Spondyloarthropathy (SpA), one of the commonest chronic rheumatic diseases, includes a spectrum of related disorders comprising the prototype ankylosing spondylitis (AS), a subset of psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease, and undifferentiated ... Spondyloarthropathy (SpA), one of the commonest chronic rheumatic diseases, includes a spectrum of related disorders comprising the prototype ankylosing spondylitis (AS), a subset of psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy (Miceli-Richard et al., 2004). These phenotypes are difficult to differentiate because they may occur simultaneously or sequentially in the same patient. Studies have suggested that a predominant shared component, including HLA-B27, predisposes to all phenotypic subsets, and that these subsets should be considered as various phenotypic expressions of the same disease (Said-Nahal et al., 2000, Said-Nahal et al., 2001). Braun and Sieper (2007) provided a detailed review of ankylosing spondylitis, including clinical features, pathogenesis, and management. - Genetic Heterogeneity of Susceptibility to Spondyloarthropathy Additional susceptibility loci for spondyloarthropathy have been identified on chromosome 9q31-q34 (SPDA2; 183840) and chromosome 2q (SPDA3; 613238).
Kidd et al. (1995) described a family in which 7 of 12 members had early onset oligo- or polyarthritis, enthesitis, or both, and fulfilled established criteria for spondyloarthropathy, although none had radiologic evidence of sacroiliitis. The mean age ... Kidd et al. (1995) described a family in which 7 of 12 members had early onset oligo- or polyarthritis, enthesitis, or both, and fulfilled established criteria for spondyloarthropathy, although none had radiologic evidence of sacroiliitis. The mean age at first symptom was 22 years, with only 1 individual having the first symptom beyond the age of 30 years. All subjects were rheumatoid factor negative. Histocompatibility showed association with HLA-B7. None had psoriasis or inflammatory bowel disease. Monnet et al. (2004) analyzed the ocular and extraocular manifestations in 175 consecutive patients with HLA-B27-associated uveitis. The male-to-female ratio was 1.3:1. The median age at first attack of uveitis was 31 years. An HLA-B27-associated extraocular disorder was seen in 136 (77.7%) patients. Ankylosing spondylitis was diagnosed in 81 (46.3%) patients and presumed in 17 (9.7%); undifferentiated spondyloarthropathy was seen in 21 (12%) patients and other HLA-B27-associated diseases in 17 (9.7%). Monnet et al. (2004) concluded that uveitis is frequently the first indication of a previously undiagnosed HLA-B27-associated extraocular disease.
The finding of B27 in 16 of 17 AS cases in India and in 2 of 60 controls (Sengupta et al., 1977) appeared to exclude genetic linkage as the basis of the association.
Calin et al. ... The finding of B27 in 16 of 17 AS cases in India and in 2 of 60 controls (Sengupta et al., 1977) appeared to exclude genetic linkage as the basis of the association. Calin et al. (1983) studied 499 available first-degree relatives of 79 HLA-B27-positive patients with ankylosing spondylitis and 69 HLA-B27-positive healthy blood donors. The rate of ankylosing spondylitis cases was estimated to be 10.6% as compared with 1.9% in B27-positive relatives of healthy persons (p less than 0.025). This suggested a genetic difference between B27-positive diseased persons and B27-positive healthy persons. It was thought that complete sequencing of HLA-B27 cDNA might help identify whether this polymorphic marker is directly related in the etiology of AS and, if so, what the mechanism of that involvement is (Szots et al., 1986). Despite the strong association between HLA-B27 and ankylosing spondylitis, linkage of this phenotype to the major histocompatibility complex region had not been established before the study of Rubin et al. (1992, 1994) involving 15 multiplex AS families. Among affected family members, 13 of 15 females and 46 of 49 males were B27 positive, as compared with 22 of 43 unaffected females and 16 of 40 unaffected males. The linkage analysis was based on a genetic model with a frequency of the AS gene of 1.8%; the risk of AS for homozygotes was placed at 99.5% and for heterozygotes at 43% with a sporadic risk of 0.1%. Analysis showed linkage with the MHC region, with a lod score of 3.36 at no recombination. The B27 haplotype did not consistently segregate with disease in 2 families, but both families still supported linkage. In a second analysis in which the population association of HLA-B27 with AS was taken into account, the maximum lod score was 7.5 at