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We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response. Methods: We studied the relation of TNFi response, quantified by change in swollen joint counts ("SJC) and erythrocyte sedimentation rate ("ESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation. Results: We detected a statistically significant association between "SJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between "SJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance. Conclusions: The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.

Objectives To evaluate (i) the association between\ud random certolizumab drug levels, antidrug antibodies\ud (ADAbs) and treatment response in patients with\ud rheumatoid arthritis (RA); (ii) longitudinal factors\ud associated with ADAbs and certolizumab drug levels.\ud Methods This prospective cohort included 115 patients\ud with RA treated with certolizumab. Serum samples were\ud collected at 3, 6 and 12 months following treatment\ud initiation. Drug levels and ADAbs were measured using\ud ELISA and radioimmunoassay, respectively, at 3, 6 and\ud 12 months. Disease Activity Score in 28 joints (DAS28)\ud were measured at each visit and 12 months European\ud League Against Rheumatism (EULAR) response was\ud calculated. Patient self-reported adherence was collected\ud longitudinally. Ordinal logistic regression and generalised\ud estimating equation were used to test the association: (i)\ud between drug levels, from serum sampled and treatment\ud response; (ii) between ADAbs and drug levels; (iii)\ud patient-centred factors and drug levels.\ud Results ADAbs were detected in 37% (42/112 patients\ud by 12 months). The presence of ADAbs were significantly\ud associated with lower drug levels over 12 months\ud (β=−0.037, 95% CI −0.055 to 0.018, p

BACKGROUND: The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA). METHODS: Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses. RESULTS: At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells. CONCLUSIONS: This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.