The interferon regulatory factor 5 gene confers susceptibility to rheumatoid arthritis and influences its erosive phenotype.

BACKGROUND: Increased expression of type I IFN genes, also referred to as an IFN signature, has been detected in various autoimmune diseases including rheumatoid arthritis (RA). Interferon regulatory factors, such as IRF5, coordinate type I IFN expression. Multiple IRF5 variants were suggested as autoimmunity susceptibility factors. OBJECTIVE: As the linkage proof remains important to establish fully any genetic RA susceptibility factor, the authors took advantage of the largest reported European trio family resource dedicated to RA to test for linkage IRF5 and performed a genotype-phenotype analysis. METHODS: 1140 European Caucasian individuals from 380 RA trio families were genotyped for IRF5 rs3757385, rs2004640 and rs10954213 single nucleotide polymorphisms (SNP). RESULTS: Single marker analysis provided linkage evidence for each IRF5 SNP investigated. IRF5 linked to RA with two haplotypes: the CTA risk haplotype 'R' (transmission (T)=60.6%, p=23.1×10(-5)) and the AGG protective haplotype 'P' (T=39.6%, p=0.0015). Linkage was significantly stronger in non-erosive disease for both IRF5 R and P haplotypes (T=73.9%, p=4.20×10(-5) and T=19.6%, p=3.66×10(-5), respectively). Multivariate logistic regression analysis found IRF5 linked to RA independently of the rheumatoid factor status. IRF5 RR and PP haplotypic genotypes were associated with RA, restricted to the non-erosive phenotype: p=1.68×10(-4), OR 4.80, 95% CI 2.06 to 11.19; p=0.003, OR 0.17, 95% CI 0.05 to 0.57, respectively. CONCLUSION: This study provides the 'association and linkage proof' establishing IRF5 as a RA susceptibility gene and the identification of a genetic factor that seems to contribute to the modulation of the erosive phenotype. Further studies are warranted to clarify the role of IRF5 in RA and its subphenotypes.

PTPN22 R620W genotype-phenotype correlation analysis and gene-environment interaction study in early rheumatoid arthritis: results from the ESPOIR cohort.

OBJECTIVES: To investigate genotype-phenotype correlation and gene-environment interaction between PTPN22 R620W environmental factors such as tobacco/hormonal treatments in an inception cohort of RA patients. METHODS: An intra-cohort study including 532 Caucasian RA patients genotyped for the PTPN22 rs2476601 polymorphism was performed. Anti-CCP and RF status at baseline, presence of bone erosions at 1 year, HLADR1 and/or DR4 status, demography, comorbidities, exposure to tobacco with the cumulative dose in pack-years, hormonal treatments and treatments received for RA were collected. Logistic regression was performed to estimate the ORs and multiplicative interaction with adjustment for confounding factors. Gene-environment interaction was estimated by the relative excess risk due to interaction (RERI), attributable proportion (AP) and synergy index (SI). RESULTS: PTPN22 620W risk allele was associated with ACPA production [odds ratio (OR) = 2.21, 95% CI 1.4, 3.4, P < 0.0001]. Hormonal treatment exposition and smoking were found to act with a protective effect against ACPA production (OR = 0.44, 95% CI 0.3, 0.7, P = 0.001) and early bone erosion (OR = 0.56, 95% CI 0.4-0.8, P = 0.003), respectively, and independently of HLADR and PTPN22 status. No evidence for a gene-environment interaction was detected. CONCLUSION: These data provide new insights into the pathogenesis of RA, underlying the pivotal key role of environmental factors in the typical heterogeneity of RA.

Association study of B-cell marker gene polymorphisms in European Caucasian patients with systemic sclerosis.

