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Objectives The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in the pathogenesis of bone erosions in rheumatoid arthritis (RA). The aim of this study was to test the association between 11 single-nucleotide polymorphisms (SNPs) located on RANK, RANKL and OPG genes and anticitrullinated peptide antibody (ACPA) presence or erosions in RA. Methods Patients: This work was performed on three independent samples of French patients with RA: the Etude de Suivi des PolyArthrites Indifferenciees Recentes (ESPOIR) (n=632), Rangueil Midi-Pyrenees (RMP) (n=249) and French Rheumatoid Arthritis Genetic Consortium (FRAGC) (n=590) cohorts. Genotyping: the genotyping of 11 SNPs located on RANK , RANKL and OPG were performed by PCR. Statistical analyses: The association between the genotypes with ACPA or erosions was first tested in the ESPOIR cohort using a χ 2 test and, in the case of significant association, replicated in the RMP and FRACG cohorts. A meta-analysis on the three cohorts was performed using the Mantel-Haenszel method. Results One SNP on RANK (rs8086340) and three SNPs on RANKL (rs7984870, rs7325635, rs1054016) were significantly associated with ACPA presence, while one SNP on OPG (rs2073618) and one SNP on RANKL (rs7325635) were significantly associated with erosions in the ESPOIR cohort. Following meta-analysis performed on the three samples, the SNP on RANK and the GGG haplotype of the three SNPs located on RANKL were both significantly associated with ACPA presence, while only the SNP on OPG remained significantly associated with erosions. Conclusions This study identified one SNP located on RANK , one haplotype on RANKL associated with ACPA presence, and one SNP located on OPG associated with erosions in three different samples of French patients with RA.

Fibromyalgia (FM) may occur with rheumatoid arthritis (RA) and systemic sclerosis (SSc), and debate remains about its diagnosis. We aimed to use three FM tools (a screening tool (FiRST), diagnostic criteria (ACR 1990 and revised 2010), to compare FM prevalence between RA and SSc patients, to describe the phenotypes of patients with comorbid FM, and to analyze links between FM and secondary Sjögren's syndrome (SS).Consecutive adult patients with confirmed RA or SSc from four university hospitals were tested with the three FM tools.FiRST detected FM in 22.6% of the 172 RA patients, with confirmation in 22.1% (ACR1990) and 19.1% (ACR2010). ACR1990FM+ RA patients had more diffuse pain, whereas ACR2010FM+ RA patients had higher BMI and pain intensity, more diffuse pain, active disease, disability, and associated SS. FiRST detected FM in 27.8% of the 122 SSc patients, with confirmation in 30.3% (ACR1990) and 23.7% (ACR2010). ACR1990FM+ SSc patients had greater disability and pain intensity, and more diffuse pain, whereas ACR2010FM+ SSc patients had higher BMI, pain intensity, more disability and diffuse pain, and associated SS. Correlations between FM diagnostic and screening tool results were modest in both conditions. Secondary SS was associated with comorbid FM.The prevalence of FM is high in SSc and RA, whatever the FM diagnostic tool used. Secondary SS is associated with FM in both RA and SSc. The revised ACR 2010 FM criteria and FiRST screening tool reveal specific phenotypes potentially useful for improving disease management.

Background An interferon signature is involved in the pathogenesis of primary Sjogren syndrome (pSS), but whether the signature is type 1 or type 2 remains controversial. Mouse models and genetic studies suggest the involvement of T H 1 and type 2 interferon pathways. Likewise, polymorphisms of the IL-12A gene ( IL12A ), which encodes for IL-12p35, have been associated with pSS. The IL-12p35 subunit is shared by 2 heterodimers: IL-12 and IL-35. Objective We sought to confirm genetic association of the IL12A polymorphism and pSS and elucidate involvement of the IL-12/IL-35 balance in patients with pSS by using functional studies. Methods The genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French control subjects. Functional studies were performed on sorted monocytes, irrespective of whether they were stimulated. IL12A mRNA expression and IL-12 and IL-35 protein levels were assessed by using quantitative RT-PCR and ELISA and a multiplex kit for IL-35 and IL-12, respectively. Results We confirmed association of the IL12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in patients with pSS carrying the risk allele ( P = .016). Serum levels of IL-12p70 were greater in patients than control subjects ( P = .0001), especially in patients with more active disease ( P = .05); conversely, IL-35 levels were decreased in patients ( P = .0001), especially in patients with more active disease ( P = .05). In blood cellular subsets both IL12p35 and EBV-induced gene protein 3 (EBI3) mRNAs were detected only in B cells, with a trend toward a lower level among patients with pSS. Conclusion Our findings emphasize involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 levels were associated with low disease activity, in contrast with serum IL-12p70 levels, which were associated with more active disease.

Objective.To assess the prevalence of autoimmune diseases in first-degree relatives of patients with systemic sclerosis (SSc), and to compare those results with control families in order to identify patterns of autoimmune diseases in relatives.Methods.A retrospective case-control postal questionnaire survey was performed in France to recruit patients with SSc belonging to an association of patients with SSc and unrelated age-matched and sex-matched controls. Each participant was asked to self-report on the existence of autoimmune diseases in their first-degree relatives. The prevalence of autoimmune diseases in the families of patients with SSc was compared with the corresponding prevalence in the families of controls.Results.A total of 121 families out of 373 (32.4%) with a member having SSc reported at least 1 autoimmune disease in 1 or more first-degree relatives. The most frequent autoimmune diseases in SSc families when adjusted for family size were autoimmune thyroid disease (AITD; 4.9%), rheumatoid arthritis (4.1%), psoriasis (3.9%), and type 1 diabetes mellitus (2.9%). Compared with control families, AITD and connective tissue diseases (SSc, systemic lupus erythematosus, or Sjögren’s syndrome) were more likely to occur in families with SSc (p = 0.01 and p = 0.01, respectively), with OR of 3.20 (95% CI 1.25–8.18) and 5.20 (95% CI 1.22–21.8). In contrast, inflammatory bowel disease was less likely to occur within families with SSc (p = 0.02, OR 0.29, 95% CI 0.11–0.80). In addition, the coexistence of more than 1 autoimmune disease in the index SSc case was associated with familial aggregation of autoimmune diseases.Conclusion.Our results show that autoimmune diseases cluster within families of patients with SSc. This supports the notion that these diseases might arise on a shared genetic basis underlying several autoimmune phenotypes.

