association of hla-dr4/dw4 and dr2/dw2 with radiologic changes in a prospective study of patients...

ASSOCIATION OF HLA-DR4/Dw4 AND DR2/Dw2 WITH RADIOLOGIC CHANGES IN A PROSPECTIVE STUDY

OF PATIENTS WITH RHEUMATOID ARTHRITIS

Preferential Relationship with HLA-Dw Rather Than HLA-DR Specificities

ADAM YOUNG, DOLORES JARAQUEMADA, JULIETTE AWAD, HILLIARD FESTENSTEIN, MARY CORBETT, FRANK C. HAY, and IVAN M . KOITT

Patients admitted to a prospective study within a year of onset of suspected rheumatoid arthritis showed a positive correlation between HLA-Dw4 and the eventual severity of peripheral radiologic changes. Dw4 and DR4 were strongly associated with severity of erosions when analysis was restricted to each of the following: patients with erosions, those under 50 at onset, and all females. Relationships were consistently stronger with Dw4 than with DR4. Another D-related specificity, MT3, was positively correlated and Dw2/DR2 negatively correlated with erosions.

Although the evidence from family studies is not conclusive, most investigators have found a definite but weak familial aggregation of rheumatoid arthritis (RA). Recent reports on genetic studics have established an association with the HLA-Dw4 and DR4 antigens (1-4). Individuals with this tissue type are at increased risk of developing the disease, where- -. - -

From the Departments of Immunology and Rheumatology, Middlesex Hospital and Medical School. London W I and Depart- ment of Immunology, London Hospital Medical College. London, E l , UK.

Supported by the Arthritis and Rheumatism Council and Medical Research Council.

Adam Young. MA, MB, BChir, MRCP: Senior Registrar, Department of Immunology, Middlesex Hospital Medical School; Dolores Jaraquemada, MSc; Juliette Awad, MSc; Hilliard Festen- stein, MU, BChir, FRCPath, FIRiol: Professor and Head of Depart- ment of Immunology, London Hospital Medical College; Mary Corbett, FRCP: Consultant Rheurnatologist, Department of Rheu- matology, Middlesex Hospital; Frank C. Hay, PhD: Senior Lectur- er ; Ivan M. Roitt, DSc, FRCPath. FRS: Professor and Head of Department of Immunology. Middlesex Hospital Medical School.

Address reprint requests to Professor I. M. Roitt, Dcpart- ment of Immunology, Middlesex Hospital Medical School, Arthur Stanley House, 40-50 Tottenham Street, London W1P 9PG, UK.

Submitted for publication January 25, 1983: accepted in revised form August 2, 1983.

as HLA-DR2 subjects have a decreased relative risk. However, an association between HLA and severity of rheumatoid disease has not been fully substantiated. These findings have generally been based on patients with certain forms of the disease. in particular erosive or classic and definite RA as assessed by the American Rheumatism Association (ARA) criteria (5) . RA is known to include a heterogeneous group of conditions with a highly variable outcome and response to treatment. This area of research is complicated by the differing methods of clinical diagnosis and selection of patients for study.

The Middlesex Hospital Rheumatoid Arthritis Prospective Study (RAPS) has now been in progress for 15 years and has been the subject of several reports (6-10). Because of the special nature of prospective studies and the particular selection criteria used in this study, a wide spectrum of patients has been observed. In an attempt to make an objective analysis of both the possible prognostic value of HI.A-DK2/Dw2 and HLA-DK4/Dw4 in RA and the clinical heterogeneity of the condition, we have recently tissue typed many of these patients and have sought a correlation with severity of radiologic changes.

