 can block BCP crystal induction of MMP-1 and that U0126, a

MEK1/2-specific inhibitor, abrogates BCP crystal MMP-1 and c-fos induction.

Plasmids encoding dominant negative Rac or Rho have no effect on MMP-1 up-

regulation. The investigators conclude that multiple elements, including AP-1 and

PEA-3, are involved in BCP crystal-induced MMP-1 gene expression and that the

induction follows the Ras/Raf/MAPK/c-fos/AP-1/MMP-1 signaling pathway [24].

Reuben and colleagues [25] demonstrate that BCP crystal stimulation of

MMP-1 and MMP-3 mRNA and protein expression in human fibroblasts is de-


pendent on the calcium-dependent PKC signal transduction pathway and also

show the specific involvement of the PKC-a isoenzyme. They also identified that

the calcium-dependent PKC pathway cooperates with the distinct calcium-

independent p44/p42 MAPK pathway, which is also activated by BCP crystals in

human fibroblasts. More recently, it has been demonstrated that activation of

ERK1/2 lies downstream of the calcium-independent PKC isoform, PKC-m, inBCP crystal-induced MMP-1 and -3 upregulation [26]. The investigators con-

clude that there are two independent but parallel pathways through which BCP

crystals activate fibroblasts, a calcium-dependent PKC-a–mediated pathway and

a calcium-independent pathway that involves sequential activation of PKC-m andERK1/2 MAPK.

Cytokine upregulation

Evidence is accumulating regarding the role of cytokines, such as trans-

forming growth factor-b1 (TGF-b1), IL-1b, and tumor necrosis factor a (TNF-a),in the pathogenesis of OA [27]. IL-1b is believed the key cytokine involved in

progression of OA, whereas TNF is involved at disease onset. TGF-b1 and IL-1bin particular are implicated in the regulation of crystal formation [28]. In turn,

BCP crystals can upregulate expression of various cytokines. BCP crystals are

shown to increase IL-1b expression in HFF [29] and in chondrocytes [2]. BCP

crystals also are shown to induce TNF-a mRNA expression and protein synthesis

in a murine monocyte cell line known to produce high levels of TNF-a, althoughthe capacity of BCP crystals to directly induce TNF-a and IL-1b in human

monocytes is weaker and less consistent than monosodium urate [30]. Aug-

mented proinflammatory cytokine (TNF-a, IL-1b and IL-8) mRNA expression

and protein secretion are detected in BCP crystal-stimulated monocyte-derived

macrophages in vitro [31]. PKC-a, ERK1/2, and c-jun N-terminal kinase (JNK)

activity are required for BCP crystal-induced TNF-a synthesis. PKC-a is an

upstream activator of ERK1/2 but not JNK. The precise contribution of cyto-

kine production in mediating the pathologic effects of BCP crystals requires

further clarification.

Increased prostaglandin production

Although the contribution of PGs to inflammation and nociception presum-

ably is the basis of the symptomatic benefit derived by OA patients taking

NSAIDs, the role of PGs in the pathophysiology of OA is not defined clearly.

Nevertheless, it is demonstrated that PGE2 mediates the IL-1b–induced cartilage

degradation in a synovial membrane-cartilage coculture model [32]. COX-2 ex-

pression is increased in the synovial blood vessels, lining cells, and fibroblast-like

cells in OA synovium [33]. COX-2 also is expressed in OA cartilage [33–35],

which releases PGE2 spontaneously in quantities 50-fold higher than normal

cartilage and 18-fold higher than normal cartilage in the presence of proinflam-

matory stimuli [35]. Knorth and colleagues, however, demonstrate that COX-1

may contribute to the pool of PGs in OA synovium [36].


It has been known for some time that BCP crystals can increase PGE2 pro-

duction in mammalian cells [14,37,38]. Only recently, however, has it been

demonstrated that this induction of PGE2 is associated with induction of both

COX isoforms in HFF [29]. Real-time PCR demonstrates a 23-fold upregula-

tion of COX-2 mRNA by BCP crystals, maximal at 4 hours. BCP crystals also

upregulate IL-1b mRNA expression peaking at 8 hours. Thus, although IL-1bmay contribute to the observed COX-2 upregulation, the different time courses of

induction suggest that BCP crystals induce COX-2 directly. Maximal (1.75-fold)

COX-1 mRNA induction is seen at 24 hours. Inhibition of PKC and PI3K

diminishes BCP crystal-induced COX-2 mRNA expression. BCP crystal-induced

COX-2 mRNA expression also is abrogated by phosphocitrate, which seems

to inhibit all biologic activities of BCP crystals. PGE2 production at 4 hours

is abolished by pretreatment with NS398, a selective COX-2 inhibitor. NS398,

however, only partially inhibits PGE2 production at 30 hours, suggesting that

COX-1 also contributes to BCP crystal-induced PGE2 production in human fi-

broblasts [29].

Increased nitric oxide production

NO is a pleiotropic mediator that is implicated in structural damage to OA

cartilage [39]. NO is generated by oxidation of arginine, catalyzed by the NO

synthases (NOS). One inducible NOS (iNOS) and two constitutive NOS are

identified. iNOS expression is upregulated in human OA cartilage [40]. Selective

inhibition of iNOS in a canine OA model results in reductions in MMP synthesis,

IL-1b expression, PGE2 production, chondrocyte apoptosis, and amelioration

of structural damage [41–44]. NO also is implicated in chondrocyte apoptosis,

which can in turn promote the formation of calcium-containing crystals [45].

Ea and coworkers find that OCP induces NO production and upregulated

iNOS expression in bovine chondrocytes [2]. This is mediated by activation of

p38 MAPK and JNK pathway by OCP, most likely under the control of AP-1.

Although OCP crystals also upregulate IL-1b expression, the induction of iNOS

expression and NO production is independent of IL-1b. Their study identified

another potential mechanism whereby BCP crystals can damage cartilage. Other

work suggests that BCP crystals induce iNOS and increase NO production

in OA synovial fibroblasts [46]. The involvement of NO production in BCP

crystal-induced MMP synthesis, IL-1b expression, and PGE2 production is

not elucidated but is of considerable interest as it would confirm the potential

of iNOS as an attractive therapeutic target in BCP crystal-associated arthritis.

Clinical manifestations of basic calcium phosphate crystal deposition

Intra-articular basic calcium phosphate deposition

The understanding of the exact relationship between intra-articular BCP

crystals and joint pathology is incomplete, especially because specialized tech-

niques are required to identify the crystals. Nonetheless, existing data support the

pathogenic role of BCP crystals in articular tissue degeneration. Intra-articular


BCP crystal deposition is associated with OA and MSS and with acute synovi-

tis and chronic arthritis, including erosive OA. The prevalence of intra-articular

BCP crystal deposition is not established. Apatite crystals are found in up to

67% of synovial fluid samples from patients who have knee joint OA [47–50].

BCP and CPPD crystals may coexist in 16% of OA synovial fluids [49]. BCP

crystals are found in 23% at first aspiration, but in 58% at the final aspiration

(at a mean interval of 3.6 F 1.6 years), suggesting that BCP crystals are gen-

erated as part of the pathologic process in OA [49]. The prevalence in normal

joints at different ages is not known. MSS and related BCP crystal-associated

destructive arthropathies also are of unknown prevalence.

OA is the most common form of arthritis and its prevalence is expected to

rise considerably as the population ages. It is the foremost cause of disability in

the elderly population, disabling approximately 10% of those over age 60 [51].

Estimates of the annual cost of OA to the United States economy exceed

$60 billion [51]. Concurrence of BCP crystals and OA is well established.

Crystals of BCP frequently are found in OA cartilage, synovium, and synovial

fluid. It is suggested that many OA joint fluids contain clusters of BCP crystals

that are too small or too few in number to be identified by conventional tech-

niques [50]. Ample data support the role of BCP crystals in cartilage degen-

eration, as their presence correlates strongly with severity of radiographic OA

[49,52], and larger joint effusions are seen in affected knee joints when com-

pared with joint fluid from OA knees without crystals [53].

MSS, a distinctive type of destructive arthropathy found in elderly patients, is

prototypic of BCP crystal-associated joint degeneration [54–56]. It is associated

with rotator cuff defects and numerous aggregates of BCP crystals in the fluids of

affected joints [55]. Although the shoulder predominates, knees, hips, elbows,

and other joints may be involved [54]. Joint effusion typically is present and may

be massive, extending into the subdeltoid region. Aspiration of affected shoul-

der joints routinely yields 3 to 160 mL of synovial fluid that frequently is blood

tinged and has a low, predominantly mononuclear, cell count. Rupture of the

effusion can lead to a massive extravasation of blood and synovial fluid into

the surrounding tissues [57]. The natural history of the condition is unclear, but

many cases seem to stabilize after a year or 2, with reduction of symptoms, joint

effusions, and no further radiographic changes. A kindred of five generations

affected with familial OA and MSS recently was described [58]. Twenty-eight

patients had varying degrees of upward subluxation of the humeral head. Of these

28 patients, seven had MSS. The mild to moderate upward subluxation of the

glenohumeral head observed in 22 remaining affected family members is be-

lieved possibly a precursor to the development of MSS.

Extra-articular basic calcium phosphate deposition

BCP crystals may form periarticular deposits that frequently are asymptom-

atic or give rise to acute calcific periarthritis or chronic calcific tendonitis. BCP

crystals also may be deposited in the soft tissues secondary to other diseases,

such as chronic renal failure, connective tissue diseases (in particular derma-


tomyositis and scleroderma), and chronic neurologic conditions. Idiopathic BCP

crystal deposition (or CPPD crystal deposition) also can occur, giving rise to

’’tumoral calcinosis,’’ or ligamentous calcification. When the latter surrounds the

odontoid process, it is termed the ‘‘dcrowded dens’’ syndrome.

There are few systematic studies of the incidence or prevalence of juxta-

articular deposits of BCP crystals. These deposits often are asymptomatic and

noted most commonly by chance on radiographs taken for other reasons. In a

large study of office workers published in 1941, a 2.7% prevalence of shoulder

deposits was noted in a North American, predominantly white, population, 34%

to 45% of which were associated with clinical problems [59]. Women were

affected more commonly than men and the prevalence was highest in those

between ages 31 and 40 (19.5%).

Pathologic assessments show that the calcific deposits are located in tendons,

peritendinous tissues, bursae, or ligaments. It is suggested that ‘‘dystrophic’’ ten-

don calcification occurs as a consequence of local trauma, ischemia, and ne-

crosis of tendons. Calcific periarthritis frequently localizes to the supraspinatus

tendon in a poorly vascularized area of the tendon sheath known as the critical

zone, a few millimeters from the bone insertion. Similarly, calcification in other

tendons seems to occur preferentially in hypovascular segments, suggesting local

necrosis followed by ectopic calcification.

Other evidence indicates that calcifying tendinitis is an active, cell-mediated

process in which local vascular and mechanical changes result in focal trans-

formation of tendinous tissues into fibrocartilaginous material containing chon-

drocytes. This is followed by local deposition of hydroxyapatite crystals within

extracellular matrix vesicle-like structures derived from these chondrocytes [60].

The most striking clinical presentation of juxta-articular BCP crystal deposits

is acute calcific periarthritis [61,62]. It most commonly involves the shoulder

but can occur at any joint. Calcific periarthritis is reported in children as young

as 3 but seems uncommon in the elderly. This suggests that many of the deposits

seen in young adults disappear spontaneously. Acute calcific periarthritis seems

to be induced by rupture of the deposit, possibly exposing the crystals to phago-

cytes. BCP crystals are shown to be intrinsically phlogistic. They are phago-

cytosed in vitro resulting in the release of inflammatory mediators [63]. Similarly,

in vivo models of inflammation show a brisk inflammatory reaction to apatite,

and injection into the tissues of human volunteers results in an inflammatory

response [64]. Phagocytosis may be one of the main ways in which the crystals

are removed.

Calcific deposits in the periarticular tissues also are associated with chronic

pain syndromes. In the shoulder, however, because chronic shoulder pain and

calcification are common and because prior damage to tendons may predispose to

the calcification, it is difficult to define what contribution, if any, the deposits

themselves make to the clinical findings. In some patients, recurrent acute attacks

around the shoulder, separated by pain-free periods of months or years, are fol-

lowed by the development of chronic pain. Damage to the tendons and muscles

of the rotator cuff may result and may lead to total disruption of the cuff apparatus.


Basic calcium phosphate crystal deposition in other diseases

Although BCP crystals long have been implicated in the pathogenesis of

several rheumatic syndromes, recent work has elucidated their potential in-

volvement in other diseases, including atherosclerosis and breast cancer. Arte-

rial intimal calcification is a common clinical and pathologic finding in patients

who have atherosclerosis [65] and the degree of intimal calcification has prog-

nostic significance [66,67]. Hydroxyapatite is the major constituent of the cal-

cific deposits seen in atherosclerotic vessels. Bostrom and colleagues describe a

microvascular pericyte-like cell that could undergo osteoblastic differentiation

under certain in vitro conditions in normal and diseased arteries [68]. These

calcifying vascular cells, as they were termed, localized to areas with increased

expression of bone morphogenetic protein 2, a potent osteogenic factor. Vascu-

lar smooth muscle cells (VSMCs) also may undergo osteoblastic differentiation.

