Introduction:There are a variety of crystals that may be

associated with joint and soft-tissue problems, due to theirdeposition in and around joints1- (Table 1). This review willfocus primarily on the potential problems associated withmonosodium urate monohydrate (MSU) crystal deposition andthe calcium crystal associated problems.

where they are associated with degenerative changes. Thecrystals may provoke an acute attack of synovitis- referred toas pseudo-gout. The deposits are often visible as a fine layerof calcification overlying the menisci and articular cartilageof the knee- termed chondrocalcinosis; and BCP crystals canalso cause acute inflammatory attacks of arthritis, usuallyaround the shoulder, referred to as calcific periarthritis2.I. Calcium pyrophosphate dihydrate (CPPD) crystalassociated arthropathies: CPPD crystal deposition disease isusually idiopathic and presents as sporadic episodes in themajority of patients. There are rare familial forms of thedisease and an association with some metabolic disorders- suchas hyperparathyroidism, haemochromatosis, hypophosphatasia,Wilson’s disease, ochronosis, hypo-calciuric hypercalcaemia(and perhaps other hypercalcaemic states), diabetes mellitusand hypomagnasaemia- has been documented3,5. Treatment ofosteoarthritis (OA) of the knee with intra-articular injectionsof hyaluronic acid preparations (such as Hylan GF-20) hasalso been associated with triggering of an acute attack ofpseudo-gout4.Familial CPPD deposition disease generally may present inone of two ways3: A rather benign, early onset (< 50 yrs),usually acute presentation, having a polyarticular distributioninvolving the knee, wrist, shoulder, elbow, hip or ankle andrecurrent episodes of crystal-positive acute pseudo-gout andchondrocalcinosis.The second a more chronicarthropathy, with a late onset (> 50 yrs), destructive oligo/mono-arthropathy, affecting the knees, wrists, shoulders orhips. Thus CPPD crystal associated disease is clinicallyheterogeneous and may cause both an acute or chronicarthritis. Some of the recognised clinical patterns of CPPDdeposition disease are5: Pseudogout is the most common form(also called CPPD disease type A) and presents as acuteepisodes of synovitis at a single joint, most often at the knee.More common in men, the ‘attack’ typically lasts from a fewdays to 3-4 weeks and is characterised by acute pain, swellingand warmth at the affected joint, often indistinguishable fromgout. X-ray of the knee may reveal typical calcification of themeniscus- chondrocalcinosis(figure 1) and the joint synovialfluid examination will reveal the typical positivelybirefringent CPPD crystals, on polarising light microscopy.Attacks may be precipitated by any intercurrent illness,recent surgery or trauma and rapid diuresis.

Address for correspondenceDr S J Gupta, FRCP (Edin), Consultant RheumatologistD-110, Defence Colony, New Delhi 110024.E-mail: sirinder@nde.vsnl.net.in

Table 1 Crystal Associated Arthropathies1

A: Commonly seen arthropathies:Crystal Association/arthropathy1. Calcium pyrophosphate Acute pseudogout; A variety dihydrate (CPPD) of chronic inflammatory or

degenerative arthritis;Chondrocalcinosis

2. Basic calcium phosphate Calcific periarthritis;Hydroxy- apatite (BCP) Acute/Chronic inflammatory

arthritis; Destructivearthropathy; Soft-tissuecalcinosis

3. Monosodium Urate (MSU) Acute/chronic goutyarthritis; Renal calculi;Tophi

B: Uncommon arthropathies:Crystal Association/arthropathy4. Calcium oxalate aluminium Acute arthritis in patients

phosphate on renal dialysis

5. Cholesterol Chronic synovial effusionsin RA/OA

6. Xanthine Acute arthritis (rare);Renal calculi; Asymptom-atic deposition in muscles

7. Cysteine/cystine Acute arthritis8. Charcot-Leyden Synovial fluid and tissues,

(lysophospho-lipase) with eosinophiliaA. Calcium Crystal Induced Inflammation:Calcium pyrophosphate dihydrate (CPPD) and basiccalcium phosphate hydroxy-apatite (BCP), are the commoncalcium containing crystals that can result in a variety of jointsymptoms due to their deposition in and around joints. CPPDcrystals may be deposited in fibrous and articular cartilage,

CRYSTAL INDUCED ARTHRITIS: AN OVERVIEWS J GuptaConsultant Physician & Rheumatologist, Apollo Indraprastha & Sant Parmanand Hospitals, New Delhi.