theta = 0.05. Identity-by-descent analyses showed a significant departure from random segregation among affected avuncular (uncle/nephew-niece) and cousin pairs. The presence of HLA-B40 in HLA-B27 positive individuals increased the risk for disease more than 3-fold, confirming previous reports. Disease susceptibility modeling suggested an autosomal dominant pattern of inheritance with penetrance of approximately 20%. In this study, which involved families from Toronto and Newfoundland, B27 alleles were detected by hybridization with sequence-specific oligonucleotide probes (SSOP) after amplification of genomic DNA by PCR. Scofield et al. (1993) used protein sequence databases to test a series of hypotheses: first, they asked whether the primary amino acid sequence of the hypervariable regions of HLA-B27 shares short sequences with the proteins of gram-negative enteric bacteria. They found that, unique among the HLA-B molecules, the hypervariable regions of HLA-B27 shared short peptide sequences with proteins from these bacteria, indicating the possibility of antigen mimicry. Second, they asked whether the enteric proteins satisfy the structural requirements for peptide binding to B27. This hypothesis also tended to be true. Scofield et al. (1993) concluded that HLA-B27 and enteric gram-negative bacteria have undergone convergent evolution. The regions of the enteric bacterial proteins that are contiguous with the short sequences shared with B27 tend to have structures that are also predicted to bind B27. The observation suggested a mechanism for autoimmunity and led to the prediction that the B27-associated diseases are mediated by a subset of T-cell receptors, B27, and the peptides bound by B27. HLA-B27 shares sequence with proteins from enteric bacteria. Scofield et al. (1995) pointed out that the B*2705 sequence contains a nonapeptide (LRRYLENGK) predicted to bind in the binding cleft of B27. Some nonapeptides from enteric organisms that share sequence with this nonapeptide of B27 also bind B27. Thus, peptides that both mimic and bind B27 may constitute the molecular components of a mechanism for spondyloarthropathies. Brown et al. (2000) performed a linkage study of chromosome 22 in 200 families with AS-affected sib pairs. Association of alleles of the debrisoquine hydroxylase gene (CYP2D6; 124030) was examined by both case-control and within-family means. While homozygosity for poor-metabolizer alleles was found to be associated with AS, heterozygosity for the most frequent poor-metabolizer allele (CYP2D6*4) was not associated with increased susceptibility to AS. Significant within-family association of CYP2D6*4 alleles and AS was demonstrated. Weak linkage was also demonstrated between CYP2D6 and AS. The authors hypothesized that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS. - Spondyloarthropathy Unassociated with HLA-B27 Gaucher et al. (1989) described a French family in which 18 members in 4 generations had spondyloarthropathy, radiologically proved in 16. The disease started during the third decade of life as an asymmetric, destructive arthropathy, predominantly affecting the wrists. Six patients had sacroiliitis. Rheumatoid serologic tests were all negative. After a destructive phase, repair took the form of ossification. Superti-Furga et al. (1990) stated that HLA-B27 antigen was not found in any members of the family and the disease did not segregate with the HLA locus. Because of the evidence that familial osteoarthrosis is sometimes linked genetically (and presumably etiologically) to the type II collagen gene (COL2A1; 120140), Superti-Furga et al. (1990) tested for linkage of COL2A1 and the arthropathy in this family. Linkage analysis excluded COL2A1 as the disease-causing locus in this family. It was significant that the Finnish families in which linkage to the cartilage collagen gene was demonstrated had no clinical or other evidence of inflammation, whereas in this French family the arthritis was inflammatory in nature and often asymmetric.
Overall, the prevalence of ankylosing spondylitis is between 0.1% and 1.4%, with most of these data coming from Europe. In mid-Europe, the prevalence is about 0.3 to 0.5% for ankylosing spondylitis and 1 to 2% for the whole ... Overall, the prevalence of ankylosing spondylitis is between 0.1% and 1.4%, with most of these data coming from Europe. In mid-Europe, the prevalence is about 0.3 to 0.5% for ankylosing spondylitis and 1 to 2% for the whole group of spondyloarthritides. The incidence of ankylosing spondylitis is between 0.5 and 14 per 100,000 people per year in studies from different countries (Braun and Sieper, 2007).