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Dear Editor, A potential association between rituximab and more severe COVID-19 outcomes has been previously raised, based on case reports, retrospective studies and mostly declarative registries.1–4 To further investigate this association, we focused on patients with inflammatory arthritides (IA) receiving intravenous biological agents at day hospitals to limit selection and recall bias, as well as missing data. All patients with IA treated in day hospitals with intravenous biological agents (rituximab, abatacept, infliximab or tocilizumab) in seven clinical centres in France (Strasbourg, Colmar, Mulhouse, Nancy, Reims, Clermont-Ferrand and Saint-Antoine hospitals in Paris) were enrolled in the study. Data were collected from 1 September 2019 (5 months before the outbreak of the epidemic in France, so that all enrolled patients had been exposed to a biologic prior to the start of the epidemic) to 1 January 2021.3 In each centre, we obtained the list of all patients receiving intravenous biological agents from the hospital pharmacist. Therefore, all patients receiving one of the four drugs within the time frame of the study were enrolled in each centre. The occurrence of hospitalised COVID-19 was the primary outcome criterion, that is, SARS-CoV-2 presence confirmed by PCR and resulting in hospitalisation or death. Data were analysed with Bayesian methods in univariate and multivariate analyses …

Resume Introduction Les patients traites par biotherapie doivent en connaitre les complications specifiques. L’acquisition de competences de securite est l’un des objectifs des programmes d’education therapeutique du patient dans les rhumatismes inflammatoires chroniques. Objectif : evaluation de l’impact du programme d’education therapeutique du patient « ETP RHIN-RIC » sur les competences de securite de patients sous biotherapie pour un rhumatisme inflammatoire chronique. Methodes Etude transversale bicentrique evaluant l’impact de l’integration a un programme d’education therapeutique du patient sur les competences des patients suivis a Strasbourg et Mulhouse pour un rhumatisme inflammatoire chronique, appreciees par le questionnaire Biosecure. Resultats Quinze pour cent des 414 patients inclus jugeaient l’information qui leur avait ete prodiguee insuffisante. Le score Biosecure median etait de 70,9/100 (Q1Q3 : 60,9–84,6). Quarante-sept pour cent des patients avaient integre le programme d’education therapeutique. Leur score Biosecure etait significativement plus eleve que celui des patients naifs d’education therapeutique (score median 74,8/100 dans le groupe ETP versus 67,20/100 ; p Conclusion L’integration des patients sous biotherapie a un programme specialise d’education therapeutique du patient est correlee a une meilleure maitrise des competences theoriques de securite.

