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Rheumatoid arthritis (RA) is the most common chronic inflammatory disease, affecting about 1% of the white population, particularly female patients, and has considerable physical, psychological, and social repercussions.1
In a paper published previously in the Annals, Dadoniene et al described and compared two cohorts of patients with RA from Vilnius (Lithuania) and Oslo (Norway).2 There were no significant differences in sex, age, extra-articular manifestations, education, or family history of RA between the groups. None the less, there were important differences in disease activity, disability, pain, emotional, mental and general health, with patients in the Vilnius group having the worst scores. The number of patients who had never used a disease modifying antirheumatic drug (DMARD) was similar in both groups. Vilnius patients had more commonly used azathioprine, sulfasalazine, and antimalarial drugs, whereas Oslo patients had used methotrexate, gold salts, cyclosporin, and d-penicillamine. Surgery was more common in the Oslo patients. That study was developed to compare the evolution and outcomes of two different populations with RA and was the first to include health related quality of life. The authors attributed the differences between these groups to differences in economic status, medical care, drugs used and, to a lesser extent, genetic differences.
During the past years the HLA system has been gaining an increasingly important role in the pathogenesis of autoimmune diseases. HLA polymorphism has multiple effects on the immune system.3
HLA-DRB1 alleles have been associated with RA in a number of populations. In the third hypervariable region of their DRB1 chain, they share a sequence of amino acids named “the shared epitope” (SE).4
In a mestizo Colombian population we found that the SE 70QKRRA74 in DRB1*04 alleles had the strongest association with RA.5 However, we did not find any significant association between HLA and RA in African Colombians, emphasising the importance of genetic differences even among populations living within the same country.6
There have been different findings from one area to another. In Latin America, the differences are important. In Chilean patients the most common HLA-DRB1 alleles were DRB1*0404 and *0408 and the SE influenced the radiographic evolution of hands erosions.7,8 In the Argentinean population the DRB1*0404 was also important but only DRB1*1001 was related to RA severity.9 In the Peruvian population an association between RA and the SE was not found.10 There was a lack of uniformity in the development of these trials, but they all showed a lack of association between DRB1*0401 and RA in the Latin American population.
These findings suggest that SE inheritance and genetic influence may vary depending on the genetic background of the studied population even in apparently closely located countries. The previous study comparing the Norwegian and Lithuanian populations without inclusion of genetic typing may be misleading. Furthermore, not only may the HLA system play a part in the disease outcome and disease progression of these patients but pharmacogenetics may also be at least as important. The efficacy of methotrexate, sulfasalazine, and other DMARDs in reducing the radiological progression of RA erosions has been proved; however, their efficacy and tolerability may be influenced by mutations in their metabolic pathways or in their cellular targets.11,12
Epidemiology of autoimmune disease is becoming more complex as our knowledge of HLA and genetics becomes more complete. The time is coming when diseases will be defined not only by their synptomatology but also by the genetic background of their hosts.
We thank Drs Cadena and Anaya for their important and interesting comments on our paper reporting differences in disease activity and health status between matched patients in Norway and Lithuania.1
Cadena and Anaya focus on the difference in the genetics of the HLA system or pharmacogenetic differences as a potential explanation for our findings. They refer to several studies, mainly from their own region of the world, where genetic markers have been associated with disease severity and progression. We agree that rheumatoid arthritis is associated with genes, mainly in the region encoding the major histocompatibility complex genes.2 However, the relative importance of genes is controversial also because low disease concordance has been found in studies of monozygotic twins. Some of the genetic studies indicate only a limited influence of genetic factors on disease susceptibility and progression, and this may suggest a relatively stronger importance of environmental factors.3
However, we completely agree with the comments of the authors that genetic factors, ideally, should have been examined in both populations. However, blood samples were not available for such analyses, but our results would have been stronger if data on the genetic background of the populations had also been available.
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