PATIENTS AND METHODS Selection of RAPS patients. The design of the RAPS

study has been previously described (6). Patients were referred to a special research clinic if the rheumatologist in the outpatient clinic had made a diagnosis of KA of less than 1 year’s duration. This diagnosis was made primarily on cIinical grounds when a patient had a persistent symmetric polyarthritis of several months’ duration, mainly in the small joints of the hands and feet, and when conditions such as psoriatic arthritis, systemic lupus erythematosus. and anky- losing spondylilis had been excluded. Patients may already

Arthritis and Rheumatism, Vol. 27, No. 1 (January 1984)

HLA-DW AND RADIOLOGIC CHANGES IN RA 21

Table 1. arthritis (RA) at latest visit

HLA specificities and radiologic findings in hands and feet of patients with rheumatoid

HLA type

Dw 1 D W 2 Dw3 Dw4 Dw5 Dw6 Dw7

Total+

Subjects

Controls* R A patients 16 23 17 18 19 29 22 38 8 8 4 5

24 20 73 104

Radiologic erosions ~

None Mild Moderate Severe

DR I 25 DR2 34 DR3 31 DR4 38 DR5 12 DR6 13 D R l 21

Total: 105

19 6 20$ 9 20 3 520 12 12 5 9 2

20 1 95 26

10 6 4 3 9 6 I 9 4 1 1 12 9 7 6 14 I 1 2 4 2 0 0 1 I 3 6 5 7 2

28 21 33 16

6 7 9

10 3 .o 5

25

4 3 2 2 5 3

18 12 4 0 3 4 6 2

16 28

* Controls consisted of a panel of healthy British individuals (white) typed in the Department of Immunology, London Hospital Medical College over the last 3 years. i Totals refer to the number of patients in each group and not the sum of numbers in columns since most patients have more than one IlLA-I)(R) specificity. t x 2 = 3.2, P =: 0.06 (patients versus controls). 8 x 2 = 6.9. P = 0.008 (patients versus controls).

have been positive for rheumatoid factor and may already have developed bony erosions. These patients were seen in a separate clinic 3 times a year during which clinical assessment and laboratory investigations were performed. There was no involvement with overall management and treatment. All patients were white, as was the control group.

Radiologic assessment. Radiographs of the hands and feet were performed once a year. The sequential films of the hands and feet were assessed independently by 1 rheumatologist and those of the cervical spine in flexion and extension by another. A previously described separate study (10) of 20 of these RAPS patients by a third rheumatologist concurred with the original classification, except for 2 patients in whom the distinction between mild and moderate was borderline. The roentgenograms of the hands and feet were assessed for the presence of erosions (more than I cortical defect of more than 1.5 mm) which were graded as mild, moderate, and severe, similar to that proposed by Lawrence and Heine- manne ( 1 1). The sequential x-ray films were evaluated for progression and timing of erosive disease, as previously described (10). ‘The radiologic appearances at the first clinic visit. at 2 years of study, and at the latest visit, and progression of erosions after 2 years were analyzed.

Tissue typing. HLA-A, B, C, and DR typing was performed at the London Hospital Medical College using sera described at the 8th International Histocompatibility Workshop (4) and local sera. HLA-D typing was performed according to the technique published elsewhere (12). One hundred four patients were typed for HLA-D, 95 of whom were also typed for HLA-DR. MB and MT specificities were inferred from their known strong associations with particular HLA-DR types (13).

Statistical analysis. Data were entered onto 80-col- umn computer cards and analyzed with the aid of the SPSS

program linked to the University of London computer. This included chi-square (x’) analysis (uncorrected for the number of cross tabulations). When the number of columns in a 2-sample contingency table was greater than 2, we also applied the Kolmogorof-Smirnoff test (K-S) for 2-sample trend analysis which was useful in reinforcing significance in the x 2 test.

When all the patients in this prospective study are being considered, they are referred to in the text as “all patients,” but in order to aid analysis, patients were also separated into groups according to age of onset of disease, sex, and whether erosions were present on roentgenograms of hands and feet.

Complete sequential radiographs of t h e hands and feet were analyzed in 104 patients with full and reproducible HLA-D typing. There were 61 females and 43 males with a mean age onset of 46.2 years. HLA-DR typing was available in 95 of the KAPS patients, 52 of whom were females and 43 were males. The mean age of onset was 48.4 years. The mean period of followup was 9.8 years (range 3-15 years).

