The seronegative spondyloarthropathies are ankylosing spondylitis, psoriatic arthritis, reactive arthritis, the arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy. These disorders are noted for male predominance, onset usually before age 40, inflammatory arthritis of the spine and sacroiliac joints, asymmetric oligoarthritis of large peripheral joints, enthesopathy (inflammation of where ligaments, tendons, and joint capsule insert into bone), uveitis in a significant minority, the absence of autoantibodies in the serum, and a striking association with HLA-B27 (eTable 20–1). HLA-B27 is positive in up to 90% of patients with ankylosing spondylitis and 75% with reactive arthritis. HLA-B27 also occurs in 50% of the psoriatic and inflammatory bowel disease patients who have sacroiliitis. Patients with only peripheral arthritis in these latter two syndromes do not show an increase in HLA-B27.
HLA-B27 may contribute to the pathogenesis of the spondyloarthropathies in a variety of ways. HLA-B27 may misfold and trigger production of inflammatory cytokines, such as IL-17 or IL-23. HLA-B27 may also present arthritogenic peptides. Experiments with transgenic rats demonstrate that HLA-B27 itself (and not a gene in linkage dysequilibrium with HLA-B27) confers susceptibility to these diseases. When the human HLA-B27 gene is expressed in rats, the animals develop a spinal and peripheral arthritis, psoriasiform nail and skin changes, and bowel inflammation. Thus, HLA-B27 is an important risk factor for the spondyloarthropathies. However, some patients with these disorders are HLA-B27-negative, and the great majority of HLA-B27-positive individuals do not develop spondyloarthropathies. The gene is therefore neither necessary nor sufficient to cause spondyloarthropathies.
Infection also appears to play a key role in some of the spondyloarthropathies, especially reactive arthritis, which characteristically develops 1–4 weeks after bacterial dysentery or a nongonococcal sexually transmitted infection (see below). The interplay of susceptibility genes and environmental infections is demonstrated by the fact that the risk of developing reactive arthritis is 0.2% in the general population, 2% in the HLA-B27 individuals, and 20% in patients with HLA-B27 who become infected with Salmonella, Shigella, or enteric organisms. Despite these gains in our understanding of the importance of HLA-B27 and infection, the precise mechanism by which genes and infection cause spondyloarthropathy is not yet known.