The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disease that, in a substantial proportion of patients, is associated with the development of extra-articular manifestations. These extra-articular RA (ExRA) manifestations can have a defining impact on disease outcome, including increased premature mortality compared with RA in general [1-4]. Severe ExRA occurs both in patients recently diagnosed with RA and in those with long-standing disease [2]. Suggested predictors of ExRA include clinical, serologic, and genetic factors [5].There is strong evidence of a role for genetic factors in the etiology of RA [6-8], and genetic polymorphisms are probably involved in the wide variation in disease expression. As for most diseases classified according to a list of criteria, rather than specific diagnostic tests, the disease phenotype in RA is heterogeneous. The presence of disease susceptibility alleles may define subsets of patients with different disease courses, including patients with mild, nonerosive disease and those with a true RA phenotype and progressive disease, with extensive joint damage and ExRA manifestations. On the other hand, genetic markers not related to disease susceptibility may influence disease progression and risk for developing ExRA.HLA (human leukocyte antigen) alleles have been implicated in a number of chronic inflammatory diseases. RA has been associated with the 'shared epitope' (SE) of HLA-DRB1, which includes DRB1*04 and DRB1*01 alleles [9]. Recent genome-wide scanning studies using microsatellite loci have confirmed that there is strong linkage between this region and RA [10,11]. RA-associated HLA-DRB1*04 alleles have been reported mainly in patients with severe disease [12-16]. A meta-analysis of studies of disease progression in RA [17] revealed an association between HLA-DRB1*04 and erosive disease, and in a recently reported survey of an extensively investigated cohort of patients with early RA [18] homozygosity for HLA-DRB1*04 was a m