RESULTS

HLA and severity of erosions in all patients. The prevalence of the Dwl to Dw7 and DRI to DR7 locus antigens in all patients within the prospective study is shown in Table 1 and compared with the presence and severity of the latest radiographic appearances in the hands and feet. An increased frequency of HLA-DR4 in RA patients with a corresponding reduced frequen-

22 YOUNG ET AL

Table 2. Severity of bony erosions in MT3-positive versus 1h4T3- negative patients*

Radiologic erosionsf


MT3+ 17 12 23 14 x2 = 10.2, P = 0.017

* MT3 was defined by association with DK4 and DR7. t When erosive patients only were analyzed (i.e., excluding those under the heading “None”), x2 = 10.2, P = 0.006; K-S = 1.52, P < 0.02.

MT3- 9 13 5 . 2 K-S = 1.43, P C; 0.05

cy of HLA-DR2 compared with healthy controls was confirmed, although similar trends did not reach significance with HLA-Dw2 or Dw4.

Most other HLA and RA studies have included only patients with erosive disease who represent an easily definable homogeneous group, although .the radiologic criteria have not always been fully docu- mented. Accordingly, we analyzed only patients with carefully defined radiologic bony erosions of the hands or feet with respect to HLA-DR/Dw specificities. Again, the prevalence of HLA-DR2 was found to be reduced in erosive RA compared with controls (x2 = 5.8, P = 0.014), and similarly HLA-DR4 was increased with an even stronger association (x2 = 7.98, P = 0.005). However, this trend did not reach significance with Dw2 (P = 0.06) or Dw4 ( P = 0.17).

Significant associations were found consistently between only the HLA-DR2IDw2 and HLA- DR41Dw4 antigens and the roentgenograms of the hands and feet.

HLA-DR4/Dw4. The degree of erosive disease in the hands and feet as judged on the latest rddio- graphs in all patients correlated with Dw4 (x2 = 11.6, P = 0.009; K-S = 1.44, P = 0.03), but this trend did not quite reach significance for DR4 (x2 = 6.6, P = 0.08; K-S = 1.2, P = 0.1). This association with Dw4 was still present even when only patients with erosive disease (i.e., mild, moderate, or severe erosions) were analyzed separately (x2 = 9.6, P = 0.01; K-S = I . 17, Y = 0.1) and just reached significance with DR4 (x’ = 5.6, P = 0.05; K-S = I . I , P = 0.1). Although there was a trend for DR4/Dw4 to be related to the severity of radiographic changes seen at the first visit and at 2 years, this did not reach statistical significance. How- ever, significant correlations were found between Dw4 and radiographic changes at the second year of study when “none and mild” changes were compared with “moderate and severe” (x2 = 4.3, P = 0.037; K-S = 0.9, P = 0.2 for Dw4; x2 = 3.52, P = 0.06; K-S = 0.9, P = 0.3 for DR4).

We previously reported that of the patients who

develop erosions over a mean 10-ycar followup period, 90% do so within 2 years of entry to the study (7). Accordingly, we have analyzed patients according to the degree of progression of erosive disease after this time. Radiologic progression after 2 years in erosive patients was significantly related to Dw4 (x’ = 7.6, P = 0.02; K-S = 1.02, P = 0.2), but this trend did not reach significance for DR4 (x’ = 2.8, P = 0.2; K-S = 0.6, P = 0.8).

HLA-DR4 and DR7 are associated with the MT3 specificity, and when patients with these 2 DR types are studied as one group, they show a stronger relationship (as assessed by a higher x2 value) with severity of erosions than did DR4 alone (Table 2). The relationship held when patients with erosions were analyzed separately, but no significant associations with MTI, MT2, MB2, or MB3 were apparent.

HLA-DR21Dw2. Although DR2/Dw2 was identified less frequently in RA patients compared with controls, when present it was significantly associated with less severe radiologic changes recorded at the latest visit when all patients were analyzed (x’ = 9.7, P = 0.02; K-S = 1.4, P = 0.03 for Dw2 and x2 = 7.6, P = 0.05; K-S = 1.3, P = 0.05 for DR2).