Practitioner Series: J Indian Rheumatol Assoc 2002 : 10 : 5 - 13

The distinguishing features of CPPD disease type B from RA,would be the presence of degenerative (OA) features, absenceof typical marginal erosions on x-rays of the hands or feet,presence of chondrocalcinosis and/or typical CPPD crystalson the synovial fluid examination and absence of rheumatoidfactor.Pseudo-osteoarthritis accounts for about 50% of CPPDpatients. It is also referred to as CPPD disease types C & D.There may be a non-inflammatory arthropathy affecting mainlythe wrists, elbows, shoulders or MCP joints. There are fairlymarked degenerative changes on radiology of the affectedjoint(s) in addition to chondrocalcinosis. Type C differs fromtype D, in that acute attacks are superimposed on the morechronic symptoms, whereas in type D, there are no acuteattacks of joint pain.

Asymptomatic is probably the most common form of CPPDdisease, also referred to as type E. It is clinically silent andasymptomatic. It is usually diagnosed by the presence ofchondrocalcinosis, detected by radiology, usually done forother reasons.Pseudoneuropathic also referred to as type F CPPD disease,is rare. It has been described in tertiary syphilis and severeneurotrophic arthritis. However, a similar clinical picture ofsevere joint destruction can also be seen in the absence of anyassociated neurological abnormalities. Joint aspiration revealsa non-inflammatory synovial fluid with a large number ofCPPD crystals.CPPD deposits can in addition, occasionally cause problemsat other sites: a) they may cause median nerve compression atthe wrist; b) may cause spinal canal stenosis due toinvolvement of the ligamentum flavum; c) and may even causea cervical spine myelopathy5.

PATHOGENESIS:CPPD deposition disease is essentially a primary

disorder of the articular cartilage with alterations in thechondrocytes being implicated in CPPD crystal formation6.Excess formation of inorganic pyrophosphate (PPi) by thechondrocytes, correlates with CPPD deposition. Other changesassociated with CPPD disease include; cartilage matrixabnormalities, presence of articular cartilage vesicles that actas sites of CPPD crystal formation, abnormalities of growthfactors and cytokines such as transforming growth factor β(TGF-β) that stimulate chondrocyte PPi generation. Onceformed, calcium crystals induce a variety of cellularsignalling molecules. Calcium crystals induce interleukin 8(IL-8) expression in monocytes2. IL-8 is a key mediator ofinflammatory synovitis and possibly also of chronic cartilagedegeneration associated with CPPD deposition disease.

DIAGNOSIS AND TREATMENT:An awareness of the clinical pattern of presentation

is essential for the diagnosis of CPPD disease. However,confirmation of the diagnosis is by the demonstration oftypical crystals of CPPD in synovial fluid of an affected joint,by polarising light microscopy. Features that help todistinguish CPPD disease from OA are the presence ofchondrocalcinosis on radiology and the involvement of jointsnot usually involved in OA.Radiological screening for CPPDdisease is done by AP views of the knees, pelvis (for pubisand hips) and both hands including wrists. Once CPPD dis-ease is diagnosed, the patient should be screened for the pres-ence of any associated metabolic disorders (vide supra). Treat-ment of CPPD disease remains empirical and symptomatic5.Non-steroidal anti-inflammatory drugs (NSAIDs) are the main-

Figure 1: Radiograph of knee showing fine line of calcifi-cation on articular cartilage (lateral compartment), typi-cal of chondrocalcinosis

S.J. Gupta

Pseudorheumatoid arthritis is seen in less than 5% of all CPPDpatients. It is also called CPPD disease type B. This isassociated with a sub-acute inflammatory polyarthritis, whichmay persist for a few months and therefore may ‘mimic’ RA

6

stay of initial therapy. In pseudo-gout, aspiration of the jointfollowed by an intra-articular steroid injection, would be thetreatment of choice. Intra-muscular injection of a long actingsteroid preparation such as triamcinalone or methyl-predniso-lone may also be helpful to abate an acute attack. Intravenouscolchicine is effective in acute pseudo-gout, however itstoxicity precludes routine use. Low dose oral colchicine (0.5mg twice or thrice a day) in addition to NSAIDs, mayhowever have an additive effect without significant toxicity.

