Racial origin and its effect on disease expression and HLA-DRB1 types in patients with rheumatoid arthritis: a matched cross-sectional study
B. Griffiths,
R. D. Situnayake1,
B. Clark2,
A. Tennant,
M. Salmon3 and
P. Emery
Rheumatology and Rehabilitation Research Unit, University of Leeds,
1 City Hospital, Dudley Road, Birmingham,
2 Tissue Typing Laboratory, St James' Hospital, Leeds and
3 Division of Immunity and Infection, University of Birmingham, UK
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Abstract
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Objective. There are a significant number of patients with rheumatoid arthritis (RA) of North Indian or Pakistani origin (Asian) now living in the UK. RA has been poorly studied in this racial group. The aim of this study was to compare RA in this Asian group with RA in the indigenous northern European (European) population. It was hypothesized that these two racial groups would have different disease expressions and immunogenetics that could be relevant to pathogenesis, prognosis and therapy.
Methods. One hundred and seven Asian RA patients, who fulfilled the 1987 American College of Rheumatology criteria, were stringently matched for age, sex and disease duration with 107 European RA patients, and were fully assessed.
Results. The Asian RA patients had significantly fewer bony erosions [median Larsen score 58.5 (interquartile range 45.577.8) vs 68 (5293) for European patients; P = 0.0066, MannWhitney U-test] and rarely had nodules (5.7 vs 20%, P = 0.0019, Fisher's exact test). The two groups had the same prevalence of rheumatoid factor positivity, number of swollen joints and level of inflammation (C-reactive protein). The Asian RA patients had a reduced prevalence of the conserved third allelic hypervariable region (3AHVR) (45 vs 82%, P < 0.0001, Fisher's exact test), particularly DRB1*0401 (4.5 vs 55%). However, the prevalence of the conserved 3AHVR was significantly increased in the Asian RA patients compared with Asian controls. By contrast, the Asian patients had more tender joints [13.5 (722) vs 5.5 (211.8); P < 0.0001 MannWhitney U-test]. The Health Assessment Questionnaire score was also significantly worse in the Asians compared with the Europeans [median 2.0 (1.132.63) vs 1.25 (0.52.13), P = 0.0001).
Conclusions. The Asian patients had similar levels of inflammation and less damage but more pain and disability than the matched European RA patients. Of the known prognostic factors for erosions (rheumatoid factor, conserved 3AHVR, swollen joints and C-reactive protein), only the conserved 3AHVR was reduced in the Asian RA patients, and this was consistent with their less erosive disease. These data also indicate the importance of pain as well as erosive damage in determining disability in Asian patients and stress the importance of adequate pain relief, in addition to disease suppression, when treating Asian RA patients.
KEY WORDS: Rheumatoid arthritis, Asian, European, Disease expression, HLA-DRB1 typing, Matched cross-sectional study.
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Introduction
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Rheumatoid arthritis (RA) is a common disease, characterized by a peripheral, symmetrical erosive polyarthritis that typically causes progressive joint destruction, deformity, disability and increased mortality []. Familial aggregation and the increased prevalence of RA in monozygotic twins indicate a genetic element [2, 3]. Certain human leukocyte antigen (HLA) types, particularly subtypes of DRB1*04, namely DRB1*0401, *0404 and *0405, are more prevalent in white Caucasian RA patients [4]. Different HLA-DRB1 types were found to be more prevalent in other racial groups, e.g. DRB1*01 in Israelis [5] and DRB1*10 in Spanish [6]. Gene sequencing of these prevalent HLA-DRB1 types in RA patients showed preservation of the amino acid sequence in the third allelic hypervariable region (AHVR) of the beta chain (QKRAA/QRRAA/ RRRAA). This led to the shared epitope (SE) hypothesis [7]. It is not known at what level the conserved 3AHVR acts, but it is assumed to be at antigen presentation. The presence of the conserved 3AHVR in white Caucasian RA patients has been linked to more severe disease, e.g. more severe radiological erosions and presence of extra-articular manifestations. Other predictive factors of erosions are the presence of rheumatoid factor (RF) and an elevated concentration of C-reactive protein (CRP) [8, 9 ]. Function is an alternative measure of outcome. In white Caucasian RA patients, function is predicted by a raised acute phase response, female sex and a poor functional status at presentation [810]. It is unknown whether the same predictive factors for function operate in other racial groups.