BACKGROUND: BANK1 and BLK B-cell genetic markers have been reproducibly and convincingly found to contribute to susceptibility to systemic sclerosis (SSc). OBJECTIVES: To determine whether other B-cell genetic markers including CD19, CD20, CD22 and CD24 polymorphisms affect susceptibility to SSc in the European Caucasian population. METHODS: A case-control study was performed in 900 patients with SSc and 1034 healthy controls. Among the whole SSc population, 304 (34%) had the diffuse cutaneous subtype, 551 (61%) had the limited cutaneous subtype, 732 (81%) were positive for antinuclear antibodies , 331 (37%) were positive for anticentromere antibodies and 228 (25%) for the topo-isomerase I. Genotyping has been performed for CD19 rs35979293, CD19 rs2904880, CD20 rs7126354, CD20 rs3802954, CD20 rs105146, CD20 rs4939364, CD22 rs10406069, CD22 rs10413500, CD22 rs10419538, CD22 rs34826052 and CD24 ins-del polymorphisms. RESULTS: Genotype frequencies were at the Hardy-Weinberg equilibrium in the control population for all the SNPs investigated and observed frequencies were very similar to those expected in the European population. Allelic and genotypic frequencies for all these tested SNPs were found to be similar in SSc patients and controls. Moreover, subphenotype analyses in particular for subgroups having the diffuse cutaneous subset or topo-isomerase I positive antibodies, which are the most associated with BANK1 variants, did not detect any difference between SSc patients and controls. CONCLUSIONS: These results obtained through a large cohort of European caucasian patients with SSc do not support the contribution of CD19, CD20, CD22, CD24 variants to the genetic susceptibility of SSc.

Hidradenitis suppurativa associated with spondyloarthritis -- results from a multicenter national prospective study.

OBJECTIVE: To determine the prevalence and characterize the inflammatory musculoskeletal symptoms of hidradenitis suppurativa (HS), a chronic inflammatory disease of skin appendages. METHODS: Patients with HS referred to 3 dermatology university hospital centers were systematically screened for peripheral arthritis, dactylitis, inflammatory back pain, or enthesitis. After careful clinical examination, patients were further classified according to clinical and imaging criteria for spondyloarthritis (SpA) using the Amor, European Spondyloarthropathy Study Group (ESSG), and ASsessment in ankylosing spondylitis (ASAS). RESULTS: We screened 640 patients with HS; 184 had musculoskeletal symptoms. In all, 43 (mean age 39.4 yrs, ± 8.3; 80% women) had arthritis, inflammatory back pain, or enthesitis and were investigated further. Signs of HS preceded the onset of articular symptoms in 39 patients (90%), at a mean interval of 3.6 years. A total of 18 (41%), 24 (55%), and 15 (34%) patients fulfilled the Amor, ESSG, and ASAS criteria, respectively, while synovitis, acne, pustolosis, hyperostosis, and osteitis (SAPHO) syndrome was established in 4 patients. The crude prevalence of SpA in all 640 patients with HS was 3.7% by the ESSG criteria. CONCLUSION: SpA may occur in patients with HS, with the prevalence in this group exceeding that in the general population. The very short time between skin and joint symptom onset in some cases suggests common pathogenic mechanisms underlying HS and SpA.

Association of IL-2RA and IL-2RB genes with erosive status in early rheumatoid arthritis patients (ESPOIR and RMP cohorts).

OBJECTIVES: To assess the impact of single nucleotide polymorphisms (SNPs) in IL-2RA (rs2104286) and IL-2RB (rs743777 and rs3218253) genes on the risk of erosions in rheumatoid arthritis (RA) patients. METHODS: This work is derived from 2 prospective cohorts of early RA: ESPOIR (n = 439) and RMP (n = 180). The proportions of patients with erosions at baseline and 1 year according to the genotypes of IL2RA (rs2104286) or the haplotypes constructed with the 2 SNPs of IL2RB were compared in the whole population and in ACPA positive patients. A meta-analysis assessing the risk of erosion depending on the haplotypes of the 2 SNPs of IL-2RB was performed using the Mantel-Haenszel method. A multivariate model was used to assess the independent effect of the haplotypes of IL-2RB on the risk of erosions. RESULTS: The AC haplotype of IL-2RB carriage was significantly associated with the rate of erosions in ACPA positive patients in ESPOIR cohort (rate of erosions: AC/AC: 78% versus GC or GT/GC or GT: 44%, p = 0.001). A meta-analysis of ESPOIR and RMP cohorts confirmed that the carriage of AC haplotype was significantly associated with the rate of erosions at 1 year in the whole sample (OR[95%CI] = 1.92[1.14-3.22], p = 0.01) and in ACPA positive patients (OR[95%CI] = 3.34[1.68-6.67], p = 0.0006). A multivariate model in ESPOIR cohort demonstrated the independent effect of the carriage of the AC haplotype (6.03[1.94-18.69], p = 0.002) on the risk of erosions in ACPA+ patients. CONCLUSION: A haplotype constructed with 2 SNPs located on IL-2RB gene was associated with erosive status in early RA.