II. Basic calcium phosphate hydroxy-apatite (BCP) crystalassociated arthropathies:The BCP crystals include hydroxy-apatite, octacalciumphosphate and tricalcium phosphate. BCP crystals may beassociated with a number of clinical situations such as5:Periarthritis / tendonitis: BCP crystals often cause aperiarthritis, usually around the shoulder joint, or a calcifictendonitis or bursitis. Patients present with acute pain andwarmth in the affected area and the diagnosis is suggested bythe presence of extra-articular calcium deposits on radiology.Patients usually respond to NSAIDs, low-dose colchicine and/ or intra-lesional injection of steroids. Recently, EDTAtreatment has been reported to be effective in the removal ofcalcific deposits2.Milwaukee shoulder syndrome (MSS): This condition ismore common in women. MSS usually affects a singlejoint- most often the shoulder, or the knee. There is a gradualonset synovitis and there may be a history of preceding traumaor overuse of the joint. There are marked degenerative changeson radiology, with the presence of loose bodies andcalcification. At the shoulder, large and extensive rotator-cufftears maybe present. Diagnosis may not be easy, asrecognition of BCP crystals is difficult and the diagnosis mayeventually depend upon excluding other causes such as goutor septic arthritis. CPPD disease may cause diagnosticconfusion, particularly as CPPD crystals maybe seen in about30% of patients with MSS. There is no specific treatment andvarious measures include- NSAIDs, repeated joint aspiration,intra-articular steroid injections and eventually (if jointdestruction is marked) arthroplasty.Osteoarthritis: BCP crystal deposition may present asosteoarthritis (OA). The quantity of BCP depositioncorrelates with the extent of degenerative change. The exactrole of BCP crystals in this situation however, remainsunclear.Erosive arthritis: An erosive arthritis associated with BCPcrystals has been described. Patients may show a peripheralor axial arthritis. Radiology reveals bony erosions withcalcification. Intramuscular steroid and low dose colchicineorally, may be helpful.

III. Calcium oxalate associated arthritis:Calcium oxalate crystals produce an unusual form of arthritisand the clinical situations that may be associated with cal-cium oxalate arthritis are end stage renal disease on dialysis;short bowel syndrome; diets rich in rhubarb, spinach or ascor-bic acid; thiamine or pyridoxine deficiency; primary oxalosis(a rare inborn error of metabolism). 5

Primary oxalosis is quite rare, though about 90% of patientson chronic haemodialysis may show evidence of depositionof calcium oxalate in kidney and bone tissue.The clinical picture is that of an acute mono- or oligo arthritismainly affecting the proximal interphalangeal (PIP) andmetacarpophalangeal (MCP) joints of the hands. Bursalinvolvement and teno-synovitis may be associated and thearthritis may become chronic. The diagnosis can be confirmedby identifying the typical calcium oxalate crystals(bipyramidal, positively birefringent, calcium oxalatedihydrate crystals) in synovial fluid. There is no specifictreatment. Symptomatic measures such as NSAIDs, intra-articular injections, colchicine and increased frequency ofdialysis, may be tried, but the response is poor.

B. Monosodium urate Monohydrate Crystal Induced Inflam-mation- GOUT:

Gout is the term given to a group of metabolicconditions, in which the signs and symptoms result from thedeposition of crystals of monosodium urate monohydrate(MSU) in various connective tissues and joints7. Thedeposition of these crystals, results from raised levels of uricacid in blood (hyperuricaemia) and various body fluids.Hyperuricaemia is however, not an essential requirement forthe diagnosis of gout and its presence in a patient witharthritis does not necessarily establish the diagnosis.However, the risk of gout increases with the degree andduration of hyperuricaemia. Established classification crite-ria for the diagnosis of gout include8 (table 2):• The presence of typical urate (MSU) crystals in synovialfluid.• The development of a tophus (figure 2).• The presence of a characteristic clinical picture, whichtypically, is an acute onset of severe, mono-articular arthritisin a peripheral joint in the leg (most often the 1st

metatarso-phalangeal- MTP- joint).The clinical manifestations of gout relate to the acute or chronicsituations and the renal syndromes associated with uric acidand include9:Acute gout; an acute inflammatory arthritis (synovitis); whichmaybe associated with teno-synovitis; bursitis; and/orcellulitis. There are recurrent attacks of acute synovitis andthe intervening period between attacks, is referred to as theinter-critical period.

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Chronic tophaceous gout; a chronic, erosive, deforming ar-thritis, associated with peri-articular and sub-cutaneous uratedeposits (called tophii).Renal disease and gout: Three main renal syndromes maybe associated with gout:1. Urate nephropathy: This is due to the formation of urate(MSU) crystals in the renal interstitium associated with renalinsufficiency. The exact relationship between the renaldysfunction and the deposition of urate crystals is, however,not clear. Renal dysfunction may be contributed byassociated uncontrolled hypertension or other medicalconditions.2. Uric acid nephropathy: This is an acute obstructiveuropathy, due to the rapid formation of uric acid crystals inthe collecting tubules, in an acutely ill and dehydrated patient(usually a patient with a lymphoproliferative disorder treatedwith cytotoxic drugs- ‘tumour lysis syndrome’.3. Uric acid nephrolithiasis: This is due to the formationof uric acid calculi in the renal tract. The risk factorsinclude- elevated urinary uric acid levels, low urine pH andhyperuricaemia.