Immunotherapy has revolutionized the treatment of inflammatory rheumatic disorders such as rheumatoid arthritis (RA). Under anti-tumour necrosis factor-α (anti-TNF-α) therapy, the risk of reactivat...

Joint Bone Spine - In Press.Proof corrected by the author Available online since lundi 6 juin 2016

Resume La genomique est une toute jeune discipline qui a recemment essaime a partir de la genetique. Elle a permis de determiner la sequence complete du genome humain et de caracteriser de facon approfondie son polymorphisme. Grâce a la technologie des puces d’ADN et aux methodes d’association genetique, des applications medicales importantes en ont deja resulte avec la decouverte de nombreux genes predisposant aux maladies communes, notamment rhumatologiques. L’application de ces memes methodes permet desormais d’esperer l’identification de biomarqueurs, qu’il s’agisse de diagnostic precoce ou de prediction de reponse therapeutique, dans la perspective d’une medecine personnalisee. Des precautions doivent etre cependant prises pour accroitre les chances de succes de ces nouvelles recherches.

Resume La medecine personnalisee est un paradigme qui vise a repondre a trois principaux objectifs : optimiser l’efficacite therapeutique a l’echelle individuelle, reduire le risque de survenue d’effets indesirables et enfin, consequence des 2 premiers objectifs, diminuer le cout de la prise en charge therapeutique a une epoque ou les depenses de sante constituent un veritable enjeu de societe. Le polymorphisme du genome humain constitue a l’evidence un des mecanismes conduisant a la variabilite interindividuelle de la reponse mais aussi de la tolerance pour une therapeutique donnee. La pharmacogenomique consiste, a partir de l’etude du genome humain, en l’identification de marqueurs genetiques predictifs de la reponse et/ou de la survenue d’effets secondaires. Bien que ces dernieres annees aient vu une augmentation des moyens mis en oeuvre, force est de constater qu’aucun des recents marqueurs identifies n’est a ce jour utilisable en pratique courante. Un element de reponse a cet echec apparent vient probablement de la nature multifactorielle qui conditionne non seulement la susceptibilite mais aussi le phenotype des pathologies etudiees. Ainsi, la constitution de larges etudes integrant une approche exhaustive des variations du genome humain et les donnees environnementales apparaissent comme un des defis a relever si nous voulons etre en mesure de proposer une approche therapeutique sur mesure a nos patients.

In the field of genetics of SSc, we are currently reaching a period of rapid data production. Several themes are already rising from the first wave of results. First, some genetic variants clearly predispose to multiple autoimmune diseases, thus providing evidence for a shared autoimmune genetic background. Second, multiple genes are involved in the SSc predisposition and as expected the genetic associations are quite modest. Third, unless for a small number of exceptions, the causative genetic variations have not been definitively identified yet. Lastly, to date, the most convincing associations detected relate to genes playing a pivotal role in both innate and adaptative immunity. Indeed, additionally to the MHC, candidate gene studies have convincingly and reproducibly identified PTPN22, IRF5, STAT4, C8orf13-BLK, BANK1 and TNFSF4 as SSc susceptibility genes. Although these results have substantially advanced our understanding of the SSc pathogenesis, both gene-gene and gene-environment studies are now awaited in order to further improve our understanding of this multifacet disease. Finally, we should keep in mind that SSc is a very severe that is until now unfortunately free of effective therapy. Therefore, the identification of new susceptibility genes may offer a rich source of new hypotheses and experimental directions to follow that we should try to assembly in a near future to generate innovative therapies to fight this dramatic disease.

Contains fulltext : 96445.pdf (Publisher’s version ) (Closed access) 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=23.1x10(-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=4.20x10(-5) and T=19.6%, p=3.66x10(-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=1.68x10(-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.

Resume L’etude du determinisme des maladies auto-immunes (MAI), dont la genetique fait partie, a connu des avancees spectaculaires lors des dix dernieres annees, permettant une meilleure comprehension des mecanismes physiopathologiques qui sous-tendent l’apparition du phenotype maladie. Les etudes d’association genetique ont permis l’identification de voies physiopathologiques essentielles a l’emergence du phenotype auto-immun. Parmi ces voies, on notera la modulation de la signalisation cellulaire T et B ( PTPN22 , BANK1 , BLK ), la modification des mecanismes de co-stimulation ( ITGAM , CTLA4, CD226 , OX40L, CD40 ), la voie NF-κB ( TNFAIP3 , c-REL , CD40 ) et la voie IFN de type 1 ( IRF5 , STAT4 ). De cette premiere vague de resultats, on retiendra plusieurs informations : (i) les MAI partagent un fond genetique commun ; (ii) consequence directe de la nature multifactorielle des MAI, le poids de chaque allele de susceptibilite est relativement modeste ; (iii) a ce jour, le role fonctionnel de ces alleles a risque n’a ete elucide que pour tres peu d’entre eux. Enfin, le determinisme des maladies complexes resulte de la conjonction d’un fond de susceptibilite genetique et de l’exposition des facteurs environnementaux. L’etude du determinisme de ces pathologies multifactorielles devra obligatoirement inclure la variable « environnement » afin d’evaluer non seulement la part de la composante environnementale, mais aussi les probables interactions gene-environnement.