Chondrocytes and osteoclasts also are identified in arterial tissue [69]. As these

osteoblasts and chondrocytes have the potential to generate matrix vesicles and

promote tissue calcification, the process of arterial calcification may be an active

cell-mediated process analogous to the deposition of hydroxyapatite in bone and

in articular tissues in BCP crystal-associated joint disease.

Macrophages play a key role in plaque development and rupture [70]. It has

been demonstrated that macrophages colocalize with hydroxyapatite particles in

the atheromatous plaque [65]. Recent work by Nadra and colleagues implicates

BCP crystals in the pathophysiology of atherosclerosis [31]. Engulfment of BCP

crystals by monocyte-derived macrophages results in secretion of TNF-a, IL-1b,and IL-8. Involvement of PKC, ERK1/2, and JNK pathways in BCP crystal-

induced TNF-a production is demonstrated. The supernatants from BCP crystal-

stimulated macrophages activate endothelial cells in vitro as assessed by flow

cytometry measuring adhesion molecule expression and promotion of leukocyte

rolling and adhesion as visualized in a flow chamber. These data suggest that

BCP crystals within the atherosclerotic lesion, through their interaction with in-

timal macrophages, likely act as an inflammatory nidus by activating endothe-

lial cells and promoting inflammation. Other potential, but unproved, effects

of BCP crystals within atherosclerotic plaque include increase in plaque insta-

bility via induction of MMPs or, possibly, by TNF-a–mediated VSMC apoptosis.

The consequent production of TNF-a could promote smooth muscle cell

osteoblastic differentiation, thus increasing hydroxyapatite deposition and es-

tablishing a vicious circle of events within the vessel wall, which could explain

the observed positive correlation between coronary arterial calcification and car-

diovascular events.

Radiographic mammary microcalcifications are one of the most pertinent

diagnostic markers of breast cancer. Breast tissue calcification in the form of

hydroxyapatite is associated strongly with malignancy [71] and with poorer out-

comes compared with patients who do not have mammographic calcification

[72,73]. Morgan and coworkers demonstrate that BCP crystals augment mito-

genesis in breast cancer cell lines MCF7 and Hs578T and in normal human

mammary epithelial cells [74]. Treatment with bafilomycin A1, a proton pump


ATPase inhibitor, diminishes BCP-induced mitogenesis to control levels [75],

suggesting endocytosis and intracellular crystal dissolution are required for

BCP-induced mitogenesis. BCP crystals also stimulated production of MMP-1

in Hs578T cells; MMP-2, -9, and -13 in MCF7 cells; and MMP-9 in human

mammary epithelial cell lines [75]. MMPs can facilitate invasion and metasta-

sis of tumor cells by degrading connective tissue matrix components, including

basement membranes. Furthermore, BCP crystals enhanced PGE2 levels in

Hs578T cells considerably, which was attributable at least in part to upregulation

of COX-2 and can be prevented by pretreatment with aspirin [75]. Moreover,

high levels of PGE2 often are associated with estrogen-receptor negative tumors

that exhibit a high metastatic potential [76]. IL-1b, which can upregulate MMP-1

gene expression and PGE2 production in human cells, is induced potently by

BCP crystals at 2 and 4 hours. Treatment with phosphocitrate block BCP crystal-

induced mitogenesis and COX-2, MMP-1, and IL-1b induction at the tran-

scriptional level [75]. These results suggest that BCP crystals contained in

mammary microcalcifications are not an innocent bystander and may aggravate

the pathologic process of breast cancer.

Calcium pyrophosphate dihydrate crystals

Pathogenesis

CPPD crystals have several in vitro properties in common with BCP crystals,

such as induction of proto-oncogenes, mitogenesis, and MMP production, that

may contribute to joint degeneration. In addition, the ability of CPPD crystals to

upregulate production of IL-8, a potent neutrophil chemoattractant, and to ac-

tivate neutrophils, with a resultant release of reactive oxygen species and de-

granulation, underlies the acute inflammation of pseudogout. CPPD crystals

increase synovial neutrophil numbers not only by cellular recruitment but also by

inhibiting neutrophil apoptosis.

Calcium pyrophosphate dihydrate crystals crystals bind Toll-like receptors

Toll-like receptors (TLRs) are the human homologs of a family of receptors

with roles in host defense and inflammation that are widespread throughout

nature. Eleven TLRs are identified, which share a cytosolic Toll/IL-1 receptor

(TIR) domain that also is found in members of the IL-1 receptor family and an

extracellular leucine-rich repeat region that mediates ligand recognition [77].

TLR1, -2, -4, -5, and -6 are localized to the plasma membrane, whereas the others

are expressed preferentially in intracellular compartments, such as endosomes.

TLRs are not restricted to the site of preferential expression; for example, TLR2

is found to localize to phagosomes after exposure to certain microbial products.

Recognition of microbial components, for example lipopolysaccharide (mainly

TLR4) and peptidoglycan (TLR2), triggers the initial innate immune response

that leads ultimately to inflammatory gene expression and clearance of the


infectious agent [78]. Several nonbacterial ligands, however, are identified for

certain TLRs, such as fatty acids, fibronectin, and hyaluronic acid [79,80]. The

TIR domain transduces upregulation of proinflammatory genes through acti-

vation of NFkB. Cytosolic proteins, known as adaptor molecules (eg, MyD88,

Mal), couple TLRs through the TIR domain to downstream signaling pathways

and activation of transcription factors [77].

Certain TLRs are expressed in normal and rheumatoid arthritis synovial fi-

broblasts [81–83], indicating the potential for innate immune responses to be

driven by mesenchyme-derived cells in arthritis. A novel study by Liu-Bryan and

coworkers investigates the potential role of TLR2 in CPPD crystal-induced NO

production in chondrocytes [84]. TLR2 is expressed constitutively in chondro-

cytes and upregulated in articular cartilage in OA. This study demonstrates that

CPPD crystals use TLR2-mediated signaling to initiate NO production in chon-

drocytes. These results indicate that innate immunity may contribute to inflam-

mation and cartilage degradation in pseudogout.

Neutrophil chemotaxis

In addition to a direct chemotactic effect, IL-8 also can enhance neutrophil

chemotaxis by stimulating production of other chemotactic factors (eg, leu-

kotriene B4 and platelet activating factor) by activated neutrophils [85]. IL-8 also

can promote neutrophil recruitment by enhancing neutrophil-endothelial cell

adhesion by upregulation of neutrophil integrins [86]. Furthermore, IL-8 can

augment neutrophil activation and protease release [85]. Thus, IL-8 can play a

key role in the generation of the acute inflammation typical of pseudogout and

also may contribute to matrix degradation in CPPD crystal-associated arthritis.

Liu and colleagues [87] have explored the signal transduction pathways involved

in CPPD crystal-induced IL-8 expression in human monocytic cells. CPPD

crystals induce activation of JNK, ERK1/2, and p38 MAPK pathways. CPPD

crystal induction of the IL-8 promoter is mediated through ERK1/2 signaling and

requires NF-kB complex c-Rel/RelA and AP-1 transcriptional activity. NF–IL-6

is involved to a lesser degree. Activation of the p38 MAPK pathway modulates

AP-1 binding to the IL-8 promoter in response to CPPD crystals, although the

downstream effectors of this response remain to be elucidated. Upregulation

of expression of certain genes that can promote IL-8 expression, such as IL-1,

TNF-a, and COX-2, may play a role given that p38 MAPK inhibitors can sup-

press these responses in CPPD crystal-stimulated cells. The significance of

activation of the JNK pathway by CPPD crystals in this study is not certain at this

time, but this cascade may participate in regulation of activation of AP-1, NF-kB,and NF–IL-6.

Neutrophil activation

Tudan and colleagues demonstrate that CPPD crystal-induced neutrophil

oxidative and degranulation responses are mediated via PKC, PLC (probably

the PLC g2 isoform), and PI3K/Akt pathways [73,88–90]. They also note an

association between ERK1/2 and neutrophil activation that is PI3K independent.


Full inhibition of any of these pathways, however, results in only a partial

suppression of CPPD crystal-induced neutrophil activation not exceeding 50%

inhibition. Most recently, they examined the role of p38 MAPK in CPPD crystal-

induced neutrophil responses [91]. CPPD crystal-induction of p38 MAPK also is

only partly responsible for the neutrophil oxidative and degranulation response,

as evidenced by the reduction by approximately 50% of CPPD crystal-induced

superoxide anion generation and myeloperoxidase and lysozyme release after

pretreatment with SB203580, a specific p38 MAPK inhibitor.

Inhibition of neutrophil apoptosis

Neutrophils generally have short lifetimes of less than 24 hours, after which

they undergo apoptosis facilitating their clearance by other phagocytic cells,

typically macrophages. A significant delay in apoptosis and clearance may lead to

excessive accumulation and tissue damage by prolonging neutrophil responses to

the inflammatory stimulus. In the study by Tudan and colleagues [91], CPPD

crystals induces a twofold transient increase in p38 phosphotransferase kinase

activity above basal levels but suppressed the TNF-a–associated sixfold in-

duction of p38 activity to levels seen with CPPD stimulation alone. This modu-

latory effect of CPPD crystals seems to reduce p38 MAPK activity below a

threshold level required to induce apoptosis in neutrophils. This probably occurs

via the inhibition of caspase 3, previously noted to be involved in CPPD crystal-

induced repression of TNF-a–induced neutrophil apoptosis [92]. Furthermore,

CPPD crystal-related suppression of TNF-a–induced caspase 3 activation and

neutrophil apoptosis is abrogated by inhibition of the MEK1/2-ERK1/2 or

PI3K/Akt pathways.

Effects on chondrocytes and osteoblasts

The deposition of monosodium urate (MSU) crystals in the joint can promote

not only acute inflammation but also chronic inflammation that may result in

cartilage damage and bony erosions. Bouchard and coworkers examined the

interaction between CPPD crystals and human osteoblastic cells in vitro [93].

CPPD crystals adhered to and were phagocytosed partly by the cells and stim-

ulated COX-2, PGE2, IL-6, and IL-8 production. They also diminished the 1,25

dihydroxycholecalciferol-induced activity of alkaline phosphatase and osteocal-

cin. Thus, CPPD crystals can alter the phenotype of these cells, potentially reduc-

ing the anabolic effect of osteoblasts on bone, which may contribute to damage

to juxtaarticular bone in crystal-associated arthritis.

Clinical manifestations of CPPD crystal deposition

Although there is some overlap, CPPD crystals differ from BCP crystals in

spectrum of their clinical manifestations, despite their frequent coexistence within

articular tissues. The most frequent manifestation of CPPD deposition is chon-

drocalcinosis, the asymptomatic radiographic finding of calcification of articular

or fibrocartilage. CPPD deposition is associated with attacks of acute pseudo-


gout, characterized by joint effusions with marked neutrophilia and a form of

secondary OA (pyrophosphate arthropathy) with a pattern of joint involve-

ment that differs from primary OA. The latter most commonly involves the knee

followed by the wrists, metacarpophalangeal joints, hips, shoulders, elbows, and

ankles. CPPD crystals, however, also may be found in the synovial fluids of

patients who have primary OA, either alone or in association with BCP crys-

tals [49,50]. CPPD also, more rarely, may present with a pseudorheumatoid or

pseudoankylosing spondylitis pattern or may mimic neuropathic arthropathy.

Tenosynovitis also is reported and is associated with tendon rupture [94]. Soft-

tissue CPPD deposits may present as tumor-like masses, analogous to the tumoral

calcinosis of BCP crystals, including presentation as the crowded dens syn-

drome [95]. These lesions may present with severe neurologic symptoms [96,97].

Yamakawa and colleagues describe five cases of tumoral CPPD deposition and

review the 54 case reports in the literature [98]. They propose that these patients

can be divided into two broad categories based on the location of the deposit:

central (head and neck) and distal (extremity). The most notable difference

between these groups was the differing modes of presentation. The central de-

posits presented most frequently with a painful mass (46%) or neurologic dis-

turbance (33%), whereas the distal type generally presented with a painless mass

or swelling (57%) or an acute attack with a picture resembling tophaceous gout

(38%). There was a histologic finding of chondroid metaplasia within and around

these lesions, as CPPD crystals can be generated within this metaplastic cartilage

analogous to the postulated mechanism in articular cartilage.