The biochemical hallmark of gout is hyperuricaemia(even though it is not absolutely essential in establishing thediagnosis). Individuals may exhibit long periods of asymp-tomatic hyperuricaemia, before developing clinical symptoms.Hyperuricaemia in turn, maybe caused by- a) Dietary excessof purines; b) an overproduction (metabolic or genetic) of

urate; or c) an under-excretion of urate from the kidneys9,10.Gout therefore, may be classed as primary or secondary,depending upon the cause of hyperuricaemia:

Table 2 Classification Criteria For Acute Gout8

A. The presence of characteristic urate crystals in synovialfluid or

B. A tophus proved to contain urate crystals by chemicalmeans or polarsing light microscopy or

C. The presence of 6 of the following 12 parameters:1. More than one attack of acute arthritis2. Maximal inflammation developed within one day3. Attack of monoarticular arthritis4. Observed joint redness5. First metatarsophalangeal (MTP) joint painful

or swollen6. Unilateral attack involving 1st MTP joint7. Universal attack involving tarsal joint8. Suspected tophus9. Hyperuricaemia10. Asymmetric swelling within a joint on radiology11. Subcortical cysts without erosions on radiology12. Negative culture of joint fluid for microorgan isms during an attack of joint inflammation

Primary denotes the absence of any underlying diseasecausing hyperuricaemia. In most (75%-90%) individuals anunder-excretion of urate at the renal tubular level is themechanism involved. There is a reduced urinary uric acidexcretion/clearance. A minority of patients (<2%) withprimary gout will have an excessive purine biosynthesis dueto an inborn enzymatic defect. This rather rare clinicalsituation should be suspected if gout presents at an unusuallyearly age and is associated with a strong family history ofgout.Secondary maybe due to a) an overproduction of urate due toincreased metabolic activity as seen in the variousmyelo-proliferative disorders, haemolytic anaemia andpsoriasis; or b) due to an under-secretion of uric acid due torenal disease or drugs (such as diuretics, pyrazinamide,cyclosporine etc).

CLINICAL FEATURES/DIAGNOSIS OF GOUT:Acute gout is eight times more common in men than

women and the first attack commonly occurs between the thirdto sixth decades. It is extremely uncommon in women beforethe menopause10. The commonest joint to be affected is thefirst metatarso-phalangeal (1st MTP) joint, also referred to aspodagra. A typical attack is sudden in onset and awakens thepatient from sleep. The joint becomes red, hot, and swollen,

Figure 2: Typical tophii on the thumb and index finger,revealing ‘cheesy’ tophaceous material (a smaller tophusis also seen on the little finger)

S.J. Gupta

8

with shiny overlying skin, which may desquamate later. Thejoint is exquisitely painful and tender and the patient isusually unable to bear weight on it. The attack is notuncommonly mis-diagnosed as local infection. During an acuteattack, there may be constitutional symptoms such as anor-exia, nausea and fever. Leucocytosis and an elevated ESR mayalso be present. An elevated serum uric acid is usually (butnot invariably) present.

With the above clinical features, the diagnosis ofacute gouty arthritis, is fairly certain. However, in about 10%of patients, the initial presentation may be polyarticular withsparing of the 1st MTP joint, especially in elderly females onthiazide diuretics. Asymptomatic hyperuricaemia, is relativelycommon and a raised serum uric acid alone, does notnecessarily prove the diagnosis of Gouty arthritis. Conversely,serum uric acid will be elevated at some point in the clinicalspectrum of gout and must be documented in the patient, tomake the diagnosis. Occasionally acute attacks may occur withnormal serum uric acid levels.

To establish the diagnosis of gout beyond doubt,synovial fluid should be aspirated from an affected jointwhenever possible and examined under polarising lightmicroscopy to look for typical MSU crystals. These crystalswill appear as needle shaped, negatively birefringent crystals.

Following the initial acute attack, some patients mayremain free of symptoms for long periods- the ‘intercritical’period. Others experience repetitive attacks with shorteningof the intercritical period and may even get polyarticularsymptoms leading to diagnostic confusion. Recurrent acuteattacks may result in chronic tophaceous gout, with tophii beingfound typically in the periarticular tissues, cartilaginous helixof the ear, bursae and tendon sheaths. The tophii appear asperi-articular swellings, filled with a soft, ‘cheesy’ or ‘chalky’material. This tophaceous material will reveal numeroustypical MSU crystals, when examined under polarising lightmicroscopy.