BACKGROUND: Genetic factors have a substantial role in determining development of rheumatoid arthritis (RA), and are likely to account for 50-60% of disease susceptibility. Genome-wide association studies have identified non-human leucocyte antigen RA susceptibility loci which associate with RA with low-to-moderate risk.OBJECTIVES: To investigate recently identified RA susceptibility markers using cohorts from six European countries, and perform a meta-analysis including previously published results.METHODS: 3311 DNA samples were collected from patients from six countries (UK, Germany, France, Greece, Sweden and Denmark). Genotype data or DNA samples for 3709 controls were collected from four countries (not Sweden or Denmark). Eighteen single nucleotide polymorphisms (SNPs) were genotyped using Sequenom MassArray technology. Samples with a >95% success rate and only those SNPs with a genotype success rate of >95% were included in the analysis. Scandinavian patient data were pooled and previously published Swedish control data were accessed as a comparison group. Meta-analysis was used to combine results from this study with all previously published data.RESULTS: After quality control, 3209 patients and 3692 controls were included in the study. Eight markers (ie, rs1160542 (AFF3), rs1678542 (KIF5A), rs2476601 (PTPN22), rs3087243 (CTLA4), rs4810485 (CD40), rs5029937 (6q23), rs10760130 (TRAF1/C5) and rs7574865 (STAT4)) were significantly associated with RA by meta-analysis. All 18 markers were associated with RA when previously published studies were incorporated in the analysis. Data from this study increased the significance for association with RA and nine markers.CONCLUSIONS: In a large European RA cohort further evidence for the association of 18 markers with RA development has been obtained.

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” (padj = 0.024, OR 1.23, 95% CI 1.07–1.40) and a mirrored protective haplotype “P” (padj = 8.8 × 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.

We have read with great interest the article by Jonsson et al that was recently published online in ARD ,1 which suggested that calprotectin, also known as S100A8/S100A9 heterodimer, was associated with radiographic progression in early rheumatoid arthritis (RA). Calprotectin correlates significantly with inflammatory markers and disease activity score.2 Besides correlations between baseline calprotectin levels, Clinical Disease Activity Index and ultrasonography power Doppler, the authors showed that baseline calprotectin levels correlated with van der Heijde modified Sharp score (SHS) progression (defined as an increase ≥1 unit/year from 0 to 24 months), independently of age, gender, Clinical Disease Activity Index, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) levels and rheumatoid factor positivity.1 We analysed the initial serum calprotectin among patients with early RA fulfilling American College of Rheumatology/European League Against Rheumatism 2010 of the French observational cohort Etude et Suivi des POlyarthrites Indifferenciees Recentes (ESPOIR). Calprotectin serum concentrations were assessed according to manufacturer method (Hycult, Frontstraat, Netherlands; …

Objective.Systemic sclerosis (SSc) is classified among the complex genetic disorders and is characterized by massive extracellular matrix deposits. These may be due to overactivation of transforming growth factor ß that may be in part a result of abnormal remodeling of extracellular matrix and microfibrils. Metalloproteinases (MMP) are a family of proteolytic enzymes, and MMP 2, 9, and 14 contribute to the degradation of microfibrils. Our aim was to determine whether polymorphisms of the MMP2, MMP9, and MMP14 genes confer susceptibility to SSc in a large population.Methods.A case–control study was performed in 659 SSc patients and 511 healthy matched controls from a European Caucasian population. Six Tag single-nucleotide polymorphisms (SNP) of the MMP2 gene and 2 SNP of MMP9 and MMP14 genes were genotyped.Results.All SNP were in Hardy-Weinberg equilibrium in the control population. There was no association between the MMP2, MMP9, and MMP14 variants we investigated and SSc for allelic and genotype frequencies. No association was observed for the different subphenotypes of SSc patients.Conclusion.Our results in a large cohort of European Caucasian SSc patients do not support that MMP2, MMP9, and MMP14 genes are involved in the genetic background of SSc.

Objective.To assess the prevalence and potential associations with the systemic sclerosis (SSc) phenotype of additional autoimmune diseases (AID).Methods.A multicenter study was performed in France and Italy to recruit consecutive European Caucasian patients with SSc systematically assessed for the coexistence of predefined AID known to occur with connective tissue diseases.Results.We recruited 585 French and 547 Italian patients with SSc. Specific AID were found in 114/585 (19%) French and 179/547 (33%) Italians with SSc (p < 0.0001). Sjögren’s syndrome and thyroiditis were the predominant AID in both cohorts (12% for Sjögren’s syndrome and 6% for thyroiditis in the combined populations). The frequency of myositis, primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus was low (< 4%) and similar in both cohorts. The coexistence of at least 1 of the AID in the whole cohort was associated in multivariate analysis with the limited cutaneous subtype, the presence of antinuclear antibodies, and a lower prevalence of digital ulcers.Conclusion.Our study shows that 21% of this large series of European Caucasian patients with SSc have developed at least 1 AID. This latter condition identified a subset of patients with milder disease. Thus, associations of AID and autoimmune background in SSc have to be considered for further therapeutic and biological investigations in SSc.

Objective Hallux valgus (HV) and gout are common pathologies of the first metatarsophalangeal joint (MTP1) leading to pain and deformation. In this study, we aimed to determine the correlation between tophus size and characteristics of HV in gouty patients. Methods In this case-control study, we included patients with gout (the presence of monosodium urate crystals in synovial fluid) and control patients with spondyloarthritis, without crystal disease disorders. Radiographic assessment and ultrasound (US) assessment were performed by two blinded operators. US features of gout (double contour [DC] sign and/or tophus) were collected. HV was defined by hallux abductus (HA) angle ≥20° and/or intermetatarsal angle (IM) ≥10°. Correlation between US findings and HV angles was estimated by Spearman correlation coefficient. Results We included 56 gouty patients (87.5% males, mean age of 63.9 ± 12.2 years) and 41 control patients (90% males, mean age of 59.0 ± 12.8 years). HV was more frequent in patients with gout than controls (62% vs 37%, P = .0007). Regardless of HV status, correlations were found between the size of US tophi and IM (r = .3381, P = .003) and HA angles (r = .2344, P = .043). Conclusions Our results confirm a high prevalence of HV in gouty patients. We also observed a correlation between the size of the US tophus and the angles defining HV, which suggests a link between urate deposition load and HV. Early urate-lowering therapy for gout could limit the occurrence of HV.