Summary

BCP and CPPD crystals are associated with distinct clinical syndromes. Al-

though there are some similarities in the cellular responses to these crystals,

specific effects of each crystal type are reported that may explain their differing

clinical presentations. Advances have been made in the understanding of the

pathophysiology of crystal-associated diseases, which may in the future be trans-

lated into effective treatments for these disorders.

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Calcium Crystal Deposition and Osteoarthritis

Ann K. Rosenthal, MDa,b,TaDivision of Rheumatology, Department of Medicine, Medical College of Wisconsin,

Milwaukee, WI, USAbZablocki VA Medical Center, Milwaukee, WI, USA

Articular calcium crystal deposition diseases and osteoarthritis are highly

prevalent conditions in elderly populations. Calcium pyrophosphate dihydrate

(CPPD) and basic calcium phosphate (BCP) crystals are the two most common

forms of pathologically relevant calcium crystals in articular tissues. Although

the relationship between calcium crystal deposition diseases and osteoarthritis

remains somewhat controversial, it is unlikely that chance explains the coexis-

tence of these two processes. Good evidence from the clinic and laboratory

suggests that the presence of one of these pathologic processes influences the

development of the other. This article reviews some background about calcium

crystals and summarizes the evidence that they are biologically active particles

that develop in the setting of cartilage damage and contribute to osteoarthritis.

Hopefully, further study of the complex factors involved in the pathogenesis of

calcium crystal deposition disease and osteoarthritis will lead to better treatments

for the many causes of cartilage degeneration.

Calcium pyrophosphate dihydrate crystals

CPPD crystals occur commonly in articular hyaline and fibrocartilage in

persons over age 60 [1]. They are visible under polarizing light microscopy in



This work was supported by a Merit Review grant from the Department of Veterans Affairs and

Grants AG015337 and AR052615 from the National Institutes of Health.

T Rheumatology Section, CC-111W, Zablocki VA Medical Center, 5000 West National Avenue,

Milwaukee, WI 53295-1000.





rosenthal402

synovial fluids of affected joints as positively birefringent rhomboid particles.

They can be identified radiographically as dense linear cartilage calcifications,

known as chondrocalcinosis. CPPD crystals initially were recognized as patho-

gens in patients who had gout-like arthritis and who had uricase-resistant intra-

articular crystals [2]. Almost simultaneously, CPPD crystal deposits were

described in a family that had early onset of osteoarthritis-like joint pathology [3].

This dual description accurately predicts the heterogeneity of the clinical

settings in which CPPD crystals are found. The most common clinical presen-

tation of CPPD crystal deposition is as a chronic degenerative arthritis [4]. The

presence of significant cartilage degeneration in unusual locations, such as the

metacarpal-phalangeal joints or wrist, and certain radiographic features [5]

suggest the presence of articular CPPD crystals. Less commonly, CPPD crystals

cause an acute monoarticular arthritis, known as pseudogout, or a more diffuse

inflammatory syndrome similar to rheumatoid arthritis. In addition, some patients

who have chronic degenerative arthritis associated with CPPD crystals describe

acute attacks of inflammation. CPPD crystals also can be found in asymptomatic

joints and in association with neuropathic arthritis [6].

The prevalence of CPPD crystal deposition in the population remains uncer-

tain. Many studies exploring the epidemiology of CPPD crystal disease use

radiographic chondrocalcinosis as a diagnostic criterion. This finding may either

underestimate or overestimate clinically relevant CPPD crystal deposition [7].

Chondrocalcinosis often is not visible in severely damaged or small joints or with

certain radiographic techniques, such as standing knee films. Recent evidence

confirms these findings, showing that ultrasonography can identify CPPD de-

posits too small to be visible on plain radiographs [8]. Nonetheless, the best

estimates rely on these studies. Data from the Framingham study demonstrate an

8% prevalence of knee chondrocalcinosis in people ages 63 to 93. Rates increase

to 27% when only people over 85 are included [9], and higher rates are seen in

hospitalized patients [10]. In the few studies in which articular tissues were

examined directly for CPPD crystals, or when only osteoarthritic joints are in-

cluded, much higher rates are described. For example, Sokoloff and Varma show

that 52% of osteoarthritis patients over age 75 had CPPD crystals in articular

tissue specimens [11]. Twenty-five to 33% of synovial fluids from patients who

had osteoarthritis contained CPPD crystals at the time of joint replacement for

osteoarthritis (Fig. 1) [12,13].

CPPD deposition can be categorized as sporadic (idiopathic), familial, or

metabolic. The vast majority of cases are sporadic. For sporadic CPPD deposition

disease, age is the best characterized and strongest risk factor. Clinically evident

sporadic CPPD deposition is rare under age 60. Prior injury, in particular menis-

cal damage in the knee, also predisposes to CPPD deposition [14]. As discussed

previously, osteoarthritis significantly increases the risk for CPPD crystal deposi-

tion [11]. Premature CPPD crystal deposition may be familial or metabolic. There

are a handful of metabolic syndromes that clearly promote CPPD crystal depo-

sition. The strongest associations are with gout, hyperparathyroidism, hemo-

chromatosis, hypophosphatasia, and hypomagnesemia [15,16].

Fig. 1. Frequency of BCP and CPPD crystals in synovial fluids from patients who have osteoarthritis.

(Black bars represent data from Nalbant S, Martinez J, Kitumnuaypong T, et al. Synovial fluid

features and their relations to osteoarthritis severity: new findings from sequential studies.

Osteoarthritis Cartilage 2003;11:50–4. Hatched bars represent data from Derfus B, Kurian J,

Butler J, et al. The high prevalence of pathologic calcium crystals in pre-operative knees. J Rheumatol

2002;29:570–4.)

calcium crystal deposition and osteoarthritis 403

Although the cause of CPPD deposition disease is not known, the current

paradigm of crystal formation in cartilage involves multiple participants. Chon-

drocytes near CPPD crystal deposits are abnormally large and share some

characteristics with the hypertrophic chondrocytes responsible for matrix

mineralization in growth plate cartilage [17,18]. Overproduction of inorganic

pyrophosphate, the anionic component of CPPD crystals [19,20], is a key feature

of these chondrocytes. Excess pyrophosphate production may be related to

abnormalities of the recently described ANK protein, a putative pyrophosphate

transporter [21]. Mutations in the ANK protein are linked to some cases of

familial CPPD crystal deposition disease [22]. Excess extracellular inorganic

pyrophosphate produced by chondrocytes complexes with ambient calcium

to form crystals. There also is increasing evidence that alterations in cartilage

extracellular matrix facilitate CPPD crystal formation. These include loss of

pericellular proteoglycans, collagen fibril disruption, and increased concentra-

tions of some matricellular proteins [23]. In addition, extracellular matrix changes

likely promote the activity of extracellular organelles, known as matrix vesicles

[24]. These small membrane-bound, chondrocyte-derived vesicles act as sites for

nucleation and growth of crystals in cartilage matrix [25].

Basic calcium phosphate crystals

BCP crystals include partially carbonate-substituted hydroxyapatite, octacal-

cium phosphate, and tricalcium phosphate. These crystals comprise calcium and

inorganic phosphate and often are referred to as hydroxyapatite because of their

chemical similarity to the normal calcium phosphate mineral found in bones and

rosenthal404

teeth. They are not visible under light or polarizing light microscopy, and, cur-

rently, there are no readily available tests for bedside identification. BCP crystals

are visible under light microscopy with alizarin red staining, but unfortunately,

this dye also binds to other calcium-containing particulates [26]. von Kossa’s

stain can be used to identify BCP crystals in tissues. For research purposes, a

semiquantitative radioactive binding assay based on the ability of BCP crystals to

bind to bisphosphonates is used [27]. Unfortunately, highly accurate techniques,

such as x-ray diffraction and Fourier transform infrared spectrophotometry, are

expensive, require large volume samples, and have limited practical use [26].

Like CPPD crystals, articular BCP crystals occur in a wide range of clinical

settings. The clinical syndromes associated with BCP crystals frequently are

misdiagnosed [28] and, lacking good diagnostic techniques, are significantly

under-recognized. When BCP crystals are found in joints, they are associated

with a severe destructive degenerative arthritis, often affecting large joints [29].

In its full-blown form, this is known as Milwaukee shoulder syndrome [30,31].

Milwaukee shoulder syndrome typically affects elderly women. They have pain,

stiffness, and loss of motion of the shoulder. Knees may be affected similarly. On

physical examination, large cool effusions often are noted. Radiographs confirm

the diagnosis by demonstrating severe rotator cuff thinning, loose bodies, and

extensive bone destruction. Synovial fluids show little evidence of inflammation,

with low white blood cell counts and high levels of active proteases [32,33]. In its

less extreme form, BCP crystals occur in the synovial fluids of 40% to 70% of

patients who have clinical osteoarthritis, where they are markers for severe joint

degeneration (see Fig. 1) [12,13]. BCP crystal deposits also are clinically signifi-

cant when they occur periarticularly. Around the shoulder, they cause the com-

mon clinical syndrome known as calcifying tendonitis. When deposits occur near

the small joints of the hands and feet, they can cause an acute inflammatory

periarthritis [34]. These young, often female, patients present with acute pain,

swelling, and redness around a finger or toe associated with flecks of soft tissue

calcium on radiographs [34].

The lack of a good clinical test for BCP crystals limits knowledge of the

prevalence of BCP-associated syndromes. Intra-articular BCP crystals almost

invariably are associated with advanced age and worsening radiographic grade of

degenerative arthritis [13,35]. Clinical syndromes associated with BCP crystals

seem slightly more common in women. Other possible risk factors for intrarticu-

lar BCP crystals include CPPD deposition disease, trauma, chronic renal failure,

and neurologic abnormalities involving the affected joint [31]. In contrast, syn-

dromes associated with periarticular BCP crystals have a different population

distribution. The incidence of calcifying tendonitis, for example, peaks at 30 to

60 years of age [36].

Less is known about the genesis of BCP than CPPD crystals. They are cer-

tainly less stringently associated with cartilage than CPPD crystals and are found

commonly in skin, soft tissues, and blood vessels. There is some support for the

hypothesis that they develop at sites of cartilage metaplasia, even in noncartilage

containing tissues [37]. Matrix vesicles, similar to those responsible for CPPD


crystal formation, likely participate in BCP crystal formation [38]. Histologic

studies demonstrate the presence of matrix vesicles near BCP crystals deposits in

tendon [38] and cartilage [39]. Isolated matrix vesicles from osteoarthritic car-

tilage can generate BCP crystals in vitro [24]. Ample evidence also supports a

role for disruption of the normal extracellular matrix at sites of BCP crystal

formation [38,40].

Mixed calcium crystal deposition

Although there are some conditions that clearly are associated with one or the

other of the pathogenic calcium crystals, these crystals often coexist in a single

patient [12,13]. Indeed, the presence of both CPPD and BCP crystals in a single

joint is not uncommon [41]. A familial form of calcium crystal deposition in

which CPPD and BCP crystals coexist also recently has been reported [42].

Relationship between crystals and osteoarthritis

There are clear and important differences between CPPD and BCP crystals in

terms of their associated clinical patterns and etiologies. There is a paucity of

studies, however, examining their role in osteoarthritis. For purposes of effi-

ciently discussing the relationship between calcium crystals and osteoarthritis,

CPPD and BCP crystals considered together. Two potential hypotheses are ex-

plored. First, the evidence is considered that calcium crystals cause or worsen os-

teoarthritis. Second, the opposite hypothesis, that osteoarthritis causes or worsens

calcium crystal deposition, is considered. These two hypotheses are not mutually

exclusive and it is likely that elements from both are true.

Evidence that calcium crystals cause or worsen osteoarthritis

Clinical evidence

Most evidence supporting the hypothesis that calcium crystals cause or worsen

osteoarthritis is based on epidemiologic studies. There is significant clinical

support for the hypothesis that intra-articular calcium crystals are risk factors for

incident or progressive osteoarthritis. For example, Sokolov and Varma show that

CPPD crystals are six times more likely to be found in osteoarthritic than in

normal joints [11]. Others confirm these findings [43,44]. Although the presence

of CPPD crystals in knee fluids from patients who have osteoarthritis is asso-

ciated with increased disability [45], whether or not this relationship can be ex-

trapolated to small joints is unclear. For example, Caspi and coworkers were

unable to demonstrate a similar relationship in hand joints [46]. Multiple studies

correlate the presence of intra-articular BCP crystals with severe radiographic

destruction [13,41]. A recent study by Nalbant and colleagues find that syno-

vial fluid CPPD and BCP crystals are predictors of rapidly worsening knee

rosenthal406

osteoarthritis [12]. Articular CPPD crystals also correlate with higher rates of

proteoglycan turnover in cartilage of affected joints [47]. The development of

severe and premature osteoarthritis in patients who have familial forms of CPPD

crystal deposition supports a causal association [3]. Similarly, the presence of

CPPD crystals in relatively normal cartilage in patients who have familial CPPD

disease precludes the theory that these particles simply are epiphenomena of

severe cartilage degeneration [48]. This hypothesis is refuted further by the rarity

of calcium crystals in joints damaged by inflammatory arthritis, such as rheu-

matoid arthritis.