Comparison of HLA-DR21Dw2 and DR4/Dw4. In view of the finding of more severe radiologic disease correlating with HLA-DR4/Dw4 and less severe radiologic changes with HLA-DR21Dw2, the radiologic status of DR4AIw4-positive patients was compared directly with that of patients with the DR2/Dw2 phenotype, excluding DR2/Dw2,DR4/Dw4 individuals. A strong positive association between radiologic status at the latest visit and DR4/Dw4 was seen relative to DR2/Dw2 (Table 3).

The analysis of only those patients with erosive disease (i.e., excluding nonerosive RA) showed similarly that Dw4-positive subjects had more marked changes than those with Dw2, while comparable associations were found with the DR4 and DR2 specificities.

Table 3. patients

Severity of bony erosions in DR2iDw2 versus DR4/Dw4

~~~ ~ - ~ -

Radiologic erosions*


Dw2 8 6 1 0 x z = 14.9. P = 0.002; Dw4 6 6 14 9 K-S = 1.9, P < 0.002

DR2 7 7 2 0 x2 = 10.4, P = 0.009; K-S = 1.58. P < 0.02 DR4 10 10 18 10

* When erosive patients only were analyzed, x z = 10.9, P = 0.005: K-S = 1.5, P < 0.02 for Dw2 versus Dw4, and x 2 = 8.8, P = 0.01; K-S = 1.39, P < 0.05 for DK2 versus DR4.

HLA-DW AND RADIOLOGIC CHANGES

Table 4. DR4/Dw4 genc dose vcrs115 scverity of bonv e i o w n s

Radiologic erosionr‘

Moder- Nonc Mild ate Severe

IIw4 negative 21 23 22 6 Dw4 heterozypous 5 4 10 5 x’ - 14.4. I’ = 0.02 Dw4 homozypous 1 2 4 6

DR4 negativc 17 19 18 5 DR4 heterozypou5 9 7 9 7 x’ = 8 . 3 . P 0.21 DK4 homozygous 3 3 9 5

* When crosive patients only werc analy/.ed. x 2 = 1 1 . 5 . P Dw4 and x2 :- 6.5, P :- 0.16 for DR4.

0.02 for

A significant rclationship with Dw4 compared with Dw? was still found whcn radiologic findings were analyzed at 2 ycars (x’ = 6.83. P = 0.03; K-S = 1.08. P > 0.1). but this trend did not reach statistical significancc with the DR spccificitics (x’ = 4.99. P = 0.08; K-S = 0.96. P > 0.1). Similarly. the dcgrcc of progression of erosive diseasc aftcr 3 ycars correlated with Dw4 relative to Dwl (x’ = 10.4, I.’ = 0.01; K-S = 1.34, P < O . l ) , but this association did not achicve significance when the DR4 and DRZ allelcs wcre compared (x’ = 6.55, P = 0.086; K-S = I . O Z P > 0. I).

Effect of DH4/Dw4 gene dose. Paticnts wcre divided into 3 groups: thosc negative for DR4/Dw4, those with DR4/Dw4 plus 1 othcr spccificity (hctcrozy- gous), and thosc with DK4/Dw4 alonc (prcsumcd homozygous. although this could includc paticnts with an as yct undefined antigen). The groups wcre analyzed with respcct to the sevcrity of radiologic changes at the latest visit. Corrclation with gcne dose was secn for Dw4 but not for DR4 (Tablc 4). When only crosivc paticnts werc analyzcd, similar correlations were still found with Dw4.

Influence of sex and age at onset of disease. Previous reports on thc association betwcen thc age of onset of disease and HLA-DR41Dw4 havc becn con- trovcrsial (3,4,14). Wc have found HLA-DR4/Dw4 to be positively relatcd to an earlicr agc of onset of RA, and although not quite reaching statistical significance in the paticnt group as a whole (x’ = 3.72, P = 0.053

IN RA 23

for Dw4: x’ = 3.01, P = 0.082 for DR4), this was significant when only crosivc patients werc considered (x’ = 4.6. P = 0.03 for Dw4; x’ = 7.42, P = 0 . 0 6 for DR4).

Whcn thc RAPS patients wcre groupcd according to age at onset and sex and reanalyzcd as separatc groups. the direct corrclations bctwecn DR4/Dw4 and radiologic changes werc stronger in 3 distinct groups: female paticnts, patients under the age of 50 at disease onset regardless of SCX. and paticnts who werc both femalc and lcss than 50 at thc onset of discasc (Table 5 ) . l’herc werc no significant associations with patients whose discase first presentcd over age 50.

The incidence of DR4/Dw4 in male patients was highly significant compared with controls (10 of 13 wcre DR4 and 9 wcre Dw4-positive). Howevcr. no association was found between thc prcsencc of DR4/Dw4 and radiologic changcs. This was probably due to the small numbcr of males in thc KAPS patients.