Gout and hyperuricaemia are often associated withobesity, type IV hyperlipidaemia, impaired glucose toleranceand ischaemic heart disease9. It is important to identify theseassociations, in the overall management of the patient.

RADIOLOGICAL CHANGES:X-rays are usually normal early in the disease. After

a few repetitive acute attacks, the typical change is a punchedout erosion, with sharp margins and overhanging edges (fig-ure 3). Other non-specific changes are a reduction in joint

space and presence of sub-articular cysts. The erosions mayhowever, be indistinguishable from those seen in otherinflammatory joint diseases. Para-articular tophii may bedetected as soft tissue swelling with partial calcification.

DIFFERENTIAL DIAGNOSIS:Acute gouty arthritis must be distinguished from

other causes of acute mono-arthritis, such as infective (septic)arthritis; traumatic synovitis; palindromic rheumatism orpalindromic onset rheumatoid arthritis; the sero-negative

Figure 3: Radiograph of foot, showing typical‘punched out’ gouty erosion at 1st MTP joint. Asub-articular cyst is also seen (at the 1st MTP head)

spond-arthritides, such as psoriatic arthritis or spondarthritiswith peripheral joint synovitis, or sarcoid arthritis.Chronic tophaceous gout maybe confused with nodular rheu-matoid arthritis; osteoarthritis with Heberden’s / Bouchard’snodes; xanthochromatosis with joint involvement; andreticulohistiocytosis.

TREATMENT:It is important to emphasise that amongst all forms

of inflammatory joint disease, the drug treatment of gout,often produces the most satisfactory results. The treatment of

Crystal induced arthritis : an overview

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gout can be considered under the following situations:A. Treatment of acute attack;B. Prevention of subsequent attacks and treatment ofhyperuricaemia;C. Management of gout in special situations.

A. TREATMENT OF ACUTE ATTACK:NSAIDs, colchicine and steroids (intra-articular or systemic)form the main-stay of treatment of an acute attack ofgout7,10-12.NSAIDs: The first line of therapy is to rest the affected jointand to use full doses of a non-steroidal anti-inflammatory drug(NSAID). The NSAIDs that are of particular benefit in thissituation, are indomethacin 50mg 8 hrly (or maximum 50mg6 hrly); naproxen 500mg 12 hrly; ketoprofen or flurbiprofen100mg 8 hrly; or diclofenac 50mg 8 hrly. However, any NSAIDcan be used in optimum doses, provided the patient’s renalfunction is normal. The use of the newer class of cox-IIinhibitors of NSAIDs may be a therapeutic option for patientswhere GI side effects preclude the use of the previousnon-selective NSAIDs. However, currently there does not seemto be any specific information on this13.

Colchicine: Colchicine can be a useful adjunct to NSAIDs ifthe acute attack does not settle rapidly. In a dose of 0.5 mgtwice or three times a day, one can avoid the GI side effectsseen with higher doses of colchicine and still obtain addedtherapeutic benefit. The ‘traditional’ way of using oralcolchicine was to give an initial dose of 0.6-1.2 mg, followedby 0.6mg every 2 hours until relief of symptoms occur ordiarrhoea develops12. Colchicine is certainly effective inrelieving most acute attacks of gout however, invariably, GIside effects (nausea, cramps, vomiting or diarrhoea) will in-tervene, if it is used in this manner. Intravenous colchicinehas been reported to be very effective in treating acute goutand some rheumatologists advocate this as the treatment ofchoice. However, others caution against the use ofintravenous colchicine, due to the potential for serious sideeffects, which include bone marrow suppression, renalfailure, alopecia, disseminated intravascular coagulation,hepatic necrosis, diarrhoea, seizures and death11. Therefore,the current recommendation would be to use colchicine in adose of 0.5mg twice or three times a day, in addition to anNSAID for the acute attack of gout. Following an acuteattack, a patient is at increased risk of further acute attacksand therefore, colchicine in a dose of 0.5mg twice a day canbe continued for a few weeks, to prevent this12.

