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SUMMARY The association of particular HLA-DR alleles and the shared epitope with rheumatoid arthritis (RA) is now well established. The strength of these links varies between races. Furthermore, the proposition that the presence of the shared epitope is indicative of severe disease has been more diAcult to sustain in non-Europeans. This study examines the frequency of HLA-DR and HLA-DRB1 amongst Pakistanis for the first time. Using the polymerase chain reaction (PCR) and sequencespecific oligonucleotide probes (PCR-SSOP) and primers (PCR-SSP), HLA-DR phenotype and genotype frequencies were ascertained in 86 RA hospital out-patients and 79 healthy controls matched for age, gender and ethnicity. HLA-DR1 and HLA-DR4 frequency was similar in patients and controls. HLA-DR10 occurred in 26 instances (15%) in RA and in eight (5%) controls (Pcorr = 0.048). HLA-DR2 was also increased in patients (P = 0.053) and its major subtype DR15 was significantly increased (Pcorr = 0.03). HLA-DR5 frequency was 5% in patients and 19% in controls (Pcorr = 0.002). The HLA- DR4 alleles possessing the shared epitope were more common in RA (Pcorr = 0.03) and this diAerence was enhanced by inclusion of other alleles possessing the shared epitope (Pcorr = 0.002). Shared epitope alleles were observed in 43 (50%) patients and 17 (22%) controls (Pcorr = 0.003). The shared epitope did not distinguish patients with more severe disease, as reflected by pain, joint deformities, disability, rheumatoid factor or X-ray damage. The distribution of HLA-DR alleles in Pakistanis with RA supports the shared epitope hypothesis. In common with other non-European racial groups, HLA-DR4 was not associated with RA. Unlike other groups, there was a weak link of RA with HLA-DR2. A protective eAect of HLA-DR5 was apparent. In accord with some other studies, the shared epitope in this hospital out-patient population was not a marker for more severe disease.

The impact of environmental factors on the causation of rheumatoid arthritis (RA) is thought to be considerable. We explored this by comparing the prevalence of RA amongst Pakistanis living in England, where it is relatively high amongst ethnic English, and in Pakistan. The frequency of other rheumatic diseases was also compared. Information on 2056 adult Pakistanis in England and 4232 in Pakistan was obtained by house-to-house surveys using identical protocols. Positive respondents were examined by the same two clinicians in both countries. Rheumatic complaints increased with age and were more common in females in both communities. The standardized morbidity ratio (SMR) (95% CI) of RA in England was 2.1 (1.1-3.1) compared with Pakistan, a difference that was entirely attributable to females. The SMR (95% CI) for women was 3.0 (0.4-5.6) and for men 0.86 (-0.84 to 2.56). In Pakistan, there was a trend to more reporting of some but not all rheumatic complaints amongst the affluent segment of the population. This was increasingly apparent amongst those resident in England and the possibility of an impact of easier ascertainment amongst the more educated cannot be discounted. Low back pain was significantly more common in England. Furthermore, the colder climate was frequently invoked as a cause of more symptoms in England. Thus, several factors may have influenced the observation that RA is more common amongst Pakistanis in England compared with Pakistan. An environmental factor cannot be excluded. However, the frequency of non-specific musculoskeletal pain was similar. The regions of Pakistan from which the two populations were derived were also different and immunogenetic heterogeneity might also have contributed to the difference in RA prevalence.