Laboratory evidence

Animal studies. There are only a handful of studies that directly examine the

effects of calcium crystals in animal models of osteoarthritis. Perhaps the

strongest work is from Fam and colleagues [49]. They injected CPPD crystals

into rabbit knees rendered osteoarthritic by partial meniscectomy and resection of

the collateral and sesamoid ligaments. Histologic osteoarthritis worsened

significantly with exposure to repeated injections of either high- or low-dose

CPPD crystals compared with controls. In some animals with spontaneous

osteoarthritis, calcific deposits precede significant articular damage. For example,

in the guinea pig model of spontaneous osteoarthritis, calcifications in the me-

niscus occur before the development of visible hyaline articular cartilage degen-

eration. The investigators propose that mechanical changes in the calcified

meniscus alter the biomechanics of the joint and contribute to hyaline cartilage

damage [50].

In vitro studies. Many laboratory studies support the hypothesis that calcium

crystals contribute to osteoarthritis. Most do so by demonstrating potential

mechanisms through which calcium crystals cause damage to articular tissues.

There is support for theories involving the induction of an inflammatory response

by calcium crystals and those postulating direct deleterious effects of crystals on

articular tissues.

Calcium crystals are phlogistic and can initiate a strong inflammatory response

under certain conditions [51,52]. CPPD and BCP crystals elicit the production of

prostaglandins, interleukins, and cytokines from phagocytes and activate neu-

trophils and the complement cascade [52]. Despite these clear effects in vitro, the

role of inflammation in clinical calcium crystal deposition diseases and

osteoarthritis is debated. Calcium crystals often are found in uninflamed joints.

Even highly phlogistic crystals, such as monosodium urate crystals, can be

present in joints in the absence of clinical signs or symptoms of inflammation

[53]. Calcium crystals are less inflammatory than urate crystals [54]. Like gout

crystals, however, their inflammatory potential likely is modulated by their size

and shape and the nature and extent of adherent proteins [52,55]. Conversely,

although inflammation of the synovium in osteoarthritis also is variable, in-

creasing evidence exists to suggest it may be an excellent predictor of rapid

progression of joint damage in osteoarthritis [56].


There also is ample and elegant support for the hypothesis that CPPD and

BCP crystals affect cartilage and synovium directly and adversely, even in the

absence of inflammatory mediators. Calcium crystals elicit mitogenesis in fibro-

blast cultures [57,58], potentially mimicking synovial overgrowth and attendant

articular damage. Calcium crystals also can induce secretion of prostaglandin E2,

collagenases, and neutral proteases from canine synovial cells [57]. BCP crystals

elicit a similar response from osteoarthritic human synovial fibroblasts and adult

porcine articular chondrocytes [59]. Nitric oxide production also is stimulated in

articular chondrocytes by BCP crystals [60], as is increased production of key

proteases, such as stromelysin and gelatinase, and decreased production of

protease inhibitors, such as tissue inhibitor of metalloproteases [61].

There is little experimental evidence to suggest that calcium crystals act as

mechanical irritants in the joint, but it remains an intriguing possibility. Hayes

and colleagues find an increase in proteoglycan turnover and cartilage wear after

exposure of equine cartilage plugs to CPPD or BCP crystals [62].

Evidence that osteoarthritis causes or worsens calcium crystal formation

Clinical evidence

There is less direct evidence to support the hypothesis that osteoarthritis

causes or worsens calcium crystal formation, yet this hypothesis remains equally

compelling. The epidemiologic studies (discussed previously) suggest that cal-

cium crystals occur commonly in osteoarthritic joints, although they are relatively

rare in normal joints or in inflammatory joint disease [11,43,44]. This observation

sheds little light on the causal nature of this association. A recent longitudinal

study of synovial fluids, however, suggests that osteoarthritis may facilitate the

development of calcium crystals. Nalbant and coworkers show that some osteo-

arthritic synovial fluids have no crystals when sampled early in the disease. When

fluids from these same joints, however, were examined years later, calcium

crystals were present, suggesting that crystals may develop as a result of pro-

gressive osteoarthritis [12].

Laboratory evidence

Animal studies. In some animal models of osteoarthritis, calcium crystals form

in cartilage after the disease is well established. For example, in a rabbit model of

osteoarthritis based on transection of the anterior cruciate ligament, calcification

of the meniscal fibrocartilage occurs late in the development of the disease. These

calcium deposits correlate with other stigmata of phenotypic changes in

chondrocytes, including the production of type X collagen and changes in cell

shape [63].

In vitro studies. Laboratory studies that support the hypothesis that osteo-

arthritis causes or worsens calcium crystal formation typically support one of two

hypotheses. The first is that the damaged extracellular matrix in osteoarthritic

cartilage facilitates matrix mineralization by reducing inhibitors or increasing

rosenthal408

stimulants of pathologic mineralization in the normally unmineralized articular

cartilage matrix. The second is that osteoarthritis produces changes in the

chondrocyte that force it to assume a hypertrophic phenotype. These altered

chondrocytes then promote mineralization of their surrounding matrix.

There is ample evidence to support the hypothesis that extracellular matrix

changes in osteoarthritic cartilage facilitate crystal formation. Histologic studies

show a loss of proteoglycans and disruption of collagen fibril formation around

calcium crystals [18]. Identical changes also occur in osteoarthritis [64]. Simi-

larly, high levels of osteopontin [65], calcium and phosphate [66], and other

mineral-promoting factors are found in osteoarthritic cartilage. Few mechanistic

studies have explored the role of matrix changes in calcium crystal development.

The strongest support comes from work with model systems of calcium crystal

formation in solution and by matrix vesicles. Mandel and Mandel demonstrate a

marked reduction in concentrations of calcium and pyrophosphate necessary for

CPPD crystal formation in a solid matrix compared with those necessary to

generate crystals in solution [67]. Derfus and coworkers show that matrix vesicles

from osteoarthritic cartilage have identical mineralization capacities to those

isolated from normal cartilage [68]. They suggest this paradoxic finding strongly

supports an important role for the extracellular milieu in matrix vesicle miner-

alization. It is likely that normal articular cartilage matrix contains mineralization

inhibitors whereas osteoarthritic matrix contains less large proteoglycans,

disrupted collagen fibrils, and increased quantities of matricellular proteins that

promote mineralization.

There also is excellent evidence to support the hypothesis that phenotypic

changes in chondrocytes from osteoarthritic cartilage facilitate calcium crystal

formation. One theory explaining both osteoarthritis and calcium crystal

formation is that in these diseases, chondrocytes undergo terminal differentiation

and assume characteristics similar to those of hypertrophic chondrocytes respon-

sible for endochondral bone formation [69,70]. This is demonstrated elegantly by

the work of Kirsch and coworkers [71]. They show that chondrocytes in

osteoarthritic cartilage have many features of the hypertrophic phenotype. These

chondrocytes display increased alkaline phosphatase enzyme activity and higher

levels of annexins and type X collagen. Furthermore, they elaborate matrix

vesicles, which seem to be actively involved in mineral formation. These features

are not seen in chondrocytes from healthy articular cartilage but are well

described in cartilage containing CPPD or BCP crystal deposits [17]. Other

features of hypertrophic chondrocytes that might promote calcium crystal for-

mation also are documented in osteoarthritis. For example, pyrophosphate levels

are increased in osteoarthritic synovial fluid [72]. Upregulation of the putative

pyrophosphate transporter, ANK, also is demonstrated in osteoarthritic chon-

drocytes [73]. Recently, polymorphisms in the gene coding for an enzyme

responsible for pyrophosphate elaboration, ENPP1, are linked to hand osteo-

arthritis [74]. Levels of activity of transglutaminase enzymes, which also

are markers of chondrocyte hypertrophy in growth plate chondrocytes [75],

are increased in osteoarthritic cartilage [76]. These enzymes contribute to cal-


cium crystal formation [77,78]. Growth factors, such as the bone morphoge-

netic proteins and transforming growth factor-beta, may contribute to minerali-

zation [79] and cartilage degeneration [80] by promoting phenotypic changes

in chondrocytes.

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Calcium Deposition and Associated Chronic

Diseases (Atherosclerosis, Diffuse Idiopathic

Skeletal Hyperostosis, and Others)

Fabiola Atzeni, MD, PhDa,T, Piercarlo Sarzi-Puttini, MDa,

Maorizio Bevilacqua, MDb

aRheumatology Unit, L Sacco University Hospital, Milan, ItalybEndocrine and Diabetes Unit, Department of Medicine, L Sacco University Hospital, Milan, Italy

Extracellular matrix mineralization or calcification is regulated strictly under

physiologic conditions and usually confined to bone tissue. Under pathogenic

situations, however, ectopic calcification may occur (1) when the concentrations

of calcium and phosphate in extracellular fluid exceed the saturation point

(metastatic calcification); (2) as a consequence of the replacement or transition of

injured, degenerated, and necrotic tissue by mineral depositions (dystrophic cal-

cification); or (3) by means of the transdifferentiation of mesenchymal cells into

bone tissue (ectopic calcification) [1,2].

Among the various forms of ectopic calcification, vascular wall calcification

is the most common and is known to involve two mechanisms: passive

calcification resulting from the breakdown of the protection system (a form of

dystrophic calcification) and active calcification resulting from the transdiffer-

entiation of mesenchymal cells in the vascular wall (ectopic ossification). Both

mechanisms contribute to the formation of vascular lesions and play a central role

in the development of atherosclerotic plaque calcification in the elderly [3].

Calcification in atherosclerotic lesions involves factors that are important for

bone mineralization, including matrix vesicles, bone morphogenetic protein

(BMP-2), osteopontin (OPN), osteocalcin, and collagen I [3,4].



T Corresponding author. Rheumatology Unit, L Sacco University Hospital, Via GB Grassi, 74,

20157 Milano, Italy.

E-mail address: [email protected] (F. Atzeni).




atzeni et al414

Several matrix proteins, such as matrix Gla protein (MGP), OPN, and osteo-

calcin, are identified as protective factors against dystrophic calcification in

nonosseous tissues [5,6]. As the inactivation of MGP in knockout animals leads

to heavy and diffuse vascular calcification, MGP seems to play a central role in

protecting the vascular wall from dystrophic calcification, and MGP deficiency or

altered carboxylation also causes a high level of BMP-2 activity that leads to

hyperostosis in diffuse skeletal idiopathic hyperostosis (DISH) [7,8].

MGP is an important regulator of calcification in cartilage and blood vessels,

but a major difference between vascular calcification and bone mineralization is

the presence of oxidized lipids, the accumulation of which in the subendothelial

space of arteries promotes arterial calcification whereas, in skeletal bone, they

inhibit bone formation [9,10]. Calcium can be deposited throughout the vas-

culature in various forms of calcium phosphates, including calcium hydroxy-

lapatite (CHA) and basic calcium phosphate (BCP). Data suggest that calcium

deposition in arteries and calcium loss from bone resulting from osteoporosis

often coexist, and vascular calcification and bone modeling may have com-

mon mechanisms.

Vascular calcification

Vascular calcium deposition can be divided into four histoanatomic variants:

atherosclerotic calcification, medial arterial calcification, vascular calciphylaxis,

and cardiac valve calcification (Table 1) [3].

Atherosclerotic calcification

Atherosclerosis is characterized by inflammatory metabolic changes with

arterial lipid accumulation, and the lesions frequently become calcified [11,12].

Cardiovascular calcification is a common consequence of aging, diabetes, hyper-

cholesterolemia, mechanically abnormal valve function, and chronic renal insuf-

ficiency and is a type of dystrophic calcification characterized initially by cellular

necrosis, inflammation, and lipoprotein and phospholipid complexes [13,14]. The

Table 1

Histoanatomic variants of vascular calcification and examples of associated diseases

Histoanatomic variants Associated diseases

Atherosclerotic calcification Atherosclerosis

Hypercholesterolemia

Medial arterial calcification Type 2 diabetes

Type 1 diabetes

End-stage renal disease

Vascular calciphylaxis Acute renal insufficiency with muscle injury

Iatrogenic hyperphosphatemia

Cardiac valve calcification Senile calcific aortic sclerosis

calcium deposition & associated chronic diseases 415

process may begin early and accelerate as the disease progresses and more

complex lesions develop. Calcium deposits in coronary arteries indicate the

presence of plaque, but it is not necessarily true that the absence of coronary

calcium indicates an absence of atheromatous plaque [15].

Plaque structure and composition greatly affect the clinical expression of

atherosclerosis. A plaque may be diffuse or amorphous, but observations of bone-

like plaque regions and a series of remarkable studies published in the past

decade support the idea that calcium deposition in plaque is an active and regu-

lated process akin to bone formation.