Purpose Xeroderma pigmentosum variant (XPV) is a rare recessive autosomal genodermatosis predisposing to multiple early onset skin cancers, including melanoma. XPV results from mutations of the POLH gene that encodes a DNA translesion polymerase. In this work, we tested the hypothesis that POLH variants could be associated with melanoma risk. Experimental design A common non-synonymous POLH variant, c.1783A>G p.M595V, was genotyped in 1075 melanoma patients and in 1091 ethnic-matched controls from France. In addition, we searched for rare POLH variants by sequencing the entire coding sequence in 201 patients having a familial history of melanoma ( n = 123), sporadic multiple melanomas ( n = 65) and a melanoma associated with a skin carcinoma ( n = 13). Results Overall, the c.1783G, p.595V allele was statistically associated with melanoma (respective allelic frequencies, 0.040 versus 0.022, P -value = 1.17 × 10 –3 , odds ratio (OR) = 1.86 [1.27–2.71]), which was further confirmed by a meta-analysis including 274 patients and 174 matched controls from Italy ( P -value = 7.7 × 10 –4 , OR = 1.84 [1.29–2.63]). Interestingly, three non-synonymous POLH variants were identified in three patients (c.295G>A p.V99M, c.815T>C p.I272T and c.1745C>T p.S582L) which were absent in 352 chromosome controls from healthy subjects. Conclusions Besides severe deficiencies in translesion synthesis which are major risks factors for skin carcinomas and melanomas, less deleterious POLH variants could act as low penetrance melanoma predisposing alleles. The ongoing identification of genetic markers implied in skin cancer predisposition could help to identify high-risk subjects as targets for clinical follow-up. Replication studies in other populations are awaited to assess these data.

Objective To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene–gene interactions between BANK1 and IRF5 as well as STAT4. Methods BANK1 single-nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls. Results The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64–0.93) and an OR of 0.73 (95% CI 0.61–0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A-T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57–0.86], P = 3.39 × 10−4) and the G-C haplotype to be a risk factor (OR 1.25 [95% CI 1.06–1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43-fold. Conclusion Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

Antibodies to cyclic citrullinated peptide (anti-CCP) and IgM rheumatoid factor (IgM-RF) are well-established serological markers for rheumatoid arthritis (RA). Lupus-like disease with antinuclear antibodies (ANA) has been reported during TNFalpha antagonist therapy. Our objectives were to investigate the effect of infliximab therapy on these three autoantibodies in patients with established RA and to look for correlations linking IgM-RF and anti-CCP titres to a treatment response (defined as a good or moderate EULAR response) after 48 weeks of infliximab therapy.Thirty-six patients with long-standing RA not responding to disease-modifying anti-rheumatic drugs (DMARDs) received intravenous infliximab (starting dose: 3mg/kg) at 0, 2, and 6 weeks then at 8-week intervals, in combination with a DMARD. At baseline, week 24, and week 48, C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were determined and the disease activity score (DAS28) was calculated. Serum samples collected at the same time points were used to measure anti-CCP (commercial second-generation ELISA), IgM-RF (quantitative nephelometric assay), and ANA (indirect immunofluorescence in HEp2 cells). Correlations linking baseline autoantibody titres to changes in autoantibody levels were examined.At baseline, tests were positive for anti-CCP in 31/36 (94.6%) patients, IgM-RF in 29/36 (80.5%) patients, and ANA in 16/36 (44%) patients. IgM-RF titres decreased significantly (p0.001), whereas anti-CCP showed little change (p=0.053). ANA titres increased significantly (p0.001). The treatment response was not associated with changes in anti-CCP or IgM-RF titres during infliximab therapy (OR for a response in patients with a 50% anti-CCP decrease, 0.77 [95%CI, 0.16-3.58]; OR for a response in patients with a 50% IgM-RF decrease, 0.82 [95%CI, 0.16-4.13]).During infliximab therapy used to treat established RA, IgM-RF titres showed larger decreases than anti-CCP titres. Changes in IgM-RF and anti-CCP failed to correlate with the 48-week treatment response.

Resume Objectifs Les anticorps antipeptides cycliques citrullines (ACPA) et les facteurs rhumatoides IgM (IgM-FR) sont des marqueurs serologiques bien etablis dans la polyarthrite rhumatoide (PR). Des maladies de type lupus avec presence d’anticorps antinucleaires (ANA) ont ete rapportees lors des traitements par agents anti-TNFα. Nos objectifs etaient de rechercher les effets d’un traitement par infliximab sur ces trois auto-anticorps chez des patients souffrant de PR averee et de rechercher des correlations entre les titres d’IgM-FR, d’ACPA et la reponse au traitement (definie comme une reponse Eular bonne ou moderee) apres 48 semaines de traitement par infliximab. Methodes Trente-six patients avec une PR ancienne et ne repondant pas aux traitements de fond classiques (DMARD) ont recu des perfusions intraveineuses d’infliximab (dose initiale 3 mg/kg) a zero, deux et six semaines, puis toutes les huit semaines, en association avec un DMARD. Avant traitement, a la semaine 24 et a la semaine 48, la proteine C reactive (CRP) et la vitesse de sedimentation (VS) ont ete mesurees et le score d’activite de la maladie (DAS28) a ete calcule. Les echantillons seriques collectes au meme moment ont ete utilises pour la detection des ACPA (test de depistage ACPA Elisa de seconde generation), de l’IgM-FR et des ANA (immunofluorescence indirecte dans les cellules Hep2). Une correlation entre les titres d’auto-anticorps initiaux et les modifications de ces taux d’auto-anticorps a ete recherchee. Resultats Au depart, 31 sur 36 (94,6 %) des patients etaient ACPA positifs, 29 sur 36 (80,5 %) patients IgM-FR positifs et 16 sur 36 (44 %) patients etaient ANA positifs. Les titres d’IgM-FR ont diminue significativement (p Conclusions Lors d’un traitement par infliximab utilise pour traiter une PR averee, les titres d’IgM-FR ont diminue de facon plus importante que les titres d’ACPA. Les modifications des taux d’IgM-FR et d’ACPA ne sont pas correlees avec la reponse au traitement a la 48e semaine.