Steroids: Most acute attacks respond satisfactorily to eitherfull doses of an NSAID, or to the combination of an NSAID

and low dose colchicine, as described above. Occasionally,the clinical response may not be as rapid as desired, or it mayprove necessary to aspirate the affected joint for diagnosticsynovial fluid analysis. In either situation, injecting theaffected joint with steroid (methyl-prednisolone ortriamcinalone) may prove to be extremely useful in rapidlyresolving the synovitis. Intra-articular steroid can also be veryuseful in situations where NSAID use is contra-indicated,either due to GI intolerance or renal involvement.Intra-articular steroids are beneficial when one or at most twojoints are inflamed. In situations where more than 2 joints areinvolved and renal/GI side-effects preclude the use of NSAIDsand colchicine, systemic steroids have been shown to bebeneficial14. Intra-muscular long acting steroid (eithermethyl-prednisolone or triamcinalone) 40mg or 80mg can bevery effective in this situation, in relieving the acute attack. Anote of Caution: an intra-articular injection should be given,only if one can be clinically sure, that one is not dealing witha septic arthritis. If in any doubt, the synovial fluid should besent for microbial cultures (in addition to being subjected topolarising microscopy) and if still indicated, the joint can beinjected once the culture and Gram’s stain examination ruleout infection.It is also extremely important to remember thatallopurinol or uricosuric drugs should not be commencedduring an acute attack of gout. These drugs should beinitiated only after satisfactory resolution of the acute attack10

and on adequate colchicine/NSAID prophylactic cover (videinfra).

B. PREVENTION/LONG-TERM TREATMENT:Prevention of recurrent attacks of acute gout and con-

trolling hyperuricaemia, are the long-term treatment goals inmanagement of patients with gout. Not all patients who havehad an attack of acute gout will require long-term treatment.Patients who continue to experience attacks of acute gout andhave persistent hyperuricaemia despite efforts to correct otherfactors causing hyperuricaemia, require treatment to lower uricacid levels12.We can consider this aspect of treatment as follows:1. Non-pharmacological treatment involves avoiding/reducing factors that contribute to the development of gout inpatients with asymptomatic hyperuricaemia. The measuresfound to be useful are11; to avoid diuretic therapy; weight gain;alcohol consumption; Aspirin therapy: In high doses, aspirinis uricosuric. However, when commenced in low dose (75-100 mg daily), aspirin initially causes a reduced excretion ofuric acid from the kidney and may increase hyperuricaemia.Diet: Providing that the above precautions are followed,stringent dietary restrictions are not required10. However,

S.J. Gupta

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patients should be advised to avoid excessive (‘binge’) eatingor drinking (to avoid an acute increase in serum uric acid) andoverweight patients should be encouraged to undertake someregular exercise, with a view to gradual weight reduction. Thisis contrary to the previously held belief that a patient withgout had to be provided with a list of food articles to avoidtotally, some that could be taken in moderation and some thatwere allowed freely. The current concept is based on therelationship between obesity, diet and insulin resistance, togout15. Insulin stimulates the renal tubular sodium-hydrogenexchanger and results in an increase in the tubularreabsorption of urate11. Therefore, a diet that is low incarbohydrate content, with a proportionate increase inproteins and unsaturated fats, will help to reduce serum uricacid levels by enhancing insulin sensitivity (and therebyreducing serum insulin levels proportionately).2. Long-term management & treatment of hyperuricaemia:Prevention of gouty attacks: Colchicine is effective inpreventing recurrent attacks of acute gout, in patients who havesustained a previous acute attack and also in patients whocommence a uric acid lowering agent10,11,16. Colchicine 0.5mg twice a day, is recommended for a patient at the time ofcommencing a urate-lowering drug. Once serum uric acidlevels are controlled and the patient has been free from acuteattacks for about 2-3 months, the colchicine can be withdrawn.Urate-lowering therapy: There is no uniform agreement onwhen to commence a patient on a urate-lowering drug. Somemaintain that this therapy should be initiated only after apatient experiences 3-4 attacks in a year17. However, othersmaintain that this treatment is cost-effective even if a patienthas one attack a year18. Unequivocal indications for startingurate-lowering treatment include:(a) Recurrent and frequent acute gouty attacks - at least 2-3per year;(b) Clinical evidence of tophii, urolithiasis or chronic jointdamage;(c) Existing renal disease;(d) A young patient, with hyperuricaemia and a significantfamily history of renal or heart disease.There are 2 main classes of drugs used to lower serum uricacid: 1) The uricosuric agents and 2) xanthine oxidaseinhibitors.1. Uricosuric agents:

The two commonly used uricosuric drugs areprobenacid and sulfinpyrazone. Adequate lowering of serumuric acid can be achieved by 1 gm probenacid daily and 400mgto 800mg sulfinpyrazone daily, respectively. However, long-term control of serum uric acid is not ideal in about 25% ofpatients with these agents7. The main potential problem withusing a uricosuric agent, is the risk of precipitating the

formation of uric acid crystals in urine with the deposition ofuric acid in the renal tubules, pelvis or ureter, causingurolithiasis and/or a further deterioration in renal function.Uricosuric agents therefore, should be considered in patientswith hyperuricaemia, who have normal renal function, noevidence of urolithiasis and have a urinary urate excretionbelow 700mg in 24 hours12. If a decision to use a uricosuricagent is taken, the previously mentioned complications canbe reduced by the following additional measures- a)gradually increasing the dose of the drug; b) ensuring anincreased fluid intake and consequently a high urine volume;and c) preferably alkalinising the urine with oral bicarbonate.

