Rheumatoid Arthritis – an Inflammatory Disease
Rheumatoid Arthritis – an Inflammatory Disease
Rheumatoid arthritis is an inflammatory disease, primarily of the joints, with autoimmune features and a complex genetic component.
INHERITANCE
Occasional families show a considerable number of cases of this common disorder. A simple Mendelian mechanism could not be proved, however. Indeed, some (Burch et al., 1964) could not demonstrate significant familial aggregation.
Lynn et al. (1995) conducted family studies and segregation analyses of RA based on consecutive patients with RA ascertained without regard to family history or known risk factors. Included in the analyses were first-degree relatives from 135 simplex and 30 multiplex families. A highly penetrate recessive major gene, with a mutant allele frequency of 0.005, was identified as the most parsimonious genetic risk factor. Significant evidence for heterogeneity in risk for RA was observed for proband gender but not for proband age at onset. Kaplan-Meier risk analysis demonstrated significant evidence for differences in the distribution of risk among first-degree relatives. Although both proband gender and age at onset were identified as important risk factors, proband gender appeared to be the more important determinant of risk, with relatives of male probands having the greatest cumulative risk for RA. For future genetic analyses, Lynn et al. (1995) suggested that families with an excess of affected males having a young age at onset might be most informative in identifying the putative recessive gene and its modifiers.
Hasstedt et al. (1994) studied 28 pedigrees ascertained through pairs of first-degree relatives with RA. RA was confirmed in 77 pedigree members, including probands; the absence of disease was verified in an additional 261 pedigree members. Members of the pedigrees were typed serologically for HLA. Analyses supported the existence of an HLA-linked RA susceptibility locus, estimated the susceptibility allele frequency as 0.0216, and estimated the lifetime penetrance as 41% in male homozygotes and 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variants with HLA genotypes to genetic or environmental effects shared by sibs. The genetic model inferred in this analysis was considered consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounted for approximately one-half of familial RA, although it accounted for only approximately one-fifth of the RA in the population.
PATHOGENESIS
In a T-cell receptor transgenic mouse model, an inflammatory arthritis that resembles human RA is initiated by T cells but is sustained by antibodies to GPI (172400). Using ELISA analysis, Schaller et al. (2001) detected high levels of antibody to GPI, independent of the presence of rheumatoid factor, in serum and synovial fluid of most RA patients; antibodies to GPI were rare in controls or in patients with Lyme arthritis or Sjogren syndrome. In addition, the authors found high levels of GPI in sera and synovial fluid and the presence of GPI-containing immune complexes in RA synovial fluid. Immunohistochemical analysis and confocal microscopy demonstrated intense expression of GPI on the surface of endothelial cells of synovial arterioles and some capillaries, but not venules or in other tissues. Intense patchy expression was observed on the surface lining of hypertrophic synovium, particularly where the hypertrophic villous formed; this expression pattern resembled that for vascular permeability factor (VEGF/VPF; 192240). Schaller et al. (2001) suggested that GPI may be presented to the immune system either on endothelial cell surfaces or as a soluble protein in synovial fluid of inflamed RA joints, leading to antibody binding or to immune complex formation with complement activation, respectively. In either case, they concluded that there is a role for autoantibody in the pathology of RA and that there may be scope for antibody treatments for the disease.
MAPPING
Cornelis et al. (1998) performed a genome scan with 114 European Caucasian rheumatoid arthritis sib pairs from 97 nuclear families. Linkage was significant only for HLA and nominal for 19 markers in 14 other regions. Four of the loci implicated in IDDM potentially overlap with these regions: IDDM6 (601941), IDDM9, IDDM13 (601318), and DXS998. The first 2 of these candidate regions, defined in the rheumatoid arthritis genome scan on 18q22-q23 and 3q13, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (P = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0.001 and suggested an interaction between