Objective.To determine whether angiotensin-converting enzyme (ACE) polymorphisms including I/D and 2 single-nucleotide polymorphisms (SNP) affect susceptibility to systemic sclerosis (SSc) in a large French Caucasian population.Methods.A case-control study was performed in 494 patients with SSc and 280 healthy controls for I/D polymorphism. Two supplementary exonic SNP of ACE gene (rs4309, rs4362) were genotyped in 659 patients with SSc and 511 matched healthy controls. Among the whole SSc population, 453 (67%) patients with SSc had the limited cutaneous subtype, 47 (7%) had precapillary pulmonary arterial hypertension, 209 (32%) had digital ulcers, and 10 (1.5%) had renal crisis. A combined analysis of the available results for ACE I/D genotypes in Caucasians was also performed.Results.There was no association between the 3 polymorphic markers and SSc for allelic and genotype frequencies. No association was observed for the different vascular subsets of the disease. Haplotype analyses did not detect any association. The lack of association for ACE I/D was confirmed by the combined analysis.Conclusion.These results in a large cohort of European Caucasian patients with SSc do not support that the ACE gene is implicated in the pathogenesis of SSc and its vascular damage.

Objective There is now growing evidence that connective tissue diseases, including systemic sclerosis (SSc), share a common genetic background. Microarray studies support a pivotal role of type I interferon (IFN) in the pathophysiology of connective tissue diseases. Interferon regulatory factors coordinate the expression of type I IFNs, and the IRF5 gene has been identified as a susceptibility gene of systemic lupus and Sjogren's syndrome. The aim of this study was to determine whether the IRF5 rs2004640 single-nucleotide polymorphism is associated with SSc. Methods The IRF5 rs2004640 (GT) functional polymorphism was genotyped in 1,641 subjects of French European Caucasian origin: a discovery set comprising 427 patients with SSc and 380 control subjects and a replication set comprising 454 patients with SSc and 380 control subjects. Results In both the discovery set and the replication set, the TT genotype was significantly more common in patients with SSc than in control subjects, with an odds ratio (OR) for the combined populations of 1.58 (95% confidence interval [95% CI] 1.18–2.11 [P for trend 0.002]). Analyses of the whole SSc population showed a significant association between homozygosity for the T allele and the presence of antinuclear antibodies (corrected P [Pcorr] = 0.04, OR 1.59, 95% CI 1.16–2.17) and fibrosing alveolitis (Pcorr = 0.001, OR 2.07, 95% CI 1.38–3.11). In a multivariate analysis model including the diffuse cutaneous subtype of SSc and positivity for anti–topoisomerase I antibodies, the IRF5 rs2004640 TT genotype remained associated with fibrosing alveolitis (P = 0.029, OR 1.92, 95% CI 1.07–3.44). Conclusion The IRF5 rs2004640 GT substitution is associated with susceptibility to SSc. These data provide new insight into the pathogenesis of SSc, including clues to the mechanisms leading to fibrosing alveolitis.

Objective To determine whether genetic variants of the PTPN22 gene, including the R620W (1858C>T) missense single-nucleotide polymorphism (SNP), are associated with systemic sclerosis (SSc). Since PTPN22 is involved in multiple autoimmune diseases, we also examined the occurrence of a concomitant autoimmune disease. We then conducted a meta-analysis of the most recent studies of SSc in order to verify the association or lack of association between the PTPN22 1858C>T variant and SSc. Methods Seven PTPN22 SNPs were analyzed in a French Caucasian cohort of 659 SSc patients and 504 healthy controls. All SSc patient sera were tested for the presence of autoantibodies against topoisomerase I (anti–topo I) and for anticentromere antibodies (ACAs). Results The co-occurrence of an autoimmune disease was observed in 22% of the 416 SSc patients who were exhaustively screened. In 33 of the 416 patients (8%), the concomitant autoimmune disease was known to be associated with PTPN22 1858T; these patients were excluded prior to analysis. No association was detected for any of the SNPs tested. PTPN22 haplotype analysis identified a strong association between SSc and the presence of a risk haplotype carrying the 1858T allele (P = 1.52 × 10–7) and a protective haplotype carrying the 1858C allele (P = 2.20 × 10–16) in our French Caucasian population. The meta-analysis provided evidence that the PTPN22 1858T allele is involved in the genetic susceptibility to SSc in Caucasian (P = 8.39 × 10–3, OR 1.08 [95% CI 1.02–1.15]) and mixed (P = 3.11 × 10–3, OR 1.09 [95% CI 1.04–1.16]) populations, particularly in the anti–topo I–positive subset. Conclusion Our results indicate that PTPN22, a shared genetic factor of multiple autoimmune diseases, also contributes to the genetic background of SSc.