Recent evidence indicates that many matrix elements play a significant role

in atherosclerotic calcification (Fig. 1) [6,7].

Matrix protein

MGP is a member of the family of extracellular mineral-binding Gla proteins

expressed in various tissues. It accumulates particularly in bone, cartilage, and

blood vessels and protects arterial walls and permanent cartilage from mineral

deposits [16,17].

In atherosclerotic arteries, Gla-containing proteins play an essential role in

clearing calcium phosphate (hydroxyapatite) for which Gla residues have a strong

affinity [18]. Gla is formed post-translationally from glutamic acid as a result of

g-carboxylation by vitamin K–dependent g-glutamate carboxylase. MGP is 10-kd

circulating protein containing five Gla residues shown to be present in association

with vascular smooth muscle cells (VSMCs), the elastic laminae of the tunica

Dysregulated calcium homeostasis

Osteogenic signals CSF-1, TNF-a, RANKL

Lipid oxidation (LDL-cholesterol)

Plaque

Foam cells

Mononuclear phagocytic-cell Osteoclast-like cells

Dysregulated Collagen Matrix protein (MGP, OPN, ONS etc.)

Necrotic foam cells debris

Calcium Deposition

Fig. 1. Possible mechanisms involved in atherosclerotic calcification.

atzeni et al416

media, and the extracellular matrix of the adventitia [19,20]. It is expressed in

chondrocytes and in normal and atherosclerotic arteries [18].

Mice lacking the gene encoding MGP show extensive calcification of cartilage

and the medial layer of arteries [21]. Furthermore, a single mutation in MGP

gene-coding regions is capable of causing Keutel syndrome, a rare human re-

cessive disorder characterized by diffuse cartilage calcifications, the presence of

which indicates the importance of MGP in preventing dystrophic calcification

[22]. Similarly, the inhibition of vitamin K–dependent carboxylation in mice

by vitamin K antagonism or poor vitamin K intake also promotes vascular

calcification [23–25]. Schurgers and colleagues [26] demonstrate that impaired

MGP carboxylation is associated with intimal (atherosclerosis) and medial

vascular calcification (Mfnckeberg’s sclerosis), suggesting that vitamin K–

induced modification is essential to the function of MGP as an inhibitor of ec-

topic calcification.

Human MGP promoter polymorphisms are identified and prove associated

with low MGP expression and low serum MGP levels and, as suggested by

animal models of impaired MGP expression, lead to an increased risk of myo-

cardial infarction [27,28]. Schurgers and colleagues [29] demonstrate that low

levels of circulating MGP and its impaired g-carboxylation at its tissue expres-

sion site are associated with the development and progression of cardiovascu-

lar disease.

The expression of the MGP gene depends on various growth factors and

hormones [30]. It is assumed that MGP precursors are processed into the general

circulation in an active or secretory form, so the physiologic functions of MGP

can be local and systemic; however, how differently these functions affect

osseous and extraosseous tissue remains to be clarified.

Etiopathogenesis

There are strong, well-documented, and well-recognized links between hyper-

cholesterolemia, lipid oxidation, and atherosclerosis, but only recently has a

connection has been made between elevated low-density lipoprotein (LDL)

cholesterol levels and dysregulated calcium homeostasis [10,31]. Parhami and

coworkers [9] and Parhami and Demer [10] examined the role of oxidized LDL

cholesterol on calcifying vascular cell (CVC) activity in vitro and found that it

upregulates CVC osteogenic mineralization and differentiation but only in con-

cert with physical cell-cell interactions between CVCs and macrophages. The

osteogenic differentiation of CVCs can be recapitulated by inducing oxidative

stress, which, intriguingly, concomitantly suppresses osteoblast differentiation,

indicating the existence of reciprocal cell type-specific responses [32]. Activated,

cholesterol-laden foam cells, therefore, participate in generating multiple osteo-

genic signals that potentially are mediated by tumor necrosis factor (TNF)-a and

oxidized lipids [33,34].

In addition to colony-stimulating factor 1 (CSF-1) and receptor activator of

nuclear factor kB ligand (RANKL), osteoclast formation and function are in-

fluenced by other cytokines, some of which (in particular proinflammatory cyto-


kines) also are implicated in atherogenesis [34,35]. The expression patterns of

RANKL, CSF-1, and TNF-a in atherosclerotic plaques are consistent with ar-

terial osteoclast-like cells developing from mononuclear phagocytic cell pre-

cursors (see Table 1) [34].

Recent studies suggest that vascular calcification not only is the result of

passive calcium-phosphate deposition on atherosclerotic arteries but also of

active mechanisms regulated by bone-associated genes [9,36]. Several studies

demonstrate the upregulation of bone-associated proteins, such as OPN, osteo-

calcin, BMP-2a, and osteonectin (OSN), at the sites of calcified atherosclerotic

plaques [18,37–40]. At the same time, and under normal circumstances, the

arterial wall is protected from mineral deposits by MGP [20,29]. In tissues as

functionally diverse as cartilage and arteries, MGP has the general function of

inhibiting mineral precipitation in extracellular fluid, in which the concentrations

of calcium and phosphate approach the salt solubility product. The micro-

environments in atherosclerotic plaques may foster conditions that favor the

precipitation of calcium: in particular, plaque sites containing necrotic foam cells

debris may act as a locus for mineral precipitation because they can release high

concentrations of mitochondrial phosphate and phosphatidylserine-containing

molecules, and this series of events could tip local ionic balance sufficiently to

instigate precipitation [12].

OPN is another bone-matrix protein expressed in arteries, and Speer and

coworkers [41] demonstrate that it inhibits the calcification of vascular structures

in vivo. Its ability to inhibit cell-mediated calcification is dependent on serine

phosphorylation. OPN is not found in normal arteries, but it is expressed in

plaque and colocalizes with calcified plaque regions [42]. It is possible, therefore,

that it may play a protective role where necessary and only be expressed in

plaque in response to local conditions that might tend to favor mineralization.

Rattazzi and coworkers [43] recently have shown that the deposition of

hydroxyapatite is preceded by the formation of fibro-fatty nodules populated by

cells that resemble chondrocytes morphologically and are surrounded by dense

connective tissue that stains positive for type II collagen; the few remaining

chondrocyte-like cells are located adjacent to, or inside, the large areas of calci-

fication. This finding suggests that the mechanism of calcification partially may

recapitulate the process of endochondral bone formation [43]. The molecular

mechanisms regulating vascular calcification remain obscure, but it is suggested

that locally disturbed calcium and phosphate metabolism in atherosclerotic

plaques may contribute to its development [44].

Medial artery calcification

Medial artery calcification is the nonendochondral ossification process of

the arterial tunica media that is highly characteristic of diabetes and end-stage

renal disease [45,46]. Vattikuti and Towler [47] hypothesize that a migratory

adventitial cell myofibroblast population responding to VSMC-OPN production

contributes to vascular remodeling, and others support that the these cells are

atzeni et al418

implicated in the medial calcification of diabetes and (potentially) end-stage renal

disease [48–50]. It is known that hyperglycemia and hyperphosphatemia (Pi)

induce OPN expression [50–52]. High serum phosphate levels correlate closely

with the extent of vascular calcification and vascular disease, and one of the most

frequent causes of hyperphosphatemia is chronic renal failure and subsequent

kidney dialysis, which typically lead to serum inorganic phosphate levels of more

than 2 mmol [53,54]. Nishizawa and colleagues [55] hypothesize that elevated

extracellular Pi levels increase Pi transport, leading to increased intracellular Pi in

VSMCs. By means of a still unknown mechanism, high intracellular Pi levels

activate specific signaling pathways that increase the expression of osteogenic

genes (including Cbfa1 and osteocalcin) and stimulate the secretion of potential

mineral nucleating molecules, such as calcium-binding proteins. The net effect is

enhanced susceptibility to vascular calcification (Fig. 2) [55].

Vascular calciphylaxis

Vascular calciphylaxis is a component of widespread soft tissue calcification

that occurs when the physiologic calcium phosphate solubility threshold is

exceeded [56].

It seems that vascular calciphylaxis has led to the evolution of various miner-

alization inhibitors, tissue pyrophosphate generating systems, and OPN. Tissue

pyrophosphate is generated by a family of three ectonucleotide pyrophosphatase/

Hyperphosphatemia

Elevated extracellular Pi levels

Increase Pi transport

increased intracellular Pi in VSMCs.

Expression of osteogenic genes (including Cbfa-1

and osteocalcin), Secretion of potential mineral nucleating molecules such as calcium-binding

proteins.

Vascular Calcification

Fig. 2. Mechanism of medial artery calcification. (Adapted from Nishizawa Y, Jono S, Ishimura E,

et al. Hyperphosphatemia and vascular calcification in end-stage renal disease. J RenNutr 2005;15:178–82.)


phosphodiesterases and plays an important role in limiting the calcification of

‘‘soft tissues,’’ such as ligaments and tendons [56].

Consequences of vascular calcification

The deleterious clinical consequences of vascular calcification are clear: the

anatomy and extent of calcific vasculopathy lead to stroke, amputation, and

cardiovascular mortality [45,57–59]. The deposition of calcification in valves

and arteries diminishes their elasticity, which is a major cause of aneurysm and

stenosis. Arterial obstruction resulting from calcification and other processes

can lead to heart attack and stroke. Mineralization in the femoral arteries can

cause intermittent claudication, leading to decreased mobility. Patients who

have diabetes have an increased mortality rate and are at higher risk of lower-

extremity amputation in the setting of medial artery calcification [45]. The risk

of stroke, particularly high in postmenopausal women, is increased in the

presence of aortic arch calcification [57,58]. Given the aging and ‘‘dysmeta-

bolic’’ population, a better understanding of vascular calcification is sorely

needed to improve human health and health care [58–61].

Diffuse idiopathic skeletal hyperostosis

DISH, a skeletal disease characterized by the ligamentous ossification of the

anterolateral spine, was described first by Forestier and Rotes–Querol [62] more

than 50 years ago.

It involves the calcification and ossification of soft tissue, in particular

ligaments and entheses, and has a marked predilection for the axial skeleton

(especially the thoracic spine) but also may affect peripheral joints [8,63]. It leads

to the ossification of the spinal anterior longitudinal ligament and causes the

production of flowing osteophytes that involve particularly the right side of the

spine while preserving the intervertebral disc space [64]. Other entheseal regions

in the peripheral joints may be affected, including the peripatellar ligaments, the

Achilles tendon insertion, the plantar fascia, and the olecranon [65]. Diagnosis is

based solely on radiographic abnormalities defined using the criteria of Resnick

and Niwayama [66].

Etiopathogenesis

The cause of DISH remains unknown, but several risk factors are implicated

on the basis of its frequent association with various metabolic conditions, in-

cluding hyperinsulinemia with or without diabetes mellitus, obesity, hyperuri-

cemia, dyslipidemia, hypertension, and the prolonged use of isoretinol [67–70].

How is the process initiated, however, and what is the link between these

metabolic disorders and new bone formation in DISH (Fig. 3)? The ossification

Metabolic disorders (diabetes mellitus, glucose intolerance, dyslipidemias, hypertension,hyperuricemi

a)

Environmental factorsMatrix Gla protein (MGP/Mgp)

ligament cell

NFkappaB

PDGF-BB and TGFbeta1

hypervascularity

Anatomical factors

atherosclerosis

damage to the endothelium and aggregation of blood platelets

Mechanical stress

PGI2 productionimmobility of the

thoracic spine

and rarefaction of

the adjacent bone

Toxic factors

growth factor (IGF-I )

osteoblastproliferation

prolonged use of isoretinol

Geneticfactors

Bone deposition

deficit of

BMP-2 ?

altered

carboxylation ?

Fig. 3. Etiopathogenesis of DISH.

atzeni et al420

process starts in the innermost layer of the anterior longitudinal ligament, at the

site of its attachment to the vertebral body, and then extends to meet the other arm

of ossification coming from the vertebra above or below. It is believed that this

new formation is the result of abnormal osteoblast cell growth/activity in the

bony ligamentous region, which may be a clue to the pathogenesis of DISH [71].

The growth of osteoblasts is maintained by several growth factors that may not

be confined to bone. Insulin-like growth factor I stimulates alkaline phosphatase

activity and type II collagen in osteoblasts and growth hormone can induce the

local production of insulin-like growth factor I and insulin-like growth factor

binding proteins in chondrocytes and osteoblasts [72]. Denko and colleagues [73]

find that patients who have DISH have high insulin and growth hormone levels,

which may explain the osteoblast cell growth and proliferation. Because the

ossification starts in certain sites, El Miedany and coworkers [71] suggest that

hypervascularity could be the localizing factor in the process. Furthermore, in

predisposed patients who have hyperlipidemia, diabetes mellitus, or (possibly)

hyperinsulinemia, there is an increased likelihood of atherosclerosis, the earliest

stages of which leads to endothelial damage, the aggregation of blood platelet-

derived growth factor, and, finally, osteoblast proliferation. Kosaka and

coworkers [74] indicate the possibility that, after being stimulated by environ-

mental factors involving platelet-derived growth factor-BB and transforming

growth factor-1b in ligament cells, nuclear factor kB influences the osteoblastic

differentiation of undifferentiated mesenchymal cells.