There are limited clinical data for HLA-DRB1 associations in British Asian RA patients [11, 12] and none relating to disability. Britain now has a large population of Asian origin, particularly from the Indian subcontinent. The number of individuals of Indian or Pakistani origin recorded as being resident in the UK at the time of the 1991 census was 1 312 000 [13]. RA is also common in this racial group and is becoming more prevalent with the ageing of this population. It is not clear if there should be different guidelines for the treatment of RA according to the patient's racial group. For the first time, sufficient numbers of these RA patients of homogeneous racial origin, living in the UK, were available for a systematic characterization of disease manifestations and genetic markers in comparison with RA patients of northern European origin. It was hypothesized that differences in the HLA-DRB1 types would be found and that these might be associated with differences in disease expression. Determinants for the development of erosions and disability in the Asian and European group were also examined. The differences found were greater than expected, and have implications for the management and the understanding of RA.
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Methods
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Patients
One hundred and seven RA patients who met the American College of Rheumatology (ACR) 1987 revised criteria for rheumatoid arthritis [14] and were of North Indian or Pakistani origin were identified. An individual was defined as being of North Indian or Pakistani origin if three or more grandparents were born in North India (the states of Kashmir, Punjab, Haryana, Himachal Pradesh and Delhi) and/or Pakistan. This group is henceforth referred to as Asian. The age, sex and disease duration of each Asian patient were tabulated and then stringently matched with corresponding data for the next RA patient of northern European origin with these demographic details. Northern European was defined as three or more grandparents born in England, Wales, Scotland and/or Ireland. This group is henceforth referred to as European. Disease duration was defined as the time from symptom onset. All patients were attending the rheumatology departments of three district general hospitals in Birmingham (City Hospital, Selly Oak Hospital and Birmingham Heartlands) and were identified from the rheumatology departmental computer databases. Ethics committee approval was granted and informed consent was obtained from all participants.
Clinical
All patients were interviewed and examined using a structured pro forma. Demographic details, including sex, age, place of birth, date of arrival in the UK (if relevant), generation, history of consanguinity and religion, were recorded. The history of their RA was noted, including the date of onset, the use of disease-modifying antirheumatic drugs (DMARDs), history of orthopaedic surgery and the presence of extra-articular manifestations. A patient was defined as having sicca symptoms and Raynaud's phenomenon if the appropriate history was given. Nodules present on examination or previously documented in the notes were recorded. The diagnosis of pulmonary fibrosis was registered if confirmatory lung function test results, a chest X-ray or a computed tomography report were available. Peripheral neuropathy was recorded if proven on nerve conduction studies.
A 52 swollen joint count, Ritchie articular joint count for tenderness [15] and total joint count were performed. Each patient also completed the Health Assessment Questionnaire (HAQ) [16]. The maximum possible score was 3.0 (severe disability and inability to perform daily activities independently with the use of aids) and the minimum score was 0 (no disability). If the patient was unable to read English, the questionnaire was completed by a nominated family member acting as the interpreter. The patient then marked a 100 mm visual analogue scale (VAS) for pain.