High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis.

OBJECTIVE: To investigate whether levels of anti-cyclic citrullinated peptide antibodies (anti-CCP2) in patients with rheumatoid arthritis (RA) are associated with the co-occurrence of lung diseases. METHODS: A total of 252 RA patients were included in a cross-sectional study. Pulmonary disease was confirmed by high-resolution chest computed tomography scan. Circulating anti-CCP2 were quantified using ELISA. Multivariate logistic regression was conducted to identify independent risk factors for lung disease. RESULTS: Male sex (OR 3.29, 95% CI 1.59-6.80) and high anti-CCP2 levels (OR 1.49, 95% CI 1.25-1.78) were identified as independent risk factors for lung disease in the RA population. CONCLUSION: High anti-CCP2 levels are associated with lung disease in the RA population.

Phenotype-haplotype correlation of IRF5 in systemic sclerosis: role of 2 haplotypes in disease severity.

OBJECTIVE: Identification of an association between IRF5 rs2004640 and systemic sclerosis (SSc) has highlighted a key role for type 1 interferon (IFN). Additional functional IRF5 variants have been identified as autoimmune susceptibility factors. Our aim was to investigate whether IRF5 haplotypes confer susceptibility to SSc, and to perform genotype haplotype-phenotype correlation analyses. METHODS: We genotyped IRF5 rs377385, rs2004640, and rs10954213 in 1623 individuals of French European Caucasian origin. SSc patient subphenotypes were analyzed according to cutaneous subsets and for SSc-related pulmonary fibrosis. RESULTS: Case-control studies of single markers revealed an association between IRF5 rs3757385, rs2004640, and rs10954213 variants and SSc. We identified an IRF5 risk haplotype "R" (p(adj) = 0.024, OR 1.23, 95% CI 1.07-1.40) and a mirrored protective haplotype "P" (p(adj) = 8.8 x 10(-3), OR 0.78, 95% CI 0.68-0.90) for SSc susceptibility. Genotype-phenotype correlation analyses failed to detect any association with a single marker. By contrast, phenotype-haplotype correlation analysis was able to detect intra-cohort association and to discriminate SSc patients with from those without the following clinical traits: "R" and/or "P" haplotypes identified diffuse cutaneous SSc (p = 0.0081) and fibrosing alveolitis (p = 0.018). CONCLUSION: IRF5 haplotypes are more informative than single markers, suggesting that they could be helpful for risk stratification of SSc patients. Our study provides further evidence of a key role of IRF5 in SSc severity.

Unexplained polyarthralgia and celiac disease.

Celiac disease is an immunological disorder whose best-known manifestations are gastrointestinal symptoms. However, early joint manifestations are common and frequently overlooked features of celiac disease. We report a case in which unexplained inflammatory polyarthralgia and iron-deficiency anemia led to the diagnosis of celiac disease. Autoimmune thyroiditis was also a feature. Early diagnosis and treatment of celiac disease protect patients against complications such as digestive neoplasis. A simple and rapid tool for achieving the early diagnosis is the measurement of the serum of anti-gliadin, anti-endomysial and anti-tissue transglutaminase antibodies. However, a duodenal biopsy remains the only means of making the definitive diagnosis of celiac disease.