Currently, research on the genetic factors associated with rheumatoid arthritis (RA) flourishes, and in recent years the number of genetic factors found to be associated with RA susceptibility has expanded. Besides the long-known HLA class II alleles, a R620W single-nucleotide polymorphism (SNP) in the PTPN22 gene has been identified and replicated in several different populations (1). Several other SNPs also confer risk of RA; some of them await replication or gave distinct results in different populations (2). The total genetic contribution to RA susceptibility is estimated by comparing monozygotic and dizygotic twins and has been reported to account for 50–60% of liability to the disease (3). Because the HLA class II alleles account for approximately one-third of the genetic contribution, it is expected that in the near future more genetic factors will be identified.
Currently, most attention is paid to the role of genetics in RA susceptibility. So far, the contribution of genetics to RA severity is not known. The recognition of genetic factors associated with RA severity might be helpful in predicting the disease course and may lead to the identification of pathways involved in joint destruction. In order to get more insight into the role of genetics in RA severity, we investigated variability in radiologic joint destruction between monozygotic and dizygotic twins and random pairs of unrelated patients with RA.
The study group comprised monozygotic (n = 20) and dizygotic (n = 8) twins with RA who were enrolled in the North American RA Consortium. The unrelated RA patients were included in the Leiden Early Arthritis Clinic (EAC) cohort (4). The median disease duration at the time of radiography was 9 years for dizygotic twins and 10 years for monozygotic twins. All of the monozygotic twins were rheumatoid factor (RF) positive (see Table 1). To match for differences in the era of disease onset and autoantibody status, the unrelated RA patients selected from the EAC cohort were RF positive and were included in the cohort during the early or mid 1990s. This resulted in 40 persons with available radiographs obtained after 8 years of disease; these patients were randomly assigned by computer to 20 pairs. All subjects were white and had radiographs of the hands, which were scored according to the Sharp-van der Heijde method (5) by a rheumatologist who was unaware of the clinical data (intraclass correlation coefficient for repeated readings 0.96, 95% confidence interval 0.83–0.99). To correct for differences in disease duration, for every subject the Sharp score was divided by the disease duration at the time of the radiograph, yielding the estimated radiologic progression per year (6). To determine the variation in joint destruction, for every pair of RA patients, the difference in radiologic progression per year was calculated. Subsequently, to evaluate the variation in joint destruction in the different groups of patients, the mean difference and variance in radiologic progression per year were compared between monozygotic and dizygotic twins and unrelated patients with RA.
|Characteristic||Monozygotic twins (n = 20)||Dizygotic twins (n = 8)||Unrelated RA patients random pairs (n = 40)|
|Sex, % female||70||63||65|
|Age at diagnosis, mean ± SD years||37.1 ± 11.4||31.5 ± 17.3||53.8 ± 12.3*|
|Disease duration at time of radiography, median years||10.5||9.0||8.0|
|Rheumatoid factor positivity, %||100||63||100|
|Estimated mean ± SEM radiologic progression per year†||2.8 ± 0.6||1.7 ± 0.8||3.3 ± 0.6|
|Difference in Sharp scores per year within pairs, mean (variance)||1.7 (3.3)||2.4 (6.1)||4.3 (16.1)‡|
Patient characteristics and radiologic joint destruction scores are presented in Table 1. Both monozygotic and dizygotic twins were significantly younger than the pairs of unrelated patients (P < 0.001 by Mann-Whitney test). The mean estimated radiologic progression per year was not significantly different between monozygotic twins, dizygotic twins, and unrelated RA patients. However, the variation in joint destruction was highest within the pairs of unrelated RA patients (mean difference 4.3 Sharp points per year), followed by dizygotic twins (mean difference 2.4 Sharp points per year), and the smallest difference was observed within monozygotic twins (1.7 Sharp points per year), with a significant difference between monozygotic twins and unrelated RA patients (P = 0.037 by Mann-Whitney test). The finding of increasing variation in the degree of joint destruction comparing, respectively, monozygotic twins, dizygotic twins, and unrelated pairs of RA patients supports the notion of a role for genetic factors in RA severity.
Results of the current study indicate that genetic factors are associated with the severity of joint destruction during the course of RA. This study has some limitations. First, because the number of dizygotic twins was low, heritability could not be properly calculated. Classic twin studies compare monozygotic and dizygotic twins and are based on the principle that environmental factors within twin pairs are (mostly) comparable, and that the contribution of genetic factors to covariance within dizygotic twins is half that within monozygotic twins. Unrelated patients are not used for quantifying the genetic contribution, because such patients differ in genetic as well as environmental factors. Nevertheless, because RA starts and progresses during adulthood, environmental factors are presumably also different within twin pairs. Therefore, a comparison of monozygotic and dizygotic twins as well as a comparison of twins and unrelated patients may be relevant. The current report adds data on unrelated pairs of RA patients to dizygotic and monozygotic twin data. We observed an increase in variation in joint destruction parallel to a decrease in genetic similarity, indicating that genetic factors are important for the severity of joint destruction in RA.
It might be a concern that although both twins and unrelated patients with RA were white, they came from different continents. However, a comparison of Sharp scores of American and Dutch patients with early RA not treated with disease-modifying antirheumatic drugs (DMARDs) revealed similar scores (7, 8).
The most important risk factor for RA severity is autoantibody status. The unrelated patients with RA were matched for RF status comparable with that of the monozygotic twins. Matching on anti–cyclic citrullinated peptide (anti-CCP) status was not possible, because anti-CCP antibodies were determined in only some of the twins. Because the presence of autoantibodies is associated with the presence of HLA shared epitope alleles (9), it is likely that by matching for autoantibodies, we also partly corrected for differences in shared epitope status. This might have underestimated the difference in variation due to genetic factors.
Given the hypothetical effect of the difference in age at disease onset between the twins and unrelated RA patients on the rate of joint destruction, the Sharp scores of EAC patients younger than age 35 years and those older than age 60 years were compared, showing no significant difference during 4 years followup.
In the patients included in this study, RA was diagnosed in the 1980s or the beginning of the 1990s. We did not provide detailed descriptions of the treatment history of all patients and cannot exclude differences in treatment. Nevertheless, during the mentioned time eras, therapy with DMARDs was started at a relatively late stage of disease, and the medications of choice were, among others, antimalarials; it is known that the ability of antimalarials to halt disease progression is limited. Therefore, we suspect that considering the relatively mild medications used in the 1980s and early 1990s, the natural disease course of the patients was only mildly affected.
In conclusion, the present study revealed, after correction for differences in disease duration and autoantibody status, an increase in variation of radiologic joint destruction in, respectively, monozygotic twins, dizygotic twins, and unrelated pairs of patients with RA. This indicates an important contribution of genetic factors to radiologic joint damage in RA. More extensive twin studies are needed to quantify the genetic contribution to disease severity.