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The association between HLA-B27 and the spondyloarthropathies (SpAs) is so strong that it is supposed that the HLA-B27 molecule plays a pathogenetic role. In whites and Indonesians, the frequency of HLA-B27 is about 10%; in Chinese it is about 8%; and in Japanese it is only about 1%. The prevalence of SpA in the Chinese is at least 0.2%, but in native Indonesians, Philippinos, and Malaysians, SpA is rarely seen. Twenty-three subtypes (B*2701-B*2723) have been distinguished. These subtypes are not equally distributed over the world. In most countries the distribution of the subtypes among HLA-B27 SpA patients is the same as that among the normal HLA-B27-positive population. In China, the subtype B*2704 is frequent and the prevalence of SpA is high. Native Indonesians, however, mostly have subtype B*2706, and SpA is rarely seen in this population. It was shown that B*2706, probably like B*2709 in Sardinia, is not associated with SpA. The difference between the SpA-associated and non-SpA-associated subtypes is limited to only two amino acid residues (114 and 116) at the bottom of the peptide-binding groove of HLA-B27. This small difference between health and disease rewards studies for different peptide-binding capacities and may help us characterize the peptides that are involved in the pathogenesis of SpA. The differences in disease associations in these countries also have clinical implications. In Southeast Asia, HLA-B27 typing without subtyping has less clinical usefulness than in parts of the world where B*2706 is rarely seen. When native Indonesians, Malaysians, or Philippinos are suspected of having ankylosing spondylitis or a related SpA, it is worth asking if they had white or Chinese ancestors. If native HLA-B27-positive Indonesians (with subtypes other than B*2706) develop SpA, the clinical features are not different from those in other parts of the world. In the Chinese population on the mainland and in Taiwan, juvenile SpA is frequently seen. The onset is often a peripheral arthritis or enthesitis.

Studies from around the world have confirmed the association between HLA-B27 and human spondyloarthropathies. The onset of many HLA-B27-linked arthritides follows an infection with enterobacteria. How bacteria interact with HLA-B27 and modify the immune system to give rise to the clinical disease is currently unclear. The roles of other genetic factors, including major histocompatibility complex class II genes and other genes located within this region (Tap/Lmp), have been postulated in certain spondyloarthropathies. We are using transgenic and knockout mice to answer some of these unsolved issues. This review discusses recent findings from our laboratories.

Predisposition to ankylosing spondylitis is largely genetic, and epidemiologic studies suggest that the environmental trigger is ubiquitous. HLA-B27 and -B60 predispose to ankylosing spondylitis, but in neither case is the mechanism of effect known. Other major histocompatibility complex and non-major histocompatibility complex genes are likely to influence susceptibility to spondyloarthritis as well as the disease pattern. Spondyloarthritis occurs in genetically predisposed individuals exposed to certain as yet undefined environmental triggers. A though genes within the major histocompatibility complex are clearly major determinants of susceptibility to spondyloarthritis, epidemiologic evidence suggests that their contribution accounts for less than 50% of the total. The mechanism of association of B27 with these diseases is unknown; we are currently unable to predict which B27 carriers will develop arthritis or which form of B27-associated spondyloarthritis they will develop. Lessons from transgenic animal experiments and technical and statistical advances in the field of genetics have greatly increased our ability to investigate these questions.

Further insight into the etiology and pathogenesis of juvenile rheumatoid arthritis (JRA) is presented in recent immunogenetic studies, particularly the allele associations of the pauciarticular pattern of disease. Evidence suggests that bacterial heat-shock proteins may be significant in the chronic inflammatory response in children with arthritis. Data on the role of complement activation and cytokines and their receptors also are presented. Coagulopathy in JRA may have more than one etiologic factor, including a viral agent, as may the disease itself. In the treatment of growth abnormalities in JRA, the neuroendocrine system, recombinant growth hormone, intravenous iron therapy, and nutritional supplementation are all areas of recent investigation. In outcome studies, ocular involvement and the presence of circulating IgM rheumatoid factor appear to be risk factors for disability. However, disease of less than 2 years' duration and absence of radiographic lesions likely predict good response to methotrexate therapy.

Clinically recognized subgroups of juvenile chronic arthritis and the juvenile spondyloarthropathies are gradually being shown to be immunogenetically distinct; greater subdivision may ultimately be required. Mechanisms by which the association of certain genes work await further elucidation. Meanwhile, therapy such as intravenous gamma globulin may be most effective in systemic disease. Sulfasalazine is recommended for patients with later-onset pauciarticular disease, particularly HLA-B27 patients. Methotrexate should probably be reserved for severe unresponsive disease, particularly polyarthritis, until side effect profiles are better evaluated.

Following three decades of study of the genetics of the spondyloarthropathies by segregation analysis of families, research has increasingly made use of new methods of molecular genetics and immunology. In the past year, most attention has been given to the structure and function of HLA-B27, which, with its various subtypes, is the major phenotype contributing to susceptibility to this group of disorders. Structural studies have revealed which structures are responsible for the common antigenic properties and which are responsible for subtype specificities. Application of increasing understanding of the function of class I HLA antigens is permitting the development of various models of disease. Successful production of HLA-B27 transgenic animals holds promise for testing these models.