Objective The aim of the study was to compare the prevalence of ASCA in spondyloarthrites (SpA) patients and to investigate the association between ASCA status and disease phenotype. Methods We performed a case-control study including SpA individuals fulfilling the ESSG SpA criteria. The following data were collected for analysis: gender, age, disease duration, clinical or associated features of SpA, treatments, HLAB27 and ASCA status. A control group of patients without SpA was also analyzed. Results A total of 235 patients with SpA and 54 control patients were studied. The median age of SpA patients (53.6% of male patients, 52.2% of HLAB27 ) was 46.0 [IQR 35.0–57.0] years old. Disease duration was 60.0 [IQR 24.0–156.0] months. Inflammatory bowel diseases were observed in 11% of SpA patients. ASCA positivity was significantly higher in SpA patients than in control patients (25.5% [95% CI 20.1–31.6] (IgG: 9.8%; IgA: 21.7%) vs. 7.4% [95% CI 2.1–17.9], P = 0.004). Multivariate analysis revealed that ASCA positivity was associated with peripheral involvement (OR: 3.30 [1.26–8.62], P = 0.015), presence of IBD (OR: 3.43 [1.15–10.20], P = 0.026), past of present history of uveitis (OR: 4.36 [1.08–17.64], P = 0.039) and arthritis (OR: 3.78 [1.57–9.15], P = 0.003). Conclusion Our results provided evidence that SpA patients had an increased prevalence of ASCA and that ASCA positivity might be associated with a particular phenotype, notably peripheral involvement and uveitis.

International audience; Objectives : To investigate DKK-1 and SOST serum levels among patients with recent inflammatory back pain (IBP) fulfilling ASAS criteria for SpA and associated factors.Methods : The DESIR cohort is a prospective, multicenter French cohort of 708 patients with early IBP (duration >3 months and

Objective.To compare the ability to detect calcium pyrophosphate (CPP) crystals deposition (CPPD) in knee cartilage by ultrasonography (US) and radiography.Methods.Patients with knee effusion were consecutively included and underwent radiography and US evaluation of knees. Diagnosis of CPPD was made by the identification of CPP crystals. Two blinded rheumatologists performed US assessment.Results.We included 51 patients (25 with CPPD). US revealed hyperechoic spots in all 25 patients with CPPD (sensitivity 100%, specificity 92.3%), whereas radiography revealed CPPD in 16 (sensitivity 64%, specificity 100%; p < 0.0001).Conclusion.US of knees is more sensitive than radiography for CPPD diagnosis.

Introduction Systemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility. Methods Sixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy). Results We observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, Padj = 7.22 × 10−5), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, Padj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, Padj = 2.49 × 10−4) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (Padj = 4.45 × 10−4 and Padj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (Padj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-γ) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). In addition, we found an epistatic interaction between NF-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10−4) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele. Conclusions An analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0572-y) contains supplementary material, which is available to authorized users.

Introduction The multifunctional nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) has potent anti-fibrotic effects, and its expression and activity are impaired in patients with systemic sclerosis (SSc). We investigated PPAR-γ gene (PPARG) single nucleotide polymorphisms (SNPs) associated with SSc. Methods Tag SNPs spanning PPARG were genotyped in a European ancestry US discovery cohort comprising 152 SSc patients and 450 controls, with replication of our top signal in a European cohort (1031 SSc patients and 1014 controls from France). Clinical parameters and disease severity were analyzed to evaluate clinical associations with PPARG variants. Results In the discovery cohort, a single PPARG intronic SNP (rs10865710) was associated with SSc (p = 0.010; odds ratio = 1.52 per C allele, 95% confidence interval 1.10-2.08). This association was replicated in the French validation cohort (p = 0.052; odds ratio = 1.16 per C allele, 95% confidence interval 1.00-1.35). Meta-analysis of both cohorts indicated stronger evidence for association (p = 0.002; odds ratio = 1.22 per C allele, 95% confidence interval 1.07-1.40). The rs10865710 C allele was also associated with pulmonary arterial hypertension in the French SSc cohort (p = 0.002; odds ratio = 2.33 per C allele, 95% confidence interval 1.34-4.03). Conclusions A PPARG variant is associated with susceptibility to SSc, consistent with a role of PPAR-γ in the pathogenesis of SSc. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0641-2) contains supplementary material, which is available to authorized users.

International audience; Objective: To group HLA-DRB1 alleles based on acid–base properties of amino acids at positions 13, 70 and 71 and analyse their association with the presence of anticitrullinated peptide antibodies (ACPA) and structural progression in 2 cohorts of early rheumatoid arthritis (RA).Methods: Patients with RA (N=612) from ESPOIR cohort and from EAC cohort (n=624) were genotyped for HLA-DRB1 alleles. The alleles containing the RAA sequence at positions 72–74 were classified into 3 groups according to the amino acid at positions 13, 70 and 71: BB encoding basic amino acids at positions 13, 70 and 71; A encoding acidic amino acids at positions 70 and 71; and BN encoding either neutral amino acids at position 13 and basic amino acids at positions 70 and 71, or basic amino acid at position 13 and neutral amino acids at positions 70 and 71. The associations between the different alleles and (1) the ACPA presence, and (2) the structural progression were assessed by χ2 test; a meta-analysis was performed on the 2 cohorts using the Mantel-Haenszel method.Results: After meta-analysis, BB alleles were significantly associated with ACPA presence (OR (95% CI) 4.08 (3.14 to 5.31)) and structural progression (OR (95% CI) 2.33 (1.76 to 3.09)). The alleles protected significantly against ACPA presence (OR (95% CI) 0.37 (0.28 to 0.50)) and structural progression (OR (95% CI) 0.34 (0.23 to 0.50)). This acid–base classification allowed to separate another group BN with an intermediate risk of ACPA production (OR (95% CI) 1.14 (0.91 to 1.44)) and structural progression (OR (95% CI) 1.01 (0.77 to 1.33)).Conclusions: This new classification permitted to make a hierarchy of HLA-DRB1 alleles in terms of association with ACPA presence or structural progression in early RA

