Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease

Background & Aims:The detection of phenotype-determining genes as opposed t o disease susceptibility genes requires precise phenotypic characterization of patients. Peripheral arthropathies in inflammatory bowel disease (IBD) are well recognized and are classified with the HL4-B*27-related spondyloar thropathies by the European Spondyloarthropathy Study Group. However, previ ous HLA studies in IBD have only shown this association with axial disease rather than peripheral arthropathy. We recently reported a clinical classif ication that describes 2 types of peripheral arthropathy, distinguished by their natural history and articular distribution. We now report the results of immunogenetic studies in these patients and compare them with other spo ndyloarthropathies. Methods: IBD patients with type 1 (n = 57) and type 2 ( n = 45) peripheral arthropathy were identified by case note review and ques tionnaire. Patients and 603 controls from Oxfordshire were assigned HLA-A, -B, -C, -DR, and -DQ genotypes by sequence-specific primer polymerase chain reaction. Patient results were compared with controls (corrected for multi ple comparisons), then with each other in light of existing hypotheses. The results were compared with those of a cohort of 30 patients with postenter ic reactive arthritis (ReA) and 16 patients with IBD-associated ankylosing spondylitis (IBD-AS). Results: Type 1 arthropathy was associated with HLA-D RB1*0103 (DR103; a rare subtype of DR1) in 33% (P < 0.0001; relative risk [ RR], 12.1), B*35 in 30% (P = 0.01; RR, 2.2), and B*27 in 26% (P = 0.001; RR , 4.0). In contrast, type 2 was associated with HLA-B*44 in 62% (P = 0.01; RR, 2.1). Similar significant associations to type 1 arthropathy were found in ReA, except that the HLA-B*27 association was significantly stronger an d an association was found with DRB1*0101 (DR1) in 43%(P = 0.001; RR, 2.2). IBD-AS was associated only with HLA-B*27 and DRB1*0101. Conclusions: These data suggest that the clinical classification into type 1 and type 2 arthr opathies describes immunogenetically distinct entities and establish that i n polygenic disorders, genes may determine clinical phenotype without confe rring overall disease susceptibility (in this case, HLA genes). Type 1 arth ropathy is clinically and immunogenetically similar to the spondyloarthropa thies, but different HLA associations may define phenotypically distinct gr oups. Type 2 arthropathy has different HLA associations and may have a diff erent etiology. Further studies are now required to confirm these associati ons and to elucidate the different pathogenetic mechanisms.