The presence of the HLA-DRB1 shared epitope correlates with erosive disease in Chilean patients with rheumatoid arthritis
L. Massardo1,,
N. Gareca1,
M. A. Cartes2,
V. Cervilla3,
A. González1,4 and
S. Jacobelli1
1 Departamento de Inmunología Clínica y Reumatología,
2 Departamento de Medicina Interna,
3 Departamento de Radiología, Facultad de Medicina and
4 Centro de Regulación y Patología Celular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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Abstract
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Objective. To assess the contribution of the HLA-DRB1 shared epitope (SE) to the radiological outcome of rheumatoid arthritis (RA) after 6 yr of follow-up in a reported series of 129 Chilean patients with established disease.
Methods. A prospective study was conducted between 1992 and 1998 using hand radiographs to assess disease outcome in a published series of patients in whom two doses of the SE were present in 20%, one dose was present in 34% and the SE was absent in 46%. At study entry, 29 of the 92 patients with hand radiographs were at Steinbrocker stages I or II (non-erosive), with a median disease duration of 2.8 yr (0.417).
Results. In 1998, 113 (87%) of the patients were alive. One hundred and eight patients underwent complete clinical evaluation. Their median age was 57 yr (range 3081) and the median disease duration was 15 yr (650). We were able to study 25 of the 29 patients who had non-erosive disease at study entry in 1992. We found that 10 of 11 patients having one or two doses of the SE developed erosive disease compared with three of 14 without the SE (Yates' corrected P=0.0023, relative risk 4.24, 95% confidence interval 1.5311.77).
Conclusions. These observations support and extend the notion that the presence of the SE in one or two doses can predict the development of erosions even in RA populations in whom the SE is not as prevalent as in Caucasians.
KEY WORDS: Shared epitope, Radiological progression, Erosive disease, Rheumatoid arthritis.
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Introduction
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The clinical course of rheumatoid arthritis (RA) differs among individual patients [1, 2], and genetic factors linked to the HLA DR alleles have emerged as potential prognostic factors in this disease. DRB1 alleles encoding the shared epitope (SE) have been associated with predisposition and disease progression in most ethnic groups [3, 4]. Weyand et al. [57] provided strong evidence suggesting that DRB1 alleles bearing the SE sequence rather associates with a more severe and erosive disease. The effect on disease outcome has also been reported in Whites and Asians from China, Korea and Japan [8]. Prospective studies have suggested that this marker can indeed be used to predict erosive disease in British patients [9] but not in a Japanese population [10]. Thus, ethnic factors might determine restriction to the use of DRB1 alleles as predictive factors, especially in populations that do not show a strong association between RA and DRB1 alleles.
In previous work [11], we studied a group of 129 Chilean patients with RA. In these patients the prevalence of the SE was 53% compared with 30% in 97 controls. A double dose of the SE was observed in 20% of the patients and was associated with the disease, especially in its more severe forms, as described previously [5]. In clinical terms, the disease had intermediate severity [12, 13], not as severe as in British patients or as mild as in Greek patients [14]. In contrast to other series [6, 15, 16], no association of the SE with erosive disease was observed in this earlier work of ours. In the present work, we studied prospectively this cohort after 6 yr by analysing the contribution of the SE to the outcome, which was radiographic damage to the hands. This follow-up allowed us to assess whether SE could predict the development of erosion in patients who had non-erosive disease at study entry.
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Patients and methods
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This was a prospective study of the clinical expression of RA in 129 patients examined in 1992 in the out-patient departments of two hospitals in Santiago. All of them fulfilled at least four of the revised criteria for the classification of RA put forward by the American College of Rheumatology [17]; 93% were positive for rheumatoid factor. In 1998, 108 of them were re-examined (16 were dead, four did not want to participate and one was living abroad). Clinically relevant information was collected at both time points. HLA-DRB1 and shared epitope determinations were made in genomic DNA, as reported previously [11]. Hand radiographs were obtained in 92 patients at study entry and in 104 patients in 1998. In all, 77 patients had hand X-rays at both time points. Radiographs were given a Steinbrocker score [18] by a radiologist who was unaware of the HLA-DRB1 status. At study entry, 29 patients had non-erosive hand radiographs; 25 of them came to a second analysis in 1998. All patients received similar treatment with anti-rheumatic drugs.
The ethics review board of the Catholic University of Chile approved this study.
For statistical analysis, the
2 test with Yates' correction and Fisher's exact test were used where indicated. Results are expressed as the median (range). Relative risk (RR) with Cornfield 95% confidence limits for RR were calculated with EPI Info version 6.0 (Centers for Disease Control and Prevention, Atlanta, GA, USA and World Health Organization, Geneva, Switzerland).
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Results
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In 1998 we were able to examine 108 patients. The SE was present in 22 (20.4%) patients in a double dose, 35 (32.4%) patients had one dose and 51 patients (47.2%) did not have the SE. These three groups had similar disease duration, and the presence of the SE in one or two doses or its absence did not differentiate the patients in 1998 in terms of the number of inflamed joints, the number of different anti-rheumatic drugs used, functional capacity, extra-articular manifestations, remission or work capacity.