Accelerated atherosclerosis has emerged as a critical issue in rheumatoid arthritis (RA). There is a need to better understand the link between RA and atherosclerosis. Our aim was to identify parameters associated with the development of subclinical atheroma in a very early arthritis (VErA) cohort.VErA-cohort patients were prospectively recruited from 1998 to 2002. Arthritis treatment was standardised from onset. The clinical, biological and radiological parameters of all patients were collected from inclusion. Carotid intima-media thickness (cIMT) was measured 7 years after their first symptoms.Among 105 patients included, 82 developed RA (mean age at onset: 51.7±12.8 years). Mean carotid artery IMT at year 7 was 0.67±0.12 mm. Larger thickness defined by values above the median (0.66) was associated with inclusion age (p10-6), swollen joint count (p=0.01), DAS44 (p=0.048) and hypertension (p=0.006). In contrast, anti-CCP positivity (50 UA/ml) was associated with thinner cIMT (p=0.03). Baseline as well as cumulated values of markers reflecting systemic inflammation, lymphocyte activation, endothelial dysfunction and oxidative stress were not correlated with carotid subclinical atherosclerosis. Major independent atheroma risk factors retained by multivariate analyses were hypertension (OR 4.33 [1.59-11.73]; p=0.004) and swollen joint count at inclusion (OR 3.87 [1.54-9.72]; p=0.004), while methotrexate use was a protective marker (OR 0.27 [0.11-0.71]; p=0.007).This study conducted from the VErA vascular cohort of community-cases of RA confirm that cIMT is under the influence of classical CV risk (hypertension), disease marker (SJC) and methotrexate intake.

Objective The gene encoding tumor necrosis factor receptor type II (TNFRII) is a strong candidate in the pathogenesis of rheumatoid arthritis (RA). An association between a single-nucleotide polymorphism (196M/R) in exon 6 of the TNFRII gene and familial RA was recently reported. The present study was undertaken to test the hypothesis that there is an association between this polymorphism and the severity of RA. Methods One hundred two white patients with early RA were included in this prospective study. The French version of the Health Assessment Questionnaire (F-HAQ) and a radiographic damage score (modified Sharp/van der Heijde method) were used to quantify the functional and structural severity of RA at baseline and after 4 years of followup. TNFRII 196M/R polymorphism genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism analysis. Results Among the 102 patients with RA, 63 (61.8%) were homozygous for the 196M allele, 36 (35.3%) were heterozygous for alleles 196M and 196R, and 3 (2.9%) were homozygous for the 196R allele. At baseline, the median radiographic and F-HAQ scores did not differ between RA patients who carried the 196R allele and those who did not. After 4 years of followup, the F-HAQ score was higher in RA patients carrying the 196R allele (median 1 [interquartile range (IQR) 0.125, 1.375]) than in noncarriers (0.375 [IQR 0, 1]) (P = 0.02), while the median radiographic score did not differ between RA patients who carried the 196R allele and those who did not. Conclusion The results of the present study support the hypothesis that there is an association between the TNFRII 196 M/R gene polymorphism and the functional severity of early RA.

Objective Results of genome scans in rheumatoid arthritis (RA) have suggested that the tumor necrosis factor receptor I (TNFRI) and TNFRII loci (TNFR1 and TNFR2) are susceptibility loci. A TNFR2 polymorphism was found to be associated with familial RA. TNFR1 is mutated in TNFR-associated periodic syndrome (TRAPS). We undertook this study to test the TNFR1 exonic polymorphism closest to the TRAPS mutations site (+36 A/G) for association with RA. Methods DNA samples were available from two groups of the French Caucasian population: 1) 100 families with 1 RA patient and both parents and 2) 86 RA index patients from families with at least 2 siblings with RA (affected sibpairs [ASPs]). The +36 A/G polymorphism of TNFR1 was genotyped by polymerase chain reaction–restriction fragment length polymorphism. The analysis was performed using the transmission disequilibrium test, the genotype relative risk, and a linkage-based test previously described. Results A negative association between RA and the +36 A/A genotype, suggested in the first sample (P = 0.084), was demonstrated in the second (ASP RA) sample (odds ratio [OR] 0.465; P = 0.012) and confirmed by the linkage-based test (OR 0.17; P = 0.008). The protective genotype, present in 41% of controls, was less frequent in RA patients: 33% in the first sample, 24% in the ASP RA sample, and 11% in the linkage-derived subgroup. Distribution of both TNFR2 196 R/R and TNFR1 +36 A/A genotypes in the ASP RA sample showed that both suspected genotypes were exclusive. Conclusion We found evidence for an association between RA and a TNFR1 protective genotype, restricted to familial RA. Distribution of the TNFR2 196 R/R and TNFR1 +36 A/A genotypes in familial RA could suggest an interaction between TNFR1 and TNFR2 in the genetic susceptibility for RA.

