Rheumatoid Disease and Other Inflammatory Arthropathies

The inflammatory arthropathies described in this chapter are multifactorial polygenic disorders. Associations with human leukocyte antigens (HLAs) were first described in 1973 although the precise mechanisms by which these cause disease remain unclear. The association of rheumatoid arthritis (RA) with HLA-DRB1* alleles is robust and an interaction with smoking as an environmental factor is strongly suggested. More than 90% of patients with ankylosing spondylitis (AS) carry HLA-B*27; its role in pathogenesis is most likely related to antigen presentation. Genome-wide association studies (GWAS) have now identified many of the susceptibility genes in these conditions. There is convincing evidence for involvement of more than 30 genes in RA and at least 14 in AS. Many of these are key factors in the regulation of inflammatory/immunological responses. The association with protein tyrosine phosphatase PTPN22 is established as the second strongest with RA and is a good example of an association common to several autoimmune conditions. The association of AS with several genes in the Th17 pathway has already marked this as a potential therapeutic target. Future work will focus on identifying the precise causative allelic variants underlying GWAS associations and determining their functional significance.