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Objectives: Despite the well-established value of currently used classification criteria for the early diagnosis of rheumatoid arthritis (RA) there is a constant demand for novel biomarkers notably in autoantibody-negative patients. Interleukin 7 (IL-7) has been reported as a candidate diagnostic biomarker based on ACR-1987 criteria. However, clinical practice has moved to using the EULAR 2010 classification criteria. Therefore, to advance the use of IL-7 alongside the RA biomarker pipeline, we repeated the original study in a new cohort., Methods: 255 patients were recruited. IL-7 was quantified by ELISA. Univariate and regression analyses were used to model RA diagnosis., Results: 123 patients were diagnosed with RA (EULAR 2010) while 132 were classified as non-RA. In univariate analysis, RA was associated with autoantibodies and SE-positivity, higher joint counts, DAS28 (all p<0.001) and CRP (p=0.024). IL-7 was lower in RA (p=0.05). Logistic regression analysis in 227 patients with complete data set confirmed IL-7 was the second best predictive marker (p=0.035) following SJC (p=0.007) with good model fit (AUROC=0.889). A second model investigated 147 ACPA-negative patients: lower IL7 was the second best predictive marker (p=0.075) behind SJC (p=0.013)., Conclusions: This study validates our previous results from a UK cohort using EULAR 2010 criteria although the predictive power associated with IL-7 is lower than in the study using ACR 1987 criteria (both French/UK cohorts). IL-7 remains a potential biomarker for ACPA-negative RA although further validation with larger numbers of ACPA-negative patients is still needed notably to translate these results into clinical applicability.

The Fcgamma receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants (FCGR) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B, additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A, FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A-FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13-8.92 [P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44-17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A-FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis.

Objective: To investigate a possible association between a functional polymorphism in the intermediate-affinity receptor for IgG called Fc-gamma receptor type IIIA (FcgammaRIIIA [CD16]) and rheumatoid arthritis (RA)., Methods: This was an allelic association study in which a single nucleotide polymorphism in FcgammaRIIIA was examined as a susceptibility and/or severity factor for RA. The FcgammaRIIIA-158V/F polymorphism was genotyped by direct sequencing in 2 well-characterized ethnic groups, UK Caucasians (141 RA patients and 124 controls) and North Indians and Pakistanis (108 RA patients and 113 controls)., Results: The FcgammaRIIIA-158V/F polymorphism was associated with RA in both ethnic groups (P = 0.028 for UK Caucasians, P = 0.050 for North Indians and Pakistanis, and P = 0.003 for both groups combined). FcgammaRIIIA-158VF and -158W individuals had an increased risk of developing RA in both populations (UK Caucasians odds ratio [OR] 1.6, P = 0.050; North Indians and Pakistanis OR 1.9, P = 0.023; and combined groups OR 1.7, P = 0.003). In the UK Caucasian group, the highest risk was for nodular RA, a more severe disease subset, associated with homozygosity for the FcgammaRIIIA-158V allele (OR 4.4, P = 0.004). There was also evidence for an interaction between the RA-associated HLA-DRB1 allele and the presence of at least 1 FcgammaRIIIA-158V allele in predicting susceptibility to RA (OR 5.5, P = 0.000)., Conclusion: We have demonstrated that the FcgammaRIIIA-158V/F polymorphism is a susceptibility and/or severity marker for RA in 2 distinct ethnic groups. This finding may ultimately provide additional insights into the pathogenesis of RA and other autoantibody/immune complex-driven autoimmune diseases.