DISCUSSION Thcre arc few rcports on the relative frcquency

of both H1.A-D and DR spccificities in thc same patients with rheumatoid arthritis. Our results confirm the increased prevalcnce of DR4 in RA with a corresponding decrease in DR2. as other workcrs have previously rcportcd (3.4). Earlicr studies havc also reported an association of Dw4 with RA ( I ) , and although we found a similar trend, this did not achicve statistical significance in our patients. Thcse rcports havc been based on rctrospcctivc studies in patients with crosive RA, and no attempt was made to corrc- late the presencc of DR4/Dw4 with an objcctive assessment of scverity of rheumatoid diseasc. It is also not clcar what radiologic standards havc becn used to define “crosivc” discase. The Middlesex Hospital RAPS consists of a group of patients dcmonstrating the full spectrum of RA from mild noncrosivc to severely progressive crosivc and extraarticular disease. This fact may partly cxplain thc lowcr ovcrall prevalencc of 54% of our patients with DR4 compared

Table 5. Dw4 and the severity of radiologic changes

Influence of sex and age at onset of rheumatoid arthritis on the relationship between DK4/

All females All <50 years Fcmales 4 0 years

Dw4 versus non-Dw4 K-S 1.3. P = 0.05 K-S - 1.35, P - 0.04 K-S - 1.4, I’ = 0.03

x? = 11.1. P = 0.01; x’ - 8.9. P = O.O?Y; X I - 9.9. P = 0.01:

DR4 versus x2 = 7.7. P = 0.05; x? = 9.1. P r- 0.ozx: x2 - 8.8. P 0.03: non-DR4 K-S 1.2. P = SS* K-S = 1.4. P = 0.03 K-S = 1.5. I’ = 0.02

* Not significant

24 YOUNG ET AL

with 70% with DR4 reported by Stastny (2) and 77% reported by Panayi et a1 ( 3 ) , both of whom examined only patients with erosive KA. It is interesting to note that contributors to the 8th Histocompatibility Work- shop (4) who used the ARA criteria of classic and definite disease for inclusion, rather than radiologic status alone, reported a prevalence of DR4 of 47.4% in white RA patients, which is similar to our findings.

There is no satisfactory method of assessing the severity of the pathologic process in KA and no universally agreed upon way for categorizing the different forms of the disease. Previous workers have relied on the ARA criteria, the presence of bony erosions, seropositivity for rheumatoid factor, or functional capacity according to Steinbrocker et a1 (15). The ARA criteria were designed as diagnostic standards for international and multicenter cooperative studies and are satisfactory for separating milder forms of the disease, but the criteria tend to lump the more severe forms into one group. It is generally agreed that the presence of erosions in a typical pattern on roentgenogram is pathognomonic of RA, and other similar arthritic conditions can usually be excluded radiologically. Most reports, however, do not document their definitions of “erosive” disease, despite the availability of accepted standards (161, which have been reviewed in detail by Lawrence and Heinemanne (1 1).

We previously demonstrated the prognostic value of yearly roentgenograms of the hands and feet in the early course of RA (7) and the association of radiologic changes with eventual clinical outcome ( 17). We have also shown that the severity of radiologic changes in the hands and feet correspond closely to clinical indices of joint inflammatory activity in RA (8) and to the severity of radiologic changes in the cervical spine (10). although fortunately the latter occur less frequently. We believe that the radiologic material from the RAPS patients represents an objective and detailed assessment of disease severity in RA and, in addition, may be helpful in categorihg different forms of the disease.

Although there is little doubt that HLA- DR4/Dw4 conveys increased susceptibility to the de- velopment of rheumatoid arthritis, the few reports correlating severity of disease with HLA have been controversial. We initially reported, on a smaller number of our patients, that those positive for both rheumatoid factor and DR4/Dw4 were more likely to have severe disease when this was assessed according to thc medication required to control disease activity (18). However, Husby et a1 (19) found no association