In 1998, 104 of the 108 patients had hand radiographs; 18 (17%) patients were in Steinbrocker class I or II. In class III or IV were all 20 (100%) patients with a double dose, 32 (91%) of 35 with one dose and 34 (69%) of 49 without the SE (P=0.0002).
In 1992, 79 of the 108 patients had hand radiographs and 32% (25 patients) were in Steinbrocker class I or II. Table 1
shows that the possession of the HLA-DRB1 SE correlated with erosive disease. Radiological progression occurred in 13 of the 25 patients who were in Steinbrocker class I or II at study entry, when they had a median disease duration of 3 yr (range 0.417). In 1998, these patients had a median age of 49 yr (3570) with a median disease duration of 8 (723) yr. Eleven patients were SE-positive and 10 of them were now in Steinbrocker class III or IV compared with only three of the 14 patients without the SE (
2, P=0.0023). The RR (95 confidence interval) of the SE for the development of erosions was 4.24 (1.5311.77) with sensitivity 77% (4693%), specificity 92% (6099.6%), positive predictive value 91% (5799.5%) and negative predictive value 79% (4994%).
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TABLE 1. Steinbrocker class of hand radiographs (class III or IV vs class I or II) in 1998 in 25 patients who did not have erosions (Steinbrocker class I or II) in 1992, according to the presence or absence of the SE
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Discussion
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Different studies have tried to define prognostic factors in patients with RA that might enable physicians to prescribe more aggressive therapies. Genetic influences in susceptibility to and the severity of RA have been studied in different countries and ethnic groups [4, 1921]. Patients who inherit a disease-linked allele from both parents are more likely to have serious disease. The SE in the combining forms HLA-DRB1*0401 and DRB1*0404 is associated with a greater risk of undergoing joint surgery later in the course of the disease or developing erosions, rheumatoid vasculitis, Felty syndrome or lung disease. Milder forms of RA are not as strongly associated with the SE [47, 9, 15, 16]. However, other reports have not found these associations with susceptibility [22, 23] or severity [10, 24, 25].
There is little information about the clinical features, epidemiology and genetics of RA in Latin America [11, 13, 26, 27]. In our patients, the SE is significantly associated with the disease, being present in 53% of them compared with 30% in 97 controls. Whereas at study entry no difference in Steinbrocker class in hand radiographs was found, after follow-up we observed that Steinbrocker class III or IV included all 20 (100%) patients with a double dose, 32 (91%) of the 35 patients with one dose and 34 (69%) of the 49 patients without the SE (P=0.0002). The presence of the SE in double or single dose was a good predictor of change to erosive disease. The 25 patients with similar disease duration and similar treatment who did not have erosive disease at study entry in 1992 were re-examined in 1998. Ten of the 11 SE-positive patients became erosive (five of five with a double dose and five of six with a single dose) compared with only three of the 14 who did not have the SE (RR=4.4). No special allele combination was associated with progression; the only patient who did not progress at the second examination had the genotype *0404/-. In our cohort, the development of erosions seems to be rather slow because erosions may appear after years of non-erosive disease.
These results support those of Gough et al. [9], who concluded that in early RA the presence of the SE predicts the development of bone erosions in the feet and hands after 1 yr of follow-up [9], and those of Reveille et al. [28], who observed 205 patients with RA for 48 weeks and found that new erosions occurred among the Caucasian patients treated with placebo. In the placebo group in that study, the odds ratio of developing erosions was 14 (95% CI 12.9215.0) for the 19 patients with the DR4 epitope (eight had new erosions), whereas of 26 patients without the epitope only four developed erosions [28]. However, this was not found by Higami et al. [10] in their study of Japanese people after 1 yr of follow-up.
These findings imply that, in our population, assessing the presence of the SE at an early stage of the disease might help us to improve treatment strategies and to stop or delay bone destruction, especially because other prognostic factors remain unknown for Chilean patients. Our observations support and extend the notion that the presence of the SE, in one or two doses, can predict the development of erosions. The value of the SE should be tested in RA populations in whom it is not as prevalent as in other populations.
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Acknowledgments
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We thank Mrs Magaly Acuña, Miss Yasna Mena and Mr Fernando Bravo for their invaluable help in locating the patients, Mrs Paola Viviani for her statistical expertise and Drs Ximena Berríos and John Reveille for helpful suggestions. This work was supported in part by PANLAR Trust Support 11/30/98, by grant 1930596 from Fondo Nacional de Ciencia y Tecnología, and Dirección de Investigación de la Escuela de Medicina Proyecto de Becado Grant PG19-98, Pontificia Universidad Católica de Chile.
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Notes
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Correspondence to: L. Massardo, Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Casilla 114-D Santiago, Chile. 
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Submitted 23 March 2000;
Accepted 7 August 2001