Sarzi-Puttini and colleagues [75] find higher serum MGP concentrations in

male and female patients who have DISH than in healthy control subjects

(5.7 nmol/L versus 3.3 nmol/L, P b 0.001) and conclude that MGP may be a

marker of hyperostosis because it is produced in larger amounts by patients

who have hyperostosis-inducing osteometabolic syndromes, such as DISH.

Chondrocalcinosis

Calcium pyrophosphate dihydrate deposition (CPPD) disease is a metabolic

arthropathy caused by calcium pyrophosphate crystal deposits. It is frequent in

the second half of life (6% of the population ages 60 to 70; 30% of the elderly

ages N80) [76,77].

The characteristic radiographic features of CPDD disease include soft tissue

calcification, joint space narrowing, bone sclerosis, subchondral cyst formation

without osteophyte formation, and large intraosseous geodes. Triangular

fibrocartilage calcification frequently is found, and isolated scapho-trapezio-

trapezoid arthritis is specific to CPDD [77,78].

The molecular mechanisms regulating joint calcification remain obscure, but

three participants now are recognized: (1) the overproduction of pyrosphosphate

secreted by chondrocytes; (2) increased calcium concentration; and (3) changes

in cartilage extracellular matrix. Histologic evidence further supports the role of

extracellular matrix changes in the formation of CPPD crystals in areas of

abnormal pericellular matrix (they are not seen in normal matrix). Laboratory

findings also support the role of enzymes called transglutaminases, which modify

extracellular matrix protein in CPPD disease post-translationally: the activation of

extracellular tranglutaminases promotes CCPD crystal formation [79–82].

The levels of calcium-binding proteins, including S-100, OPN, and OSN

(secreted protein acid-rich and rich in cysteine), are increased in the extracellular

matrix of CPPD-diseased cartilage [83]. OPN may play an important role in

CCPD crystal formation because (1) it has a large calcium-binding capacity; (2) it

is seen in other conditions involving pathologic calcification, such as athero-

sclerosis; (3) it is increased in the areas in which the crystals are formed; and (4) it

is a transglutaminase substrate. The levels of S-100, another calcium-binding

protein, are increased around CCPD crystals [84–86]. It is believed [81] that

matrix vesicles are involved in CCPD crystal formation insofar as those isolated

from articular cartilage can produce CCPD in vitro. The mechanisms, however,

by means of which the extracellular matrix changes and matrix vesicles form

CPPD crystals are understood poorly.

Miscellaneous

BCP crystals frequently may form asymptomatic deposits that may give rise to

several clinical syndromes, including calcific periarthritis, Milwaukee shoulder

atzeni et al422

syndrome, osteoarthritis, calcific tendinitis and bursitis, and mixed crystal depo-

sition in and around joints [87,88].

Milwaukee shoulder syndrome is one of the better-defined BCP crystal-

associated syndromes [88]. It is characterized by the gradual onset of mild to

moderate shoulder pain that often is bilateral and worse at night. Renal disease

may be a predisposing factor. The pathogenesis of Milwaukee shoulder syndrome

remains obscure but recent data show that low doses of warfarin are effective in

some cases of soft tissue calcification because it depresses the synthesis of the

vitamin K–dependent Gla protein, suggesting that this matrix protein may play a

pathogenetic role [89].

Calcific tendinitis of the shoulder is a dynamic process. It is reported that the

cells surrounding tendon calcifications contain OPN [90]. Resorption probably is

mediated by cathepsin K–containing multinucleated giant cells. Metalloprotein-

ases are found in the synovial fluids of patients who have rotator cuff tears

[90,91].

Recent advances in areas of medicine, such as oncology, have strengthened the

argument that BCP crystals, once believed inert structures, have many potential

pathophysiologic functions. Microcalcifications containing CHA often are

associated with malignant human breast lesions. OSN, OPN, and bone sialo-

protein (BSP), three bone matrix proteins involved in bone matrix mineralization,

are expressed in human breast cancers. Hirota and coworkers [92] find that the

OPN protein produced by macrophages seems to play a significant role in the

development of calcifying foci within the necrotic areas of breast cancers. Recent

studies show that BSP, an Arg-Gly-Asp (RDG)–containing phosphoprotein,

initiates CHA deposition and mediates the attachment of osteoclasts to the same

crystals before their resorption [93]. The level of BSP expression correlates with

the development of bone metastases and poor survival, suggesting that the

ectopic expression of bone matrix proteins may be involved in conferring osteo-

tropic properties to circulating metastatic breast cancer cells [93].

In conclusion, several matrix proteins are identified as protective factors in

nonosseous tissues, and alterations in them are found associated with several

calcium deposition diseases.

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Imaging Features of

Crystal-Induced Arthropathy

Marc H. Choi, John D. MacKenzie, Murray K. DalinkaT

Department of Radiology, Hospital of the University of Pennsylvania,

3400 Spruce Street/1 Silverstein, Philadelphia, PA 19104, USA

Crystal-induced arthropathies constitute a spectrum of inflammatory arthriti-

des that is induced by cellular reaction to crystal deposition in and around joints.

A variety of microcrystals may be deposited and can induce an inflammatory

response. The three most common types of crystal-induced arthropathy are gout,

calcium pyrophosphate dihydrate (CPDD) deposition disease, and calcium

hydroxyapatite deposition disease (HADD). Each has a characteristic clinical pre-

sentation, crystal type that may be aspirated from affected tissues, and ra-

diographic appearance. Each of these entities may occur as a primary abnormality

or secondary to an underlying disorder. Sometimes these diseases may coexist

in the same joint or individual. Imaging frequently plays a crucial role in the

diagnosis of crystal-induced arthropathies and may help to monitor disease pro-

gression and treatment response.

Gout

Gout is a common peripheral arthritis that develops from the deposition of

sodium urate crystals in one or more joints. When left untreated, crystal depo-

sition leads to recurrent episodes of joint inflammation and joint destruction.

The clinical manifestations of gout may be subdivided into early and late

presentations and acute and chronic attacks of arthritis. Imaging aids in the

clinical evaluation of patients who have gout aids in monitoring patients with

this disorder.



T Corresponding author.

E-mail address: [email protected] (M.K. Dalinka).




choi et al428

Etiology

Gout may be caused by uric acid overproduction or underexcretion. Altered

metabolism of urate precipitates urate salt deposition and leads to gout [1].

Diseases that are associated with uric acid overproduction include primary enzy-

matic defects of purine synthesis or increased nucleic acid turnover, such as

myeloproliferative and lymphoproliferative disorders, hemoglobinopathies, mas-

sive cell lysis from chemo- or radiation therapy, and saturnine gout. Decreased

uric acid excretion and elevated serum uric acid levels may occur secondary to

chronic renal failure, thiazide or other diuretic therapy, or pharmacologic agents

that alter renal function.

The combination of elevated serum and soft tissue uric acid levels and acido-

sis likely accelerates urate crystal formation. Rapid changes in uric acid levels

are believed to be responsible for acute attacks of gout; however, the presence of

hyperuricemia is not diagnostic of gout because most patients who have hyper-

uricemia do not have gout. If untreated, hyperuricemia increases the risk for gout,

and approximately 90% of patients who have chronic hyperuricemia develop

gout within 30 years [2]. The key to the diagnosis is joint aspiration with synovial

fluid analysis depicting negatively birefringent urate crystals on polarized light

microscopy, or classic radiographic findings [3]. Imaging in conjunction with

tissue aspiration/biopsy helps to establish a firm diagnosis of gout before initi-

ating potentially toxic therapy.

Clinical features

Gout is the most common form of crystal arthropathy. Although gout affects

less than 0.5% of the population, the prevalence of the disease increases with age

[4]. Typically, patients present with acute signs and symptoms years before

radiographic abnormality is manifest; however, on rare occasions patients may

present with chronic arthritis.

Classically, the disease begins at night in men between the ages of 30 to

60 years with the sudden onset of acute and severe pain with a predilection for the

metatarsophalangeal (MTP) joint of the first digit (podagra). The first MTP joint

is involved in approximately 50% of patients at onset, and eventually in 90% of

patients who have untreated gout. The excruciating joint pain usually subsides

within 2 to 24 hours with less severe pain occasionally lasting for a few weeks.

The acute attacks of gout recur frequently and when they increase in number the

disease is more likely to become polyarticular. Approximately 25% of patients

have five or more acute attacks per year before treatment. Patients with early

onset of gout typically have more frequent attacks than do patients in the chronic

stage. After an initial series of acute attacks, patients may enter a symptom-free

period (‘‘intercritical gout’’) that may last from months to years [2].

With chronic gout, tophi are deposited in a periarticular location. Tophi are the

hallmark of chronic gout and they may be identified on radiographs; biopsy rarely

is necessary because the diagnosis of gout usually is well established by the time

imaging features of crystal-induced arthropathy 429

tophi appear. The rate of tophi formation is dependent upon the level of uric acid;

approximately half of the patients who have untreated gout develop tophi after

10 years and more than 70% have tophi after 20 years [5]. The early diagnosis

and treatment of gout has resulted in a decline in the incidence of chronic

tophaceous gout although it still occurs, in part secondary to misdiagnosis,

mismanagement, and poor patient compliance/adherence.

Imaging gout

Radiographic examination in patients who have gout is used mainly to evalu-

ate joint destruction and disease progression, to document the presence of tophi,

and to help exclude other diagnoses. Radiographic findings may be categorized

into the nonspecific changes that are seen in early gout, the subtle alterations of

intercritical gout, and the more specific changes of chronic tophaceous gout [3].

In the early stage of gout, the radiographs usually are normal or show nonspecific

soft tissue swelling in the affected joint secondary to synovitis, capsular disten-

tion, and periarticular soft tissue edema. As the attack subsides, the radiographic

abnormalities usually disappear [3]. Other causes of monoarticular soft tissue

swelling, including infectious arthritis, pseudogout, and trauma, must be ex-

cluded [6]. In the intercritical period, which occurs between the acute period and

the development of chronic tophaceous gout, subtle joint alterations (eg, small,

well-defined erosions) may be visualized at the periphery of affected joints.

The distribution of radiographic abnormalities in gouty arthritis is variable,

but the disease tends to affect the lower extremities more often than the upper

extremities and the small joints more often than the large joints. An asymmetric

and monoarticular distribution is characteristic of gout with the first MTP

joint (podagra) affected most often followed by the first interphalangeal and

tarsometatarsal joints. Approximately 85% to 90% of patients who have gout

experience podagra at some point in the disease. Most first presentations are

monoarticular. Bilateral and symmetric or asymmetric polyarticular involvement

may be present within any of the foot joints. All compartments of the hand and

wrist, knee, shoulder, hip, and sacroiliac joint (15% unilateral) are favored sites.

The ankle, tarsal, and knee are involved frequently early in the course of

the disease. There is preference for peripheral joints with the feet, elbow, and

wrist [7].

Characteristic findings occur in chronic gout. These include tophi, erosions

with overhanging edges, relative preservation of the joint space, and lack of

osteopenia. The hallmark of chronic gout is the presence of multiple macroscopic

tophi (Figs. 1 and 2)—a mixture of monosodium monohydrate crystals in a

matrix of amorphous debris containing urate, proteinaceous deposits, and lipids

with a surrounding foreign body reaction. Generally, they are ovoid and asym-

metric and usually are radiographically invisible until they reach 5 mm to 10 mm

in diameter [8,9]. Large tophi may be palpable. Faint calcification may occur in

up to 50% of tophi; however, cloudlike masses of densely calcified tophi are

atypical [9] and may reflect a coexisting abnormality of calcium metabolism,

Fig. 1. Tophaceous gout. Large tophus at MTP joint of first toe and erosion with overhanging edge

at fifth metatarsal. Additional small erosions are present at the medial cuneiform–first metatar-

sal articulation.

choi et al430

such as renal insufficiency (Fig. 3) [10,11]. Erosions in chronic gout are common

and usually are associated closely with the tophaceous deposits because the

erosions may occur secondary to chronic pressure from the adjacent tophus.

When characteristic erosions are seen along with tophi the diagnosis of gout is

almost certain. Frequently, these erosions are round or oval in shape and well

circumscribed, and typically are eccentric and oriented along the long axis of

bone (see Figs. 1 and 2). Most often they are juxta-articular but may be intra-

articular or located at a distance form the joint. Intra-articular erosions tend to

involve the joint margins before extending to the middle of the joint [5].

Interosseous erosions may have sclerotic borders that produce a punched-out

appearance [12].