2. Xanthine oxidase inhibitors:This class of drug remains the drug of choice for

lowering serum uric acid and consequently the long-term treat-ment of gout, due to its convenience of administration andfreedom from side-effects10. Allopurinol is the onlyavailable drug in this class and can be used in bothoverproducers as well as underexcretors of uric acid12. A doseof 300 mg daily is usually adequate to lower serum uric acidto normal values in about 85% patients7. A single daily doseis adequate, as its main active metabolite oxypurinol, has along half-life. The usual practice is to start with 100mgallopurinol daily (to avoid the risk of precipitating an acuteattack of gout) and to build up the dose slowly by incrementsof 100 mg, to the least dose (usually 200 mg-300 mg) requiredto adequately lower the serum uric acid. The risk ofprecipitating an acute attack can be reduced further, by usingcolchicine in a dose of 1 mg daily, starting about 2 weeksbefore initiating treatment with allopurinol and continuing forabout 2-3 months. Once the urate-lowering therapy has beensuccessfully introduced, the therapy should be continuedlife-long7. Allopurinol is particularly indicated in patients withestablished gout and particularly if they have additionalurolithiasis. The aim of therapy would be to lower the serumuric acid to 6 mg/dl to prevent recurrent attacks of acute goutand preferably to 5 mg/dl, to further reduce tophaceousdeposits7. In addition, allopurinol is indicated in patients withrenal disease (vide infra) and in patients with secondary goutand myeloproliferative disorders with increased cell turnover7.

C. MANAGEMENT OF GOUT IN SPECIALSITUATIONS:

There are 3 clinical situations that pose special prob-lems in the management of gout: 1) Management of an acuteattack in a patient intolerant to NSAIDs; 2) Management ofacute and chronic gout in patients with renal disease; and 3)Long-term management of gout in a patient who is hypersen-sitive to allopurinol.

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1. NSAID intolerance: As has been mentioned earlier,patients in whom traditional NSAIDs cannot be used due totheir GI effects can be managed by:• Using the newer cox-II inhibitor NSAIDs;• Using steroids- either intra-articular or intramuscular- to treatthe acute attack, together with a very low dose of colchicine ifneeded;•Using allopurinol as long-term therapy (possibly even aftera single attack of acute gout) with the aim of trying to abolishacute attacks as far as possible, thereby obviating the need forNSAIDs.2. Renal disease: The management of gout in patients withrenal disease can be considered in the following situations:In patients with renal impairment, NSAIDs arecontra-indicated or should be used with extreme caution.Therefore, managing an acute attack of gout in a patient withrenal failure, essentially involves the use of steroids- eitherintra-articular or intra-muscular and if needed, even a shortcourse of oral prednisolone- commencing with 30 mg to 40mg prednisolone daily, and tapering the dose over 2-3 weeks11.The dose of allopurinol needs to be reduced appropriately inrenal failure, reducing to about 200 mg daily with a GFRbelow 60 mls/mt and to 100 mg daily at a GFR below 30 mls/mt respectively12.In patients following renal transplant, some importantissues in the management of gout need to be considered11.Renal transplant recipients are usually on cyclosporine, whichitself impairs the renal handling of uric acid. In addition, con-comitant renal impairment and the use of diuretics, may causefurther hyperuricaemia. The use of colchicine can cause amyoneuropathy and this is particularly so in transplantrecipients. The diagnosis is suggested by proximal weaknessand absence of deep tendon reflexes and can be confirmed bymuscle biopsy11. A modified regime of colchicine is proposedfor renal transplant patients- a maximum dose of 1.2 mg dailyfor the first 2 days, reducing to 0.6mg daily after this andstopping after 7-9 days. Steroids are the anti-inflammatoryagents of choice in transplant recipients, as NSAIDs wouldfurther compromise renal function. The incidence oftophaceous gout is perhaps more in renal transplant patients(probably aggravated due to the use of cyclosporine) andtherefore uric acid lowering therapy with allopurinol, shouldbe used in all transplant recipients with gout, who are also oncyclosporine11. If a patient is on azathiaprine, then themaximum daily dose of allopurinol in this situation shouldnot exceed 50 mg daily (due to the potentiation of azathiaprineactions by allopurinol). Alternatively, azathiaprine can besubstituted by mycophenolate mofetil (MF), as this agentblocks de novo purine synthesis by its effect of inhibition ofthe enzyme inosine monophosphate dehydrogenase11. Patients