between HLA-DR4 and severity of RA using the ARA classification for functional capacity. Similarly, the 8th Histocompatibility Workshop (4) reported no HLA- DR association with disease severity evaluated on the basis of joint scores, functional grade, and clinician’s assessment of rate of progression of disease. Can- versely, Panayi et al (3) reported that patients with DR2 had rheumatoid nodules less frequently and lower titers of rheumatoid factor.

Using the extent and progression of radiologic bony erosions of the hands and feet as a marker of severity of rheumatoid synovitis, a strong association was found with the presence of DR4/Dw4. It was of interest that although HLA-Dw4 was not as strongly associated with RA as the DR4 allele in our study, whether all patients or only those with erosions were included, this specificity was more highly correlated with severity of erosions than DR4. Whether this proves to be a statistical quirk or represents a real consequence of the differences in genetic background revealed by Dw and DR typing systems requires greater illumination of the precise antigenic relationships between the Dw4 and DR4 phenotypes. It should be emphasized that these correlations have not been corrected for the number of cross-tabulations, and therefore the conclusions should be looked upon as indicative, providing a pointer to further studies with a new group of patients to specifically validate the relationship. In this respect, we have found that inclusion of 2 new groups comprised of 76 patients with definite or classic RA in our analysis strengthens the association with Dw4, the P value decreasing from 0.003 (Table 3) to 0.0009.

It is certainly of interest that the MT3 specificity, identified in this study by combining DK4 and DR7 rather than by the use of specific serologic reagents, showed a much stronger relationship with radiologic changes than did DR4 alone. We have also found a good correlation between the Dw4 gene dose and severity of erosive disease, with 71% of patients presumed to be homozygous showing extensive radiologic changes compared with 38% of Dw4-negative patients.

In addition to this strong positive association of bony erosions with DR4/Dw4, we have also identified a significantly negative correlation with the presence of DR2/Dw2. These associations with both DR4/Dw4 and DR2/Dw2 were still present when only erosive RA patients were analyzed. This latter point is important because of the possible heterogeneity of RA, and it raises the question of whether, in a group of patients like those in our prospective study, we are dealing

HLA-Dw AND RADIOLOGIC CHANGES [N RA 2s

with a single underlying pathogenic disease process with H L A influencing the severity o r with two different diseases, one nonerosive and unrelated to H L A and the other erosive and HLA-dependent. Our results d o not resolve this issue, but if we are achieving any greater clinical homogeneity by restricting analysis t o only those patients showing erosive changes. then our data clearly suggest that HLA-DR4/Dw4 confers susceptibility to more marked erosive RA and bK2/Dw2 to less severe erosions. Our finding of strong correlations between DR4/Dw4 and severity of radiologic changes in only certain groups of patients (all female, all patients under the age of SO at onset of disease. and females under 50 at onset) and not in other groups (over 50 at onset and males) could favor the view that 2 different diseases may be represented within a prospective study group. The increased incidence of HLA-DR4 and MT3 in male compared with female patients as reported by Ohta et al (20) may he relevant t o this point; ou r da ta showed a similar trend, but although thc difference was significant, i t did not seem to be associated with erosions, though this could be due to the small numbers studied.