A characteristic feature of gouty erosions is the overhanging edge, an elevated

margin of bone that extends over the expected confines of the cortex at the site

Fig. 2. Gouty arthritis. Multiple changes of gouty arthritis are present in the hand. There is

asymmetric soft tissue swelling and small erosions at the second metacarpophalangeal articulation.

Large erosions are identified about the proximal interphalangeal joint of the second digit that are

more marked on the radial aspect of the joint where there is an overhanging edge. Smaller erosions are

present in the other digits.

Fig. 3. Calcified tophus. Classic tophus with increased density at the first MTP joint and additional

tophus at the medial aspect of the interphalangeal joint of the first digit in this patient who had gout

and renal failure.


of erosion (see Fig. 1) [13]. The overhanging edge is seen in approximately 40%

of patients who have tophaceous gout and may represent new bone formation

around a gradually enlarging tophus. Occasionally, extensive osseous erosions

produce a mutilating arthritis that mimics the opera-glass hand deformity that is

seen occasionally with rheumatoid or psoriatic arthritis [14].

The joint space is relatively well preserved, even in the presence of extensive

juxta-articular erosions. Large tophi are an important radiographic feature that

helps to differentiate gout from other causes of arthritis. If joint space narrowing

has occurred, the radiographic appearance may mimic the uniform narrowing of

rheumatoid arthritis or advanced osteoarthritis (OA) [2]; however, patients who

have joint space narrowing generally have had long-standing disease and the

clinical diagnosis of gout already is well established (Fig. 4). Ankylosis with

obliteration of the joint space is rare [11,15].

Osteopenia is an atypical feature of gout. When bone density is diminished in

long-standing gouty arthritis, disuse is believed to be the underlying cause of the

osteopenia [15]. Periarticular osteopenia may be seen during an acute gouty

attack, presumably from inflammation-induced hyperemia; however, this is tran-

sient and the bone density tends to be preserved, even in advanced chronic gout

with articular destruction. Infrequently, a zone of osteoporosis in the subchondral

bone may progress to a cystic abnormality [9]. Interosseous tophi and sub-

chondral cysts may mimic focal osteoporosis and should not be confused with

diffuse periarticular osteopenia.

Localized increased bone density may be seen in a minority of patients (~6%)

that has advanced tophaceous gout, predominantly in the hands and feet. The

increased bone density may represent calcification of interosseous monosodium

urate deposits [5]. The radiographic appearance may resemble an area of bone

infarction or enchondroma.

Occasionally, bone proliferation is present in gouty arthritis. Enlargement of

the ends and shafts of involved bones can produce club-shaped metatarsal and

Fig. 4. Advanced gout with joint destruction. Radiograph of the foot shows marked joint destruction

and large tophus at the first MTP joint. Joint destruction and erosions are identified at the

tarsometatarsal joints and the second MTP joint with lateral subluxation.

choi et al432

phalangeal heads (see Fig. 1). This is termed ‘‘mushrooming.’’ Irregular bone

spicules at sites of muscle and tendon insertion, such as the calcaneus, olecranon,

and patella, may be observed [16]. A fine lacy periosteal new bone formation

may occur secondary to periosteal reaction that is caused by cortical destruction

by adjacent crystal deposition; often, this is seen best on the medial aspect of the

first MTP joint [17]. Bilateral olecranon bursitis (Fig. 5) is characteristic of gout

as is bilateral swelling at the dorsum of the foot and calcaneus.

Hyperuremic patients may present with urinary calculi before developing

gouty arthritis [18]. A non-contrast CT scan performed with thin slices (3–5 mm)

through the urinary-collecting system has replaced intravenous urography as the

gold standard for detecting urinary calculi [19]. Urate stones as small as 2 mm

may be detected readily [20]. CT rarely is useful in patients who have gout other

than for the detection of urinary calculi. Although several papers have de-

Fig. 5. Olecranon bursitis. Soft tissue swelling and calcification about the olecranon bursa, a

characteristic finding in gout that often is bilateral.


scribed MRI findings in patients who have gout, MRI is not used in diagnosis

or management.

Calcium pyrophosphate dihydrate deposition disease

CPPD deposition disease is characterized by the presence of CPPD crystals

within and around joints. CPPD crystals elicit an inflammatory response that

results in arthritis, synovitis, or tendonitis. The soft tissue calcification from

CPPD crystal deposition and the joint degeneration that result from CPPD

arthropathy tend to have characteristic imaging appearances. Before discussing

the clinical and imaging features, a review of nomenclature is helpful to under-

stand better the clinical and radiographic manifestations of CPPD deposition

disease [21].

Chondrocalcinosis signifies deposits of calcium salts in cartilaginous tissue.

Most often, articular chondrocalcinosis results from CPPD crystal deposition in

hyaline and fibrocartilage; however, chondrocalcinosis also may occur from the

deposition of calcium apatite, dicalcium phosphate dehydrate, or calcium oxalate.

Chondrocalcinosis may be seen without symptoms of arthropathy. Articular and

periarticular calcifications are general terms that are used for the radiologic

description of calcification in or around a joint but not necessarily in cartilage.

CPPD deposition disease describes a crystal arthropathy that is induced by

CPPD crystals. CPPD deposition disease is synonymous with CPPD arthropathy

and pyrophosphate arthropathy. It is characterized by joint inflammation and a

typical pattern of structural joint damage that may occur with or without radio-

graphically visible chondrocalcinosis [22,23]. Pseudogout syndrome is a subset

of CPPD deposition disease that mimics the clinical manifestations of gout, but is

caused by calcium pyrophosphate crystals rather than monosodium urate crystals.

Clinical features

The prevalence of CPPD deposition increases with age; it is common in the

geriatric population where it frequently is asymptomatic. There is a 5% incidence

of radiographic chondrocalcinosis by age 70 and a 50% incidence by age 90 [24].

An autosomal dominant form of CPPD has been described with an earlier age of

onset than the idiopathic form [25]; it often is associated with severe symptoms.

CPPD deposition disease may cause an idiopathic arthritis in middle-aged or

elderly patients; it affects both sexes equally. Additionally, CPPD deposition has

been reported in association with a host of disorders. The incidence of primary

hyperparathyroidism is as high as 15% in patients who have CPPD [26].

Chondrocalcinosis is found in up to 41% of patients who have hemochromatosis

and the articular manifestations share many similarities with CPPD arthropathy

[27–29]. CPPD deposition disease also has been described in patients with

secondary hemochromatosis related to hereditary spherocytosis [29].

choi et al434

Although common, CPPD deposition disease was described first in the

1960s [30,31]. CPPD deposition disease is a great mimic, because the clinical

presentation may resemble gout, rheumatoid arthritis, OA, traumatic arthritis,

neuropathic joint, ankylosing spondylitis, rheumatic fever, or psychogenic

arthritis [32]. The clinical presentation of CPPD arthropathy generally falls

into five distinct clinical patterns: lanthanic, pseudogout syndrome, pseudo-

rheumatoid arthritis, pseudoneuropathic arthropathy, and pseudoostoeoarthritic

types [33].

The lanthanic or asymptomatic type is the most common clinical pattern of

CPPD deposition disease. CPPD deposits are visible on radiographs but the

particular joint is without the clinical signs and symptoms of an arthropathy,

although symptomatic CPPD arthropathy may be present in other joints. The

pseudoosteoarthritis type (pseudo-OA) of CPPD deposition disease simulates

OA clinically and radiographically, often with chondrocalcinosis superimposed

upon the typical radiographic findings of OA. Additionally, some patients pres-

ent with progressive joint degeneration that is typical of OA, with joint space

narrowing, osteophyte formation, and subchondral sclerosis and cysts, but with-

out radiographic chondrocalcinosis. There may be superimposed acute inflamma-

tory episodes in addition to the chronic arthritic symptoms. The pseudo-OA

pattern may be present in approximately 50% of patients who have CPPD arthropa-

thy. An atypical joint distribution may occur in joints that are not affected

readily by OA (ie, predominant involvement of the patellofemoral joint in the

knee and the radiocarpal and metacarpophalangeal (MCP) joints in the wrist

and hands).

The pseudogout syndrome manifests with self-limited acute or subacute epi-

sodes of mono- or pauci-articular arthritis similar to gout; however, the aspirated

crystals are weakly positive under polarizing light and are characteristic for

CPPD as is the radiographic appearance. The pseudorheumatoid type manifests

with symptoms and signs that are similar to rheumatoid arthritis: morning stiff-

ness that lasts for weeks to months, fatigue, synovial thickening, restricted joint

motion, and elevated erythrocyte sedimentation rate with a symmetric pattern;

however, the presence of classic chondrocalcinosis differentiates the two [34]. In

the pseudoneuropathic type patients present with radiographic findings that

simulate a neuropathic joint (joint destruction, subluxation, and heterotopic new

bone formation), but without neurologic abnormality [35,36].

The pathophysiology of CPPD deposition disease is not understood com-

pletely. In some cases, CPPD crystal deposition in cartilage seems to be related to

defects in calcium and inorganic phosphate metabolism [24]. This theory is sup-

ported by the association of CPPD with hypophosphatasia and hyperparathy-

roidism. Synovial fluid pyrophosphate has been found to be increased in patients

who have CPPD. Because not all individuals who have hypercalcemia or

hypophosphatasia develop calcium pyrophosphate crystals other factors must be

involved. The phenomenon of CPPD crystal shedding is believed to explain acute

bouts of arthritis [37]. Cartilaginous deposits of crystals are cast into the articular

cavity and subsequently precipitate acute arthritis.


The diagnostic criteria for definitive, probable, or possible CPPD deposition

disease were outlined by McCarty [26]. A definite diagnosis is established when

a characteristic x-ray diffraction pattern of crystals from aspiration/biopsy of the

joint is demonstrated or when the combination of polyarticular chondrocalcinosis

on radiographs and absent/weakly birefringent crystals from joint aspiration/

biopsy is found on polarizing microscopy. If only one of the latter two criteria is

present then the diagnosis is probable [38]. A possible diagnosis can be suggested

when acute or chronic arthritis occurs in a typical location and is accompanied by

the characteristic radiographic features, without chondrocalcinosis. Because the

diagnosis and the consequent therapeutic measures may be based, in part, upon

the radiographs, an understanding of the varied radiographic manifestations of

CPPD deposition disease is important.

Imaging features in calcium pyrophosphate dihydrate deposition disease

Radiography is the imaging modality of choice for the diagnosis and evaluation

of patients who are suspected of having CPPD deposition disease. Radiographs

can document the presence of chondrocalcinosis and periarticular calcifications,

characterize the distribution and severity of the arthritis, evaluate disease pro-

gression, and exclude other diagnoses. Characteristic radiographic findings

coupled with absent/weakly birefringent crystals on polarizing microscopy makes

a definitive diagnosis of CPPD deposition disease.

CPPD crystals may be deposited in and around joints and often have a char-

acteristic radiographic appearance and distribution. The crystal deposits occur in

fibrocartilage and hyaline cartilage, most frequently in the knee, symphysis pubis,

wrist, elbow, and hip [36]. From anatomic and radiologic studies of knee joints,

the prevalence of cartilage CPPD deposits in the elderly is between 2% and 28%

[39]. In one autopsy survey, the incidence of intra-articular calcifications in-

creased with age; between the 60- and 69-year age group and the older than

80-years age group the incidence increased from 11% to 38% for women and

from 20% to 29% for men [40].

Fig. 6. CPPD knee. The calcifications clearly outline the fibrocartilage in the menisci and the more

central hyaline articular cartilage.

Fig. 7. CPPD wrist. The triangular fibrocartilage is calcified densely as is the articular cartilage over

the distal ulna (arrows).

choi et al436

Fibrocartilage calcification is most common in the menisci of the knee,

triangular fibrocartilage of the wrist, symphysis pubis, annulus fibrosis, and

glenoid and acetabular labrum (Figs. 6 and 7). Fibrocartilaginous calcifications

are shaggy and irregular radiodense areas that most often are located centrally in

the joint. Hyaline cartilage calcifications are identified as a thin line parallel to,

and a few millimeters subjacent to, the subchondral bone (Fig. 8). Hyaline car-

tilage calcification occurs most commonly in the wrist, knee, elbow, and hip

(Fig. 9).

Calcification within the synovial membrane is a common feature of

CPPD; it usually is seen with chondrocalcinosis, but at times it may be the

dominant radiographic feature. Synovial calcification is seen most often about

the knee, MCP and MTP joints, and the radiocarpal and distal radioulnar articu-

lations of the wrist (see Fig. 9). They tend to appear amorphous or cloudlike

and are located at the joint margins where they may simulate idiopathic syno-

vial osteochondromatosis.

Fig. 8. (A,B) CPPD elbow and shoulder. The articular cartilage calcification (arrows) parallels the

subchondral bone. Note the synovial calcification in the lateral elbow (arrowhead).