Laboratory tests and X-rays
Blood was taken for determination of RF, anti-nuclear factor, plasma viscosity (PV) or erythrocyte sedimentation rate and C-reactive protein (CRP). A patient was defined as being RF-positive if they had ever been documented as having a RF titre
1:40. EDTA blood was stored at -20°C for HLA-DRB1 typing. Standard X-rays of the hands and feet were taken and scored blindly using the Larsen method for osteoporosis, joint space narrowing and erosions by two of the authors (BG and RDS) [17]. The proximal interphalangeal (PIP) joints, metacarpophalangeal joints, wrists, first interphalangeal joints of the feet and the second to fifth metatarsal joints were assessed. The joint score was 0 for normal appearance, 1 for periarticular osteoporosis and loss of joint space, 2 for a small erosion, 3 and 4 for more severe erosions, and 5 for a completely destroyed joint (maximum score 200).
Controls
Healthy Asian controls were recruited from the local Birmingham community for HLA-DRB1 typing. This included general practitioners' Well Women clinics, a Sikh temple, hospital employees and medical students. Again, for the individual to be classified as Asian, three or more of their grandparents had to be born in North India or Pakistan. The individual had to be taking no regular medication, except for the oral contraceptive pill, and have no family history of RA. Healthy European controls were recruited from blood donors registered with the Blood Transfusion Service. They were multiple donors with no family history of RA. They were matched for sex.
HLA-DRB1 typing
Tissue typing was performed at the Tissue Typing Laboratory at St James' Hospital, Leeds. A 21-probe, reverse-line-blot format, polymerase chain reaction, sequence-specific oligonucleotide probe system was used to detect HLA-DR1-DR16 (Roche) [18]. The probes used could identify *01010102 from *0103. Specificity subtyping for DRB1*04 was performed with primers to identify DRB1*0401-DRB1*0419 (Dynal) [19]. The conserved 3AHVR was defined as including HLA-DRB1*01, *0401, *0404, *0405, *0408 and *10 in this study.
Statistics
The SPSS Inc. 6.0 software package (Chicago, IL, USA) was used to analyse the data. For non-parametric data analysis, the MannWhitney U-test was used for ordinal variables and Fisher's exact test for dichotomous variables. Using the International Classification of Impairments, Disabilities and Handicaps on a conceptual framework, models were derived by multivariate analysis to determine the disease activities and impairments contributing to the severity of the erosion score (impairment) and the HAQ score (disability). Univariate analysis was followed by stepwise multivariate analysis in the three subsets: Asian RA patients; European RA patients; and the two racial RA groups combined. The significance level used was P < 0.05.
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Results
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Demographic details (Table 1
)
More than 95% of the patients contacted in each group agreed to participate in the study. 83% of the patients were female, the median age was 52 yr and the median disease duration was 6 yr. Ninety-seven per cent of the Asian population were first-generation. Their median duration of residence in the UK was 28 yr [interquartile range (IQR) 2233]. In the Asian RA group, results were not significantly different for groups defined by religion (data not shown). More than 74% of the Asian RA grandparents originated from the Punjab (Jullundur was cited in particular) and at least 16% came from Kashmir (particularly Mirapur). Eighty-three per cent of the Asian control grandparents came from the Punjab and 13% from Kashmir.
Laboratory markers, extra-articular manifestations and radiology (Table 1
)
Positivity for RF had similar frequencies in the two groups but antinuclear antibodies (ANA) were less common in the Asians. The median CRP values were the same in the two groups, and similar numbers had a raised CRP (defined as >5 mg/l; 62.5% for the Asians and 59% for the Europeans). The median PV was higher in the Asians. Sicca symptoms and Raynaud's phenomenon were common in both groups. Rheumatoid nodules were significantly more prevalent in the Europeans (P = 0.0019, Fisher's exact test). The majority of patients had erosive disease (98% of Asians and 100% of Europeans).The median Larsen score was significantly lower in the Asians (median 58.5 vs 68 in the Europeans, P = 0.0066, MannWhitney U-test). Wrist disease was more prevalent in the Asian patients (Fig. 1
).

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FIG. 1. (A) Hand X-ray of Asian RA patient showing predominantly wrist disease. (B) Hand X-ray of European RA patient showing predominantly MCP and PIP erosive disease.