The eventual clinical outcome of a patient pre- senting with a symmetric polyarthritis is extremely variable as shown in ou r prospective study, and HI,A typing would help the clinician predict radiologic outcome in the early stages of disease when decisions concerning second linc treatment a re paramount. Clearly other factors must also be taken into account, and i t is likely that the technique of discriminant analysis using additional clinical, serologic, and radiologic pal-ameters will be of considerable help in terms of prognosis and perhaps also in the study of the clinical heterogeneity of this condition.

ACKNOWLEDGMENTS We wish to thank Drs. A. C. Boyle, S. Mattingly,

and D. L. Woolffor permission to study their patients.

REFERENCES Stastny 1’: Mixed lymphocyte culture typing cells from patients with rheumatoid arthritis. Tissue Antigens

Stastny P: Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 298:869-871. 1978 Panayi GS, Wooley P, Batchelor JR: Genetic basis of rheumatic disease: HLA antigens, disease manifcsta- tions and toxic reactions to drugs. Br Med J 2: 1326- 1368, 1978

4:571-579. 1974

4. Stastny P: Joint report: rheumatoid arthritis, Histocom- patibility Testing 1980. Edited by PI Terasaki. Los Angeles, UCLA, 1980. pp 681-686

5. Kopes MW, Bennett GA, Cobb S, Jacox R , Jessar KA: Kevision of diagnostic criteria in rheumatoid arthritis. Ann Kheum Dis 18:49-53, 1959

6. Fleming A, Crown JM, Corbett M: Prognostic value of early features in rheumatoid disease. Br Med J i:1243- 1245, 1976

7. Brook AS, Corbett M: Radiographic changes in early rheumatoid disease. Ann Rheum Dis 36:71-73, 1977

8. Young A, Brook AS, Corbett M: The clinical assessment of joint inflammatory activity in rheumatoid arthritis related to radiological progrcssion. Rheumatol Reha- bil 19:14-19, 1980

9. Winfield J , Cooke I>, Brook AS, Corbett ,W: A prospective study of the radiological changes in the cervical spine in early rheumatoid disease. Ann Rheum Ilis 40:109-114, 1981

10. Winfield J. Young A, Williams P, Corbett M: A prospective study of the radiological changes in hands, feet, and cervical spine in adult rheumatoid disease. Ann Rheum Dis (in press)

I I . Lawrence JS. Heinemanne W: Kheurnatism in Popula- tions. London. Medical Books Ltd.. 1977. pp 164-169

12. Sachs J, Jaraquemada D, Festenstcin H: Intra HLA-D region recombinant maps H1.A-DR between HLA-H and HLA-D. Tissue Antigens 17:43, 1981

13. Terasaki PI, Park MS. Bernoco D, Opelz G, Mickey MR: Overview of the 1980 International Histoeompati- bility Workshop, Histocompatibility Testing 1980. Edit- ed by PI Terasaki. Los Angeles, UCLA. 1980, pp 1-17

14. Hatchelor JK, Morris I’J: HI,A and disease: rheumatoid arthritis. Histocompatibility Testing 1977. Edited by WF Bodmer, JK Batchelor, JG Bodmer, H Festenstein. PJ Morris. Copenhagen, Munksgaard, 1978. pp 218-220

IS. Steinbrocker 0. Traeger CH, Hatterman RC: ’l’herapeu- tic criteria in rheumatoid arthritis. JAMA 140:659-662, I949

16. Kellgren JH, editor: The epidemiology of chronic rheumatism. Atlas of Standard Radiographs. Vol. 2. Oxford, Blackwell Scientific Publications, 1963

17. Brook AS. Fleming A, Corbett M: Relationship of radiological changes to clinical outcome in rheumatoid arthritis. Ann Rheum Dis 39:274-275, 1977

18. Roitt IM, Corbett LM, Festenstein H. Jaraquemada D, Papasteriadis C, Hay FC, Nineham LJ: HLA-DRw4 and prognosis in rhcumatoid arthritis. I>ancet i:990, 1978

19. Husby G. Gran J’I, Ostenscn M, Johannessen A. Thorsby E: HLA-DKw4 and rheumatoid arthritis. Lan- cet i:548. 1979

20. Ohta N . Nishimura Y K , ‘l‘animoto K. Horiuchi Y , Abe C, Shiokawa Y, Abc T. Katagiri M, Yoshiki I., Sasazuki T: Association between HLA and Japanese patients with rheumatoid arthritis. Hum Immunol 5:123. 1982

association of hla-dr4/dw4 and dr2/dw2 with radiologic changes in a prospective study of patients...

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