Fig. 9. CPPD knee. Extensive calcification in the meniscus (large arrow), articular cartilage (arrows),

and synovium (long arrows).


CPPD crystal deposition of the joint capsule is most common in the elbow and

MTP articulations, but it also may be found in the MCP and glenohumeral joints.

Capsular calcifications tend to be fine, irregular linear densities that span the

articulation. They may be associated with joint contractures, particularly in the

elbow [36].

Tendon calcifications occur commonly in the Achilles, triceps, quadriceps,

and supraspinatus tendons. Tendon calcifications are thin, linear, and extend a

considerable distance from the osseous insertion; they imitate findings of idio-

pathic calcific tendonitis. Unlike the thin and linear appearance of tendon and

ligament calcification, bursa calcifications typically are amorphous or cloudlike

[41]. Bursa calcification is associated commonly with olecranon bursitis. In the

shoulders, tendon and bursa calcifications frequently are asymptomatic; when

symptomatic, they present with acute pain and tenderness. Occasionally, CPPD

may be be mistaken for gout, particularly in the digits where CPPD soft tissue

tumorlike collections of calcifications can resemble gouty tophi [42].

Structural joint changes that are associated with CPPD crystal deposition are

common and often are characteristic of the disease. The changes are similar to

OA with joint space narrowing, subchondral sclerosis, and subchondral cyst for-

mation (Figs. 10 and 11). They are not always accompanied by radiologically

evident calcification [41], and in the absence of calcification it may be difficult to

differentiate OA from CPPD arthropathy. The intra-articular joint distribution and

the joints that are involved aid in this differentiation.

The location of the structural damage in particular joints helps to distinguish

CPPD arthropathy from OA. As with OA, CPPD arthropathy tends to be bilateral

and asymmetric and is most common in the knee (see Fig. 11); however, ad-

vanced, asymmetric, or isolated involvement of the patellofemoral compartment

should raise the possibility of CPPD, particularly when accompanied by erosions

of the adjacent supracondylar femoral cortex. CPPD favors the radiocarpal

Fig. 10. CPPD arthropathy with scapholunate advanced collapse of the wrist. There is narrowing of

the radiocarpal joint with a large ‘‘cystic’’ lesion (geode) in the distal radius. There is widening of the

scapholunate ligament with proximal migration of the capitate. Calcification adjacent to the proximal

lunate is likely in articular cartilage.

choi et al438

compartment of the wrist and frequently involves the MCP joints, atypical loca-

tions for OA. Isolated involvement of the radiocarpal or trapezioscaphoid articu-

lations in the wrist is much more typical of CPPD crystal deposition disease.

Scapholunate advanced collapse of the wrist is seen in OA, rheumatoid arthritis,

and CPPD. CPPD crystal deposition in the scapholunate ligament predisposes to

disruption of the joint with subsequent scapholunate-associated collapse [43]. A

pattern of joint degeneration that is atypical of OA, but typical for CPPD,

involves the MCP joints.

Nonweight-bearing joints, which are affected infrequently by OA, are in-

volved commonly by CPPD arthropathy. The subchondral cysts that are asso-

ciated with CPPD arthropathy often are more numerous and larger. Cysts in

Fig. 11. CPPD arthropathy simulating neuropathic joint. AP (A) and lateral (B) view of knee reveal

extensive joint destruction, particularly in the medial compartment. The widening of the lateral

compartment may be from ligamentous laxity. There is extensive lateral meniscal and synovial

calcification (arrows).


CPPD arthropathy also tend to have sclerotic margins and vary more in shape

and size. Variable osteophyte formation is seen more commonly with CPPD

arthropathy. Large, irregular bony excrescences are sometimes present in

CPPD arthropathy.

Hydroxyapatite deposition disease

In 1966, calcium hydroxyapatite (HA) crystals were implicated as a cause of

calcifications of the periarticular soft tissues and tendons, particularly in the

shoulder [44]. It is now known that deposits of this crystal may be responsible for

an idiopathic disorder (HADD), in which HA crystals are deposited particularly

in the periarticular tissues, mainly tendons and bursa. This entity has been

described under several names, including ‘‘calcific periarthritis,’’ ‘‘periarticular

apatite deposition,’’ and ‘‘calcifying tendinitis’’ [45].

Clinical features

HADD usually is monoarticular and occurs most frequently about the

shoulder, although other or multiple joint involvement may occur. The crystal

deposits may be asymptomatic; symptoms occur in 34% to 45% of patients in

whom calcifications are present. The disease has no gender predilection and

typically occurs between the ages of 40 and 70 years. The disorder may be

familial; recently, certain histocompatibility antigens were identified as having a

frequent association with this disorder [46]. The crystal deposition also may

occur in an intra-articular location. It may be a primary phenomenon or occur in

association with other disorders, including trauma, renal osteodystrophy, and

collagen vascular disease, particularly scleroderma and mixed connective tissue

disease. Deposition of this crystal also may be seen in patients who have tumoral

calcinosis and as a complication of multiple intra-articular steroid injections [47].

Typically, the onset of symptoms is acute with severe pain, tenderness, and a

local inflammatory response that may be associated with restrictive motion. Less

commonly, the disorder may be chronic, with less severe symptoms leading to

various degrees of incapacitation [44]. HADD is a well-recognized cause of

periarticular inflammation that may cause bursitis or tendonitis. More recently,

intra-articular HA deposition has been implicated as a cause of acute arthritis

[48,49].

Etiology

The mechanism by which calcification occurs within a tendon is understood

poorly. A ‘‘degenerative theory’’ proposes that trauma or stress that is associated

with a local decrease in blood supply leads to tendinous tears with resulting

calcification [50]. Uhthoff and coworkers [51] suggested that hypoxia in the

region of the tendon that is induced by mechanical, metabolic, or other factors

choi et al440

results in transformation of this region into fibrocartilage. The calcification is

mediated by the chondrocytes and is associated with vascular proliferation and

subsequent resorption of the calcific focus by macrophages. Calcification may

not be the inciting agent, and symptoms may occur with the dissolution of

calcium. When rupture of the calcific deposit occurs the HA crystals are spilled

into the surrounding soft tissue space or bursa, which sets off the acute inflam-

matory response.

The needlelike crystals on electron microscopy may be identified as purple

clumps by light microscopy with Wright’s stain. Complementary techniques for

identifying the crystals include electron microscopy and electron probe analy-

sis [45].

Imaging features in hydroxyapatite crystal deposition disease

The clinical features of periarticular HADD may mimic fracture, infection,

gout, or CPPD crystal deposition disease. Radiographic examination frequently

allows a definitive diagnosis of HA deposition. Often, imaging features vary,

depending on the chronicity and activity of disease. The general radiographic

features of periarticular HA crystal deposition are cloudlike and poorly defined

calcific deposits that initially blend into the surrounding soft tissues. With time

the HA crystal deposition may appear denser, homogenous, and more sharply

delineated, with a linear or circular configuration. Although osteoporosis, cystic

lesions, reactive sclerosis, and contour irregularities may be present, adjacent

osseous tissues usually are normal.

Capsular, tendinous, and bursal tissues about the shoulder are the most

common sites of articular and periarticular calcific deposits. In the shoulder, HA

Fig. 12. Classic HADD in supraspinatus tendon. (A) Calcification in supraspinatus tendon adjacent to

its insertion into the greater tuberosity of the humerus. (B) T2-weighted fat-suppressed coronal image

reveals low signal (calcification) in supraspinatus tendon with extensive edema and fluid in the

subacromial-subdeltoid bursa, mainly about the calcification.

Fig. 13. Calcific tendonitis with adjacent erosion. HADD deposition in distal supraspinatus tendon

with adjacent erosion in the humeral head (arrow).


crystal deposition is bilateral in nearly 50% of cases, and it is most common in

the supraspinatus tendon (Fig. 12). The other tendons of the rotator cuff and the

bicipital tendon may be involved. Calcification in the subacromial bursa appears

as a teardrop-shaped, ulcerated, or ‘‘skullcap’’ radiodensity that extends under the

greater tuberosity [52]. Osseous erosions may be located adjacent to tendon and

ligament insertion sites (Fig. 13). These may be associated with marrow edema

on MRI.

Besides the shoulder, HA crystal deposition may occur in the collateral

ligaments of the elbow—at the insertion of the triceps tendon into the olecranon

process (Fig. 14)—which is associated occasionally with triceps tendon rupture.

Fig. 14. HADD in a patient who had chronic renal failure and was on dialysis. Extensive calcification

in triceps tendon.

Fig. 15. Calcific periarthritis HADD in the gluteus maximus tendon at its insertion into the greater

trochanter (arrow).

choi et al442

Deposition of HA crystal also may occur in the axial skeleton. The longus

colli muscle, the principal flexor of the cervical spine, is involved most com-

monly in the neck. Other locations with HA crystal deposition in the spine have

been reported, including the infraoccipital region and interspinous bursae in

association with neck pain. In the hip, pelvis, and thighs, calcifications that have

a varied appearance are frequent in the gluteal insertions into the greater tro-

chanter and surrounding bursae (Fig. 15) [53–57].

HA crystal deposition may remain static for a long time. In other instances,

calcified deposits may change in size over time and become larger, smaller, or

disappear entirely (Fig. 16); however, reappearance of calcification also has been

reported [45]. Frequently, these changes in size and appearance occur in the

Fig. 16. HADD with disappearance of calcification. (A) Calcification adjacent to lateral acetabu-

lar margin in patient who had acute hip pain. (B) Two years later the calcification has re-

sorbed completely.


absence of symptoms. In addition, there is no definite correlation between the

sizes of periarticular calcifications and symptoms.

Articular deposition

HA crystals may become deposited in the synovial membrane, in the joint

capsule, or occasionally in cartilage (chondrocalcinosis). Joints frequently in-

volved by HA crystal deposition include the shoulder, knee, hip, and small joints

of the hand and feet. Generally, the calcifications appear as homogeneous,

cloudlike, intra-articular radiodensities that do not follow anatomic structures. In

some patients, synovial fluid or cartilage may reveal calcium HA and CPDD

crystals, a condition that is termed ‘‘mixed calcium phosphate crystal deposition

disease.’’ This disorder should be suspected if radiographs reveal extensive car-

tilage calcification and diffuse intra-articular and capsular calcification or dense,

homogeneous calcific deposits within tendons.

Intra-articular accumulation of HA crystals may occur in the absence of ra-

diographically apparent calcification. Synovial membrane, capsule, or both can

be involved that contain amorphous or fluffy cloudlike areas of increased ra-

diodensity. Rarely, chondrocalcinosis also is present within the meniscus of the

knee. Because HA crystal deposition is associated with OA, the radiographic

feature of one may accompany the other. Typically, small joints are affected, but

involvement of other joints, such as the wrist, knee, hip, and shoulder, have

been reported.

Destructive arthropathy that is associated with HA crystal deposition in the

shoulder is referred to as a Milwaukee shoulder syndrome. This consists of joint

space loss, subchondral sclerosis, osseous debris, joint disorganization, and

deformity. A large effusion that contains calcified debris may be present. The

humeral head is displaced superiorly, and even may contact the acromion as a

result of associated disruption of the rotator cuff with remodeling and erosion of

the acromial undersurface.

Associated arthropathy of the knee in patients who had shoulder arthropathy

has been reported. Unicompartmental involvement is typical, particularly the

lateral fibisfemoral articulation, which leads to narrowing, collapse of the articu-

lar surface, sclerosis and fragmentation, and valgus angulation.

Summary

The radiographic appearance of MSU, CPPD, and HA crystal-induced ar-

thropathies have been reviewed. The recognition of the often distinctive radio-

graphic appearance of crystal-induced disease may allow a specific diagnosis.

Radiography has a small role in the diagnosis of initial attacks of acute gouty

arthritis. Radiographic findings are a late manifestation of the disease, and in-

clude lobulated eccentric soft tissue masses, intra-articular and extra-articular

osseous erosions, relative preservation of joint space, subperiosteal apposition

choi et al444

of bone, intraosseous calcification, and secondary degenerative changes, with-

out osteoporosis.

In CPPD crystal disease, characteristic radiologic features include articular

and periarticular calcification and an arthropathy that consists of joint space

narrowing, bone sclerosis, prominent subchondral cyst formation, occasional se-

vere and progressive destructive bone changes, and variable osteophyte forma-

tion. Often, these findings are seen in a characteristic intra-articular distribution

with involvement of characteristic sites, such as the patellofemoral compartment

of the knee and the radiocarpal compartment of the wrist. The findings may occur

in the absence of radiographically demonstrable chondrocalcinosis.

HA crystal deposition leads to periarticular calcifications that are associated

with typical radiographic findings. These are observed most frequently in the

shoulder, with calcifications of varying size and shape in the tendons, bursae, and

capsule. The disease may be mono- or polyarticular in distribution. When intra-

articular, HA crystals can cause joint destruction.

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