BackgroundSpondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. Besides the major histocompatibility complex (MHC), more than 25 loci have already been associated to the disease using an unrelated case-control design but they explain only a minor fraction of total heritability.ObjectivesWe conducted a family-based genome-wide association study (GWAS) to identify new non-MHC genetic factors associated with SpA.MethodsNine hundred and six subjects from 156 French multiplex families, including 438 affected with SpA, were genotyped using Affymetrix 250K microarray. After quality control, 230,801 single-nucleotide polymorphism (SNPs) were kept for further analyses. Association was tested with Unphased. The best-associated non-MHC SNPs were then genotyped sequentially in two independent familial trio cohorts, one from France and the other from North America (including 215 and 294 subjects, respectively) in order to replicate associations.ResultsForty-three non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1x10-4). In the extension studies, association was replicated at a nominal p-value <0.05 for 16 SNPs in the second cohort and for 3 of these 16 SNPs in the third cohort. Pooled analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=6.2 x 10-7). Such association was independent of HLA-B27.ConclusionsWe report here for the first time a family-based GWAS study on SpA and identified a highly associated polymorphism in MAPK14 that codes for the p38-a MAP kinase, a key kinase in immune cell signalling. Further analyses are needed to understand the functional significance of this genetic association.Disclosure of InterestNone declared
BackgroundThere is currently no consensual definition of flare in axial spondyloarthritis (axSpA).ObjectivesThe aims of this study were to determine thresholds of variations of BASDAI associated with patient-reported flare and to test performance of ASAS preliminary definitions of flare1.MethodsThis prospective study was proposed to all patients registered on the Spondy+ platform, a secure e-health platform for SpA patients. Every week during one year, patients were invited to connect to the platform to fill a BASDAI questionnaire, a 0-10 pain visual analogic scale and to answer to the following question: “has your disease flared up since last week?”. Variations of BASDAI and pain between connections were assessed and associated to the change of perception of flare. ROC curves were built to assess performances of BASDAI and VAS to identify patient-reported occurrence and resolution of flare. Performance of ASAS preliminary definitions of flare was also assessed.Results99 patients participated to this study for an average duration of 309 ± 148 days. 92% of them reported at least one episode of flare over follow-up. Area under the ROC curve (AUC) was significantly higher for ΔBASDAI than for Δpain, to predict outbreak of flare (0.81 vs 0.77, p=0.02). In contrast, ΔBASDAI and Δpain were comparably accurate to predict flare resolution with no significant difference of AUC (0.78 vs 0.80, p=0.4). Best performance was obtained for an increase of 0.2 points of BASDAI (sensitivity=70%; specificity=79%) and 0.5 of pain VAS to predict outbreak of flare and a decrease of 0.4 points of BASDAI and 0.5 of pain VAS to predict flare resolution (Figure 1). None of the ASAS definitions yielded sensitivity values higher than 37% whereas specificity was higher than 95% for all of them.Figure 1.Sensitivity (red dots) and specificity (blue dots) according to ΔBASDAI (panels A,C) and Δpain (panels B,D) threshold as predictors of outbreak (panels A,B) or resolution (panels C,D) of flare.ConclusionΔBASDAI appeared as a suitable variable to monitor both occurrence and resolution of SpA flare, as reported by patient.References[1]Gossec L et al. Ann Rheum Dis 2016;75:991–6. doi:10.1136/annrheumdis-2015-208593AcknowledgementsThe authors thank MSD France for unrestricted financial support to the SPONDY+ platform and Frédéric Durand-Salmon for giving us the possibility to use SPONDY+, a patient support program developed by BEPATIENT.Disclosure of InterestsNone declared
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