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Immunogenetics (Tables 2
and 3
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Samples were available for HLA-DRB1 typing in 91 Asian RA patients, 125 Asian controls, 100 European RA patients and 93 European controls. HLA-DRB1 typing was not technically possible for all samples. This may have been related to storage of the blood sample. The HLA-DRB1 results for the European RA and control groups were both similar to those previously published for this racial group [8, 12, 20, 21]. The number of Asian RA patients possessing the conserved 3AHVR was significantly reduced compared with European RA patients (P < 0.0001, Fisher's exact test). Interestingly, the prevalence of the conserved 3AHVR in the healthy Asian population was very low (17%). DRB1*0401 was the most common HLA-DRB1 type in the Europeans (55% positive) but was rare in the Asians (4.5%), whilst DRB1*10 was the most prevalent HLA-DRB1 type in the Asians (24.7 vs 2% in the Europeans, P < 0.0001, Fisher's exact test). The odds ratio for the association between RA and the conserved 3AHVR in Asians with RA was 3.93 [95% confidence interval (CI) 2.17.4] and 3.91 (2.007.61) in the Europeans. Only 9% of the Asians were compound heterozygotes or true homozygotes compared with 21.4% of the Europeans (P = 0.025, Fisher's exact test). For the Europeans, there was a strong correlation between RF positivity and having the conserved 3AHVR, but this correlation was not found in the Asians (P < 0.0001, Fisher's exact test). Eighty-nine per cent of the Europeans who were RF-positive were also 3AHVR-positive (55/62) compared with only 49% of the Asians who were RF-positive and 3AHVR-positive (28/57).
Joint counts, pain and disability (Table 4
)
The swollen joint counts were the same for the two groups. The tender joint count and VAS for pain were significantly higher in the Asians than in the Europeans. The Asians were more disabled; this was reflected by the significantly higher HAQ scores in the Asians compared with the Europeans, (P = 0.0001, MannWhitney U-test). Disability HAQ scores in the Asians were higher in the females than in the males [median 2.13 (IQR 1.632.63) and 1.19 (0.252.56) respectively].
Treatment
The DMARDs used as monotherapy or in combination included sulphasalazine, methotrexate, gold (Myocrisin and auranofin), penicillamine, azathioprine and cyclosporin. The Asian patients had received significantly fewer DMARDs than the Europeans [median 1 (IQR 12) vs 2 (13.75), P = 0.0019, MannWhitney U-test]. Less frequent orthopaedic intervention was also seen in the Asians (15% vs 24% in the Europeans), but the difference was not significant.
Predicting the severity of erosions
In this analysis the dependent variable was the Larsen score. The results for univariate analysis for this model are summarized in Table 4
. The independent predictors for the severity of the erosion score, using stepwise regression analysis, are reported in Table 5
. The European model was the most effective, with an adjusted R2 of 0.48. In this model, each year of disease duration increased the Larsen score by 2.93 when adjusted for age. Disease duration was always the most important contributing variable. Other significant variables included age, CRP, RF positivity and race.
Predicting disability using the HAQ score
The above method was repeated to predict disability, using the HAQ score as the dependent variable. The results for the univariate analysis for this model are summarized in Table 6
. The results of stepwise regression analysis are summarized in Table 7
. The tender joint count contributed most to the score in all groups. The model for Europeans was the most effective, with an adjusted R2 of 0.46. For the Europeans, each additional tender joint increased the HAQ score by 0.04 when adjusted for the Larsen score and the presence of RF. The presence of RF increased the HAQ score by 0.43 in Europeans. When the two racial groups were combined, the tender joint count remained the most important predictor, and the Asians were shown to have a level of disability on the HAQ score that was increased by 0.36.
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Discussion
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This is the first matched systematic study comparing RA in patients of Asian and European origins living in the UK. It has highlighted major differences in disease expression and immunogenetics between RA patients from these two racial groups. This has provided insight into the inter-relationship of the different components of outcome, namely function and erosions.
