Search

OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome were selected for a family trio-based association study. METHODS: A total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies. RESULTS: Four SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genes UBA1, TIMP1, and IL9R. These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA with TIMPL The sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048). CONCLUSION: We provide evidence for an association of at least 2 X-chromosomal genes with RA: TIMP1 (rs6520278) and IL9R (rs3093457).

OBJECTIVE: To analyze the frequency of anti-viral citrullinated peptide (anti-VCP) antibodies in sera from patients with rheumatoid arthritis (RA) by an Epstein-Barr virus (EBV)-derived peptide in which arginine is replaced with citrulline.METHODS: Anti-VCP antibodies were determined in 627 serum samples, 300 from patients with RA and 327 from controls, including connective tissue diseases, chronic arthritides, and healthy donors. Among patients with RA, a possible correlation with systemic involvement, disease severity, and disease activity was investigated; in 94 RA patients antibodies to cyclic citrullinated protein (anti-CCP) were also measured. RESULTS: Anti-VCP antibodies were found in 45% of RA sera versus less than 5% of controls; anti-VCP levels correlated with anti-CCP levels (p < 0.0001), rheumatoid factor (p = 0.02), and erythrocyte sedimentation rate (p = 0.0058). No correlation was found with extraarticular manifestations of the disease or with disease severity. CONCLUSION: Anti-VCP antibodies are helpful in discriminating RA from other chronic arthritides or connective tissue disorders. The level of positivity is positively correlated with the anti-CCP level, suggesting that VCP can be considered a novel substrate to detect anti-citrullinated peptide/protein antibodies (ACPA). The reactivity of RA-specific antibodies with a viral citrullinated antigen raises questions on the role of EBV in the induction of ACPA.

OBJECTIVE: Subclinical gut inflammation has been described in patients with ankylosing spondylitis (AS) or psoriatic arthritis (PsA). Joint involvement has also been reported related to celiac disease. We investigated IgA antibodies to bovine tissue tranglutaminase (tTg) and IgA and IgG antibodies to human tTg and to Saccharomyces cerevisiae (ASCA) in patients with AS and PsA. METHODS: We evaluated the frequency of IgA antibodies to bovine tTg, and of IgA and IgG antibodies to human tTg and to ASCA in 43 patients with AS and 75 with PsA. As control groups we considered 79 patients with rheumatoid arthritis (RA) and 78 healthy blood donors. RESULTS: We detected antibodies as follows: IgA antibodies to bovine tTg in 1/43 patients with AS, 3/75 with PsA, 1/79 with RA, and in 9/78 healthy controls; IgA antibodies to human tTg in 1/43 patients with AS, 1/75 with PsA, 1/79 with RA, and in 3/78 healthy controls; IgG antibodies to human tTg in 1/43 patients with AS, 4/75 with PsA, 5/79 with RA, and in 7/78 healthy controls. IgA ASCA were confirmed in 10/43 patients with AS, 7/75 with PsA, 14/79 with RA, and in 7/78 healthy controls; IgG ASCA were present in 5/43 patients with AS, 4/75 with PsA, 8/79 with RA, and in 8/78 healthy controls. No statistically significant difference was observed in the prevalence of IgA or IgG antibodies to bovine and human tTg and in the frequency and in mean level of IgA or IgG ASCA between the studied groups or between each group and healthy controls. CONCLUSION: Our data fail to show an increased prevalence of autoantibodies associated with celiac and Crohn's disease in patients with AS and PsA.

OBJECTIVE: It has been proposed that noninherited maternal HLA-DR antigens (NIMA) might play a role in the susceptibility for rheumatoid arthritis (RA). This hypothesis has not been thoroughly tested in patients with familial RA, in whom genetic factors, either inherited or not, might have stronger influence than in patients with sporadic RA. We investigated the NIMA hypothesis in a large cohort of European patients with familial RA. METHODS: The distribution of NIMA, noninherited paternal antigens (NIPA), and inherited HLA-DR antigens was assessed in patients with familial RA from all family sets collected from 1996 onwards by the ECRAF. HLA-DRB1 oligotyping from patients and all available nonaffected siblings and parents was carried out. Familial RA was defined by the presence of at least 2 affected first-degree relatives in the same family. The frequencies of HLA-DR NIMA and NIPA were compared using odds ratios after stratification for HLA-DR*04, *0401, and/or *0404 and shared epitope (SE) status. NIMA/NIPA that coincided with inherited parental HLA-DR antigens were considered redundant and were excluded from analysis. RESULTS: NIMA and NIPA could be analyzed in 165 RA patients with familial RA and 84 nonaffected siblings. Patients were predominantly female, rheumatoid factor positive, and had erosive disease (81, 75, and 84%, respectively). Possession of HLA-DR*04 and *0401/*0404 alleles tended be more frequent in patients than in nonaffected siblings but this did not reach statistical significance. SE possession was similar in patients and healthy siblings, although the former had a double dose SE more often (37.6 vs 17.8%; p = 0.002). Transmission of SE encoding alleles from parents to offspring was skewed only in patients [OR (95% CI) 3.56 (2.55-4.95) vs 1.16 (0.75-1.79) in nonaffected siblings]. Using the NIPA as control, the frequencies of HLA-DRB1*04, *0401/*0404, and SE positive NIMA were not increased in patients lacking these susceptibility alleles. The frequencies of NIMA encoding susceptibility alleles in DR*04 and *0401/*0404 negative patients were lower than in nonaffected siblings. CONCLUSION: Our results corroborate the association between RA and inherited SE alleles and do not support a role for noninherited HLA-DR maternal antigens in the susceptibility for familial RA.

OBJECTIVE: To evaluate the prevalence and clinico-serological correlations of anti-enolase, anti-C1q, and anti-dsDNA antibodies in patients with systemic lupus erythematosus (SLE). METHODS: Sixty-eight sera randomly obtained from SLE patients were examined. Anti-a-enolase antibodies were detected by immunoblot on recombinant protein; anti-C1q and anti-dsDNA antibodies were detected using an ELISA. RESULTS: Anti-a-enolase, anti-C1q, and anti-dsDNA antibodies were positive in 21%, 62%, and 63% of patients, respectively. A correlation was found between anti-dsDNA and anti-C1q antibodies, while anti-enolase antibodies did not correlate with the other 2 specificities. Anti-a-enolase antibodies were not correlated with any of the clinical and serological variables examined. Anti-C1q antibodies were correlated with ECLAM score, leukopenia, complement levels, and active renal involvement. Anti-dsDNA antibodies correlated with arthritis, leukopenia, complement levels, and the presence of renal involvement, independent of activity. In patients with active renal disease anti-dsDNA antibodies were correlated with a poor renal outcome, occurring after a mean period of 24 months. CONCLUSION: These data suggest the association of anti-C1q antibodies with disease flares and active renal disease in SLE. The observed association of anti-dsDNA antibodies and renal disease was expected. Further analysis is required to fully assess the clinical significance of anti-a-enolase antibodies.