on MF should be given allopurinol in a dose of 100 mg daily.In transplant recipients, where the GFR is greater than 50 mls/mt, a uricosuric agent such as probenacid in a dose of 250 mgtwice daily could be considered as further uric acid loweringtherapy, together with maintaining adequate hydration andalkalisation of the urine11. A new uricosuricagent- benzbromarone available in some European countries(not yet available in India), has been found to be useful inrenal transplant patients.

3. Allopurinol Sensitivity: Approximately 2% of patientstreated with allopurinol develop a rash. Usually this is mildand resolves on stopping the drug. Allopurinol can often becautiously re-introduced at a lower dose, without a recurrenceof the rash7. However, about 0.1% patients may develop themore serious problem of exfoliative dermatitis and requiresystemic steroids. De-sensitisation by the oral or intravenousroute may be attempted and is occasionally successful. Onemust however be extremely cautious as a severe reaction couldbe provoked. In a very small minority of patients, whereallopurinol cannot be used, a uricosuric agent can besubstituted for long-term treatment of gout.

References:1. Nuki G. Crystal deposition diseases. In: Haslett C, Chilvers

ER, Hunter JAA & Boon NA Eds: Davidson’s Principlesand Practice of Medicine 18th Edn 1999. ChurchillLivingstone. 829-830.

2. Halverson Paul B, Derfus Beth A. Calcium crystal-inducedinflammation. Curr Opin Rheumatol; 2001. 13: 221-224.

3. Fam Adel G. What is new about crystals other thanmonosodium urate? Curr Opin Rheumatol 2000. 12:228-234.

4. Luzar MJ, Altawil B. Pseudo-gout following intra-articularinjection of sodium hyaluronate. Arthr Rheum 1998;41: 939-940.

5. Rosenthal Anne K. Crystal Arthropathies. In: Maddison PJ,Isenberg DA, Woo P & Glass DA Eds: Oxford Textbook ofRheumatology 2nd Edn 1998. Oxford University Press.1567-1575.

6. Rosenthal Anne K. Formation of calcium pyrophosphatecrystals: biologic implications. Curr Opin Rheumatol 2000.12: 219-222.

7. Emmerson B T. The management of gout. New EnglandJournal of Medicine 1996; 334: 445-450.

8. Wallace SL, Robinson H, Masi AT et al. Preliminary criteriafor the classification of the acute arthritis of primary gout.Arthritis Rheum 1977; 20: 895-900.

9. Rosenthal Anne K. Crystal Arthropathies. In: Maddison PJ,Isenberg DA, Woo P & Glass DA Eds: Oxford Textbook ofRheumatology 2nd Edn 1998. Oxford University Press.1560-1561.

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Crystal induced arthritis : an overview

10. Nuki G. Gout. In: Haslett C, Chilvers ER, Hunter JAA &Boon NA Eds: Davidson’s Principles and Practice ofMedicine 18th Edn1999. Churchill Livingstone. 831-834.

11. Schlesinger N, Schumacher Ralph H Jr. Gout: canmanagement be improved? Curr Opin Rheumatol 2001;13: 240-244.

12. Wise Christopher M, Agudelo Carlos A. Diagnosis andmanagement of complicated gout. Bull on Rheum Diseases1998. Atlanta Page no -

13. Schumacher Ralph H Jr. Crystal-associated disease.(Editorial) Curr Opin Rheumatol 2001; 13: 219-220.

14. Groff GD, Franck WA, Raddatz DA. Systemic steroid therapyfor acute gout: a clinical trial and review of the literature.

Semin Arthritis Rheum 1999; 19: 329-336.15. Agudelo Carlos A, Wise Christopher M. Gout: diagnosis,

pathogenesis and clinical manifestations. Curr OpinRheumatol 2001; 13: 234-239.

16. Paulus HE, Schlosstein LH, Godfrey RC et al. Prophylacticcolchicine therapy in intercritical gout. Arthritis Rheum 1987.17; 609-614.

17. Fam AG. Should patients with interval gout be treated withurate lowering drugs? (Editorial) J Rheumatol 1995; 22:1621-1623.

18. Ferraz MB. An evidence based appraisal of the managementof tophaceous interval gout. J Rheumatol 1995;22:1618-1620.

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