Aim: Tumor necrosis factor inhibitors (TNFi) are effective in controlling disease activity in spondyloarthritis (SpA). However, in a proportion of patients these treatments are ineffective or lead to adverse events. Recently, alternative therapies, such as interleukin (IL)-17 or IL-23 inhibitors, have emerged in the treatment of these pathologies. This study aimed to determine clinical and genetic predictors of non-response to TNFi treatment in 118 spondyloarthritis patients diagnosed according to Assessment in SpondyloArthritis International Society (ASAS) criteria.Method: From the literature, 41 single nucleotide polymorphisms (SNPs) were selected that had previously been associated with TNFi treatment response in spondyloarthropathies, rheumatoid arthritis and psoriasis. A clinical non-response was defined as a decrease of <50% of initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in axial involvement, or a reduction of less than 1.2 of initial Disease Activity Score of 28 joints-C-reactive protein (DAS28-CRP) in patients with only peripheral involvement. Univariate and multivariate hazard ratios (HR) were determined using Cox proportional hazard models to analyze the potential prognostic factors affecting non-response to TNFi treatment. Results:The clinical factors that significantly increased the non-response rate were: global visual analog scale (VAS), CRP, BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), and the number of TNFi used. Only rs11591741 SNP showed an association with non-response. In the multivariate analysis, females had a non-response rate 4.46 times higher than males; each one-point increase in the BASFI index increased the non-response rate by 75%, and being a genotype GG vs GC or CC carrier was associated with an almost 4 times greater non-response rate. Conclusion:We developed a clinical-genetic model to identify SpA patients with a long-term non-response to TNFi therapy. K E Y W O R D Santi-TNF treatment, genetics, single nucleotide polymorphisms, spondyloarthritis

BackgroundNowadays genetic-association studies have discovered new genes, other than HLA-B27, as IL-23R associated with AS. The signalling pathway trough IL-23R is negatively regulated by the SOCS proteins. However, the reports regarding the roles of SOCS in AS are very rare at present.1,2ObjectivesThe aim of this study is to assess the gene expression of SOCS-1, -2, -3and -6 in peripheral blood mononuclear cells (PBMCs) in relation with IL-23R SNPs previously associated with AS.MethodsWe studied 74 patients (64,8% males) recruited from the Rheumatology Unit of the Puerta de Hierro Hospital diagnosed of AS following the Modified New York Criteria. The study cohort included patients with a mean age of 55.2±11, 2 years. Total RNA was extracted from PBMCs using the Nucleospin RNA kit (MN) and reverse transcribed into cDNA. mRNA expression was assessed by real-time quantitative RT-PCR using specific primers and Power SYBRGreen PCR Master Mix (Applied Biosystems).SNP genotyping [rs1129026 (G/A), rs10489629 (T/C), rs1343151 (G/A) rs2201841 (C/T), rs1004819 (C/T) y rs11209032 (A/G)] was performed using the Sequenom MassARRAY platform. In 17 cases there were two samples from the same patient. These samples were obtained from two scheduled visits and 99 samples were analyzed so. To determine the effect of independent variables on levels of SOCS genes expression, we fitted population-averaged models by generalized linear models, nested by patient, using the xtgee command of Stata v.12. P-values of <0.05 were considered statistically significant.ResultsCellular SOCS-1,-2 and -6 expression did not show significant differences between the risk alleles carriers and the protective alleles carriers in any of the IL-23R SNP studied. SOCS-3 increased significantly in protective alleles carriers of the IL-23R intronic SNP rs10489629-C (CC>CT>TT; P=0.028), the IL-23R non-synonymous SNP (Arg381Gln) rs11209026_A (AG>GG; P=0.047) and the IL-23R intronic SNP rs1343151-A (AA>AG>GG, P=0.005).ConclusionsHigher SOCS-3 expression levels for AS patients carriers of protective alleles of the IL-23R rs10489629-A, rs11209026-A and rs1343151-A as compared to carriers of risk genotypes could influence the pathogenesis of this disease.References Mol Biol Rep. 2014;41(6):3773–80.Clin Exp Rheumatol. 2016;34(1):100–5. AcknowledgementsThis work have been supported by Fondo de Investigaciones Sanitarias (PI11/00400) and by RETICS Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), within the VI PN de I+D+I 2008–2011, (FEDER).Disclosure of InterestNone declared

BackgroundTNF inhibitors (TNFi), are effective in controlling the activity of spondyloarthritis. But, there is a proportion of patients, who have to stop treatment due to its ineffectiveness or to the appearance of adverse events. In addition, these therapies imply high economic costs. To identify predictors of response, would help us to make decisions and to improve the risk/benefit ratio, in patients candidates who are candidates to initiate TNFiObjectivesTo determine clinical, biological and genetic predictors of nonresponse to treatment with TNFi in patients with AS and PsA.MethodsWe analyzed 118 patients [49 AS and 69 PsA (24 axial and peripheral involvement and 45 only peripheral)], under treatment or who were to start treatment with TNFi. Data were collected, prior to the start of the TNFi and at the last scheduled visit to the Rheumatology Service of the Hospital Puerta de Hierro, during the period 2013–2014. A clinical response was defined as the reduction ≥50% of the initial BASDAI, in patient with axial involvement, and if the final DAS 28 PCR was <2.6, in those patients with only peripheral involvement. A total of 73 men and 45 woman, mean age 53±11.2 years, and a median duration of illness of 15 years (IQR 10–23) were included. The baseline ESR and CRP were (10mm/hr IQR 5.0–27.0 and 2mg/l IQR 0.0–9.0) respectively. The mean and SD of BASDAI, DAS28 CPR and BASFI were (6.0±1.9, 3.0±0.6 and 5.4±2.5) respectively. A univariate analysis was performed using a Cox proportional hazard regression model which included: Smoker status, axial pain, peripheral arthritis, sacroiliitis, IBD, uveitis, psoriasis, HLA B27, VSG, PCR, BASDAI, BASFI, VGP, the number of TNFi and 45 single nucleotide polymorphism (SNPs) previously reported to be associated with response to TNFi. SNP genotyping was performed using de Sequenom MassARRAY plataform.Variables with a P-value <0.1 were included in a multivariate analysis. The discrimination capacity of the model was assessed using the Harrell C index. P-values <0.05 were considered statistically significant. Statistical analysis was performed with the SPSS v.17 software.ResultsThe median duration of treatment was 62.9 months (IQR 40.7–96.5), the response to TNFi was 79.7% of patients, with mean and SD of BASDAI, BASFI and DAS 28 PCR (2.7±2.2, 4.2±2.8, 1.5±0.6) respectively. The factors that increased the non-response rate, were: the group of peripheral PsA versus AS (HR 2.94, P=0.023), VGP (HR 1.47, P<0.001), BASDAI (HR 1.80, P=0.001), BASFI (HR 1.52, P=0.001) and the number of TNFi used (P<0.001). There was a trend of significance (P <0.10) for females, with a 2.13-fold lower response rate than males (P=0.065). The SNPs associated were: rs4240847 of the MAPKAPK2 gene (allele A, HR 1.63, P=0.019), rs11096957 of the TLR-10 gene (T allele, HR 1.49, P=0.011), rs11541076 of the IRAK-3 (allele T, HR 1.47, P=0.050), rs916344 of the MAPK14 gene, in a recessive form,since CC alleles against CG or GG increased 10.12 times the non-response rate (HR 10,12; P=0.027) and rs11591741 of the CHUK ...