Introduction La pneumopathie interstitielle diffuse (PID) est l’une des causes majeure de mortalite chez les patients atteints de polyarthrite rhumatoide (PR). Malgre une prevalence et une mortalite importante, la physiopathologie de la PID associee a la PR (PR-PID) reste meconnue. La PR-PID partage plusieurs caracteristiques phenotypiques avec la fibrose pulmonaire idiopathique (FPI) telles que l’aspect de pneumopathie interstitielle commune sur le scanner et un pronostic tres severe. Enfin, les similitudes entre PR-PID et FPI concernent egalement les facteurs environnementaux (tabac,…) suggerant que ces deux pathologies pourraient egalement partager des facteurs de risques genetiques tels que ceux predisposant a la FPI familiale (FPF). Methodes Nous avons utilise des donnees d’exome obtenue par whole-exome sequencing (WES) de patients atteints de PR-PID provenant de differents centres de rhumatologie et de pneumologie francais. L’ensemble des patients PR-PID+ repondaient aux criteres ACR/EULAR 2010. Le diagnostic de PID etait realise apres analyse de scanner thoracique de haute resolution. Apres une analyse restrictive de 9 genes rapportes comme etant associes aux FPF, nous avons compare le nombre de mutations retrouvees parmi les patients PR-PID au nombre de mutations retrouvees chez des individus temoins. Un burden test a ete effectue pour definir l’exces de mutations chez les patients PR-PID au sein de ces 9 genes d’interet. Resultats Parmi les 101 patients PR-PID inclus, 12 (11,9 %) presentaient des mutations au sein des regions codantes des genes TERT, RTEL1, PARN et SFTPC. Le burden test comparant 81 patients PR-PID a 1010 individus temoins caucasiens europeens a confirme un exces de mutations parmi ces genes chez les patients PR-PID (P = 9,45 × 10−4 ; OR = 3,17 ; IC 95 % 1,53–6,12). Chez les patients PR-PID porteurs de mutations des genes TERT, RTEL1 et PARN, appartenant au complexe telomerase, la taille des telomeres etait significativement plus petite que celle observees chez les temoins (P = 2,87 × 10−2). Conclusion Ces resultats sont en faveur d’un fond genetique commun entre FPI et PR-PID, suggerant une physiopathologie commune entre ces deux pathologies. En cas de confirmation de ces resultats, les avancees therapeutiques realisees dans la prise en charge des FPI pourraient alors beneficier aux patients atteints de PR-PID.

Objective Tumor necrosis factor α (TNFα) binds the receptors TNFRI and TNFRII. Results of genome scans have suggested that TNFR2 is a candidate rheumatoid arthritis (RA) locus. A case–control study in a UK Caucasian population has shown an association between a TNFR2 genotype (196R/R in exon 6) and familial, but not sporadic, RA. The present study was undertaken to test this association in the French Caucasian population. Methods To test for an association in sporadic RA, 100 families were genotyped for the 196M/R polymorphism and analyzed using the transmission disequilibrium test and haplotype relative risk. To test for an association in familial RA, RA index cases from 100 affected sibpair (ASP) families were genotyped for 196M/R. Linkage analysis was performed with 3 TNFR2 microsatellite markers. Results The TNFR2 196R/R genotype was not associated with sporadic RA (odds ratio [OR] 0.59, P = 0.72), but was associated with familial RA (OR 4.0, P = 0.026). The association was most marked in the context of TNFR2 “twin-like” RA sibs (affected sibs sharing both TNFR2 haplotypes) (OR 9.2, P = 0.0017). Linkage analysis results were consistent with the association; most of the TNFR2 linkage evidence was found in the subgroup of families with 196R/R ASP index cases. Conclusion This study is the first to replicate evidence of the involvement of TNFR2 in RA genetic heterogeneity. Our data refine the initial hypothesis, to suggest that a TNFR2 recessive factor, in linkage disequilibrium with the 196R allele, plays a major role in a subset of families with multiple cases of RA.

Background The type 1 interferon (IFN) pathway has been identified to potentially affect the response to rituximab (RTX) for rheumatoid arthritis (RA), which suggests the contribution of type 1 IFN pathway genes such as IFN regulatory factor 5 and 7 ( IRF5 and IRF7 ), tyrosine kinase 2 ( TYK2 ), signal transducer and activator of transcription 4 ( STAT4 ) and osteopontin ( SPP1 ). Our objective was to study functional variants of these IFN pathway genes as predictors of the European League Against Rheumatism (EULAR) response to RTX for RA at week 24 (W24). Methods Logistic regression analysis with a stepwise multivariate model adjusted for sex, age and DAS28-CRP (Disease Activity Score in 28 joints with C reactive protein) in 115 patients from the SMART randomised studywas used to analyse the association between the candidate variants and W24 EULAR response. Because the variant TNFSF13B rs9514828 was previously found associated with RTX response in the same population, it was included in the analysis. Results The combination of IRF5 rs2004640, SPP1 rs9138 and TNFSF13B rs9514828 was strongly associated with good/moderate EULAR response to RTX at W24: p=9.34×10 −6 , OR 11.37 (95% CI 4.03 to 35.28), positive predictive value 91% and negative predictive value 54%. Conclusion Our results support the contribution of the IRF5 , SPP1 and TNFSF13B genotypic combination in the response to RTX for RA at W24.

Excess adipose tissue in obese individuals may have immunomodulating properties and pharmacokinetics consequences. Previous studies have suggested that obesity could negatively affect the response to anti-TNF-α agents, notably infliximab (IFX). We aimed to determine whether body mass index (BMI) is involved in the response to IFX in rheumatoid arthritis (RA).We retrospectively examined data for 76 RA patients receiving IFX. BMI was calculated before treatment, and change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate, C-reactive protein level, tender and swollen joint count was analysed at 6 months after treatment. The primary outcome was decrease in DAS28 ≥1.2. Secondary outcomes were good response and remission according to EULAR.At baseline, the median [interquartile range] BMI was 26.6 [22.6-30.6] kg/m2. The number of patients with normal weight, overweight and obesity was 25, 29 and 22. In multivariable analyses, IFX treated patients with lower BMI showed a more frequent DAS28 decrease ≥1.2 (25.5 [22.3-28.3] vs. 28.0 [23.2-32.5], p=0.02, odds ratio [OR] 0.88 [95% confidence interval 0.79-0.98]), EULAR good response (25.3 [21.9-27.5] vs. 27.5 [24.3-31.2], p=0.03, OR 0.87 [0.76-0.99]) and EULAR remission, although not significant (25.3 [21.9-26.4] vs. 27.5 [23.2-30.9], p=0.14, OR 0.88 [0.75-1.04]).Obesity may negatively influence the response to IFX in RA. These data could help physicians to choose biologic agents for obese RA patients.

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.