Asian RA patients have less damage, as demonstrated by both the significantly reduced X-ray erosion score and the reduction in orthopaedic operation rate, despite similar disease durations. When considering the known prognostic factors for the development of erosions (conserved 3AHVR, RF and CRP), the conserved 3AHVR seemed to be the most important as this was significantly reduced in the Asians. There was no difference between the two groups in the level of inflammation (at a single time-point) or in the prevalence of RF. The pattern of the bony erosions seen in the Asians needs further evaluation. Preliminary results suggest a relatively high prevalence of wrist disease [22], as reported in other Asian populations, e.g. Malaysians [23]. Nodules were also significantly reduced in the Asians; again, this may be explained by the reduced prevalence of the conserved 3AHVR. In contrast, subjective findings, particularly the HAQ disability score, were significantly worse in Asians. This was accounted for by the significant increase in tender joint score and VAS for pain.
The very low prevalence of the conserved 3AHVR in the healthy Asian population should be noted. DRB1*04 had particularly low prevalence both in healthy Asian controls and in RA patients. However, the odds ratio for a conserved 3AHVR-positive Asian individual developing RA was similar to that quoted for Europeans [24] and that seen in the Europeans in this study. This evidence suggests an equivalent role for the SE in Asian patients.
In studies of Asian RA patients living in native North India, milder disease has been reported but with a high prevalence of the conserved 3AHVR. In one study, 68% of patients possessed DRB1*04 [25]. This prevalence was similar to that in white Caucasians and much higher than in our study. The explanations for the differences are not clear but could include selective migration or the more severe disease in the patients attending the North India hospitals. However, more recently the clinical features and HLA-DRB1 typing in native Pakistanis have been published by Hameed et al. [26, 27]. The disease was also shown to be milder but the prevalence of the conserved 3AHVR in RA patients and controls was reduced (to 50 and 22%, respectively). Hameed's results were very similar to ours, particularly the radiological damage and the prevalence of nodules, and the prevalences of the HLA-DRB1 alleles. Our HLA-DRB1 results were also consistent with two small, previously published British studies [11, 12].
All the patients in this study were attending district general hospitals and were resident in the appropriate catchment areas and, therefore, represent typical secondary care patients, thus removing the bias of a tertiary referral centre population. The results from this study should, therefore, be generalizable to any secondary care population of either racial group in the UK. Although the HAQ has not been tested previously in the British Asian population, it is important to note that an analysis using the strict psychometric criteria of the Rasch model [28] showed no differential item functioning for race or completion by proxy [29].
Our findings have important implications for the management of RA in patients of Asian origin. Whilst inflammation still needs to be suppressed to prevent damage, it is clear in this population that the burden of pain has a particularly significant impact on disability. Pain management should, therefore, assume a higher profile in Asian RA patients. Additional pain-modulating medication, e.g. low-dose amitriptyline or the introduction of alternative strategies for coping with pain may help. These approaches and the effect of culture need to be explored in a prospective study.
In summary, Asian RA patients are genetically different from European RA patients, with a lower prevalence of the conserved 3AHVR but with the same odds ratio for developing RA. The disease shows less erosive damage and fewer nodules and results in less surgical intervention in Asians. Despite this, Asian RA patients have an equivalent amount of inflammation and swollen joints and a paradoxical increase in pain and tenderness associated with significantly increased disability compared with European RA patients. These findings indicate the need to improve pain management as well as disease suppression when treating Asian RA patients.
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Acknowledgments
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The authors would like to thank Dr R. Jubb and Dr M. Farr for permission to allow the assessment of their RA patients in this study and Dr J. Gooi for expert advice. The work was supported by a West Midlands Health Project Grant.
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Notes
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Correspondence to: P. Emery, Rheumatology and Rehabilitation Research Unit, 36 Clarendon Road, Leeds LS2 9NZ, UK. 
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Submitted 16 June 1999;
revised version accepted 28 January 2000.