BackgroundVaccination against SARS-CoV-2 is effective in preventing severe forms of COVID-19, but there remain concerns about a reduced vaccine response in patients suffering from inflammatory arthritides who are treated by immunosuppressive therapies.ObjectivesWe analysed the impact of bDMARDs on the humoral anti-SARS-CoV-2 vaccine response of patients followed in day hospitals.MethodsWe studied the vaccine response after a complete vaccine regimen followed in day hospital in 5 French hospitals and treated with an intravenous bDMARD between September 2019 and August 2021. After obtaining their informed consent, we included patients with an anti-SARS-CoV-2 serology. They were considered non-responders if the antibody level detected was inferior to the threshold of positivity of the kit used.Results205 patients were included (148 females/57 males). The median age was 64 years (Interquartile Range [IQR] 56-71). 25 were treated with tocilizumab (TCZ), 36 with abatacept (ABA), 53 with infliximab (IFX) and 91 with rituximab (RTX). When considering both patients after a complete vaccination schema (2 doses, or 1 dose in case of prior COVID-19) and those with 1 booster dose, 34 patients (16.6%) were non-responders (2 [5.9%] treated by IFX, none treated by TCZ, 9 [26.5%] treated by ABA and 23 [67.7%] treated by RTX). In multivariate analysis, the only characteristics that significantly and independently differed between responders and non-responders were last bDMARD and corticosteroid therapy at the time of 1st vaccination (Table 1). In RTX-treated patients, the delay from last infusion to 1st vaccine dose was significantly shorter in non-responders (median 4.3 IQR [2.9-6.1] months in non-responders versus 8.4 IQR [5.7-14.5] in responders, p=0.0007). Median survival, i.e. achieving a vaccine response in 50% of RTX-treated subjects, was achieved after 277 days (95CI [209-310]) in patients vaccinated with 2 or 3 doses (Figure 1). In ABA-treated patients, the delay from last infusion to 1st vaccine dose was not different between non-responders and responders.Table 1.Patients’ characteristics and comparisons between responders and non-responders.All patients (n=205)Responders (n=171)Non responders (n=34)Univariate p valueMultivariatep valueAge (median [IQR]), in years64 [56-71]64 [54-70]69 [57-75.5]0.070.40Female sex, n (%)148 (72.2)125 [73.1)23 (67.7)0.53Inflammatory arthritides, n (%)0.16**0.24 Rheumatoid Arthritis156 (78.0)128 (74.9)28 (82.4)0.51 Spondyloarthritis33 (16.1)31 (18.1)2 (5.9)0.12 Others*16 (7.8)12 (5.9)4 (1.9)0.31Last bDMARDs at time of 1st vaccination, n (%)0.0004ABA/RTX versus IFX/TCZ < 0.00010.00024 Infliximab53 (25.9)51 (29.8)2 (5.9) Tocilizumab25 (12.2)25 (14.6)0 Abatacept36 (17.6)27 (15.8)9 (26.5) Rituximab91 (44.4)68 (39.8)23 (67.7)Associated treatments at time of 1st vaccination CsDMARDs, n (%)126 (61.5)107 (62.6)19(55.9)0.56 Methotrexate91 (44.4)78 (45.6)13 (38.2)0.46 Median dose in users (mg /week) [IQR]15 [10-17.5]13.8 [10-15.6]15 [13.8-20]0.07 Corticosteroids, n (%)25 (12.2)19 (11.1)6 (17.6)0.29 Median dose (mg /day) [IQR]0 [0-0]0 [0-0]0 [0-2]0.0350.016Previous COVID-19 infection, n (%)23 (11.2)21 (12.3)2 (5.9)0.38Type of vaccine, n (%)0.62 Pfizer169 (82.4)142 (83.0)27 (79.4)0.62 Moderna14 (68.3)11 (6.4)3 (8.8)0.71 Astra-Zeneca17 (8.3)15 (8.8)2 (5.9)0.74 Janssen5 (2.4)3 (1.8)2 (5.9)0.19Vaccination, n (%) Complete167 (81.5)141 (82.5)28 (16.8)0.47 Complete + 1 booster dose56 (27.3)43 (25.1)13 (38.2)0.14Figure 1.Cumulative seropositive rate according to the interval (days) between the last course of rituximab administration and vaccinationConclusionABA and RTX alter the anti-SARS-CoV-2 vaccine response and were associated with nearly all vaccine non-responses in the present study. Corticosteroid therapy was associated with a lower vaccine response regardless of its indication or the concomitant use of bMARD.Disclosure of InterestsNone declared

In vitro studies indicate IFNγ is central to Chlamydia trachomatis (Ct) eradication, but its function may be compromised by anaerobes typically associated with bacterial vaginosis (BV), a frequent co-morbidity in women with Ct. Here we investigated the associations between natural clearance of cervical Ct infection, the vaginal microbiome, and the requirements for IFNγ by evaluating the vaginal microbial and cytokine composition of Ct treatment visit samples from women who cleared Ct infection in the interim between their Ct screening and Ct treatment visit. The pilot cohort was young, predominantly African American, and characterized by a high rate of BV that was treated with metronidazole at the Ct screening visit. The rate of natural Ct clearance was 23.6% by the Ct treatment visit (median 9 days). 16S rRNA gene sequencing revealed that metronidazole-treated women who had a Lactobacillus spp.-dominant vaginal microbiota (CST 2 or 3) at the Ct treatment visit, were more prevalent in the Ct clearing population than the non-clearing population (86% v. 50%). L. iners (CST2) was the major Lactobacillus spp. present in Ct clearers, and 33% still remained anaerobe-dominant (CST1). Vaginal IFNγ levels were not significantly different in Ct clearers and non-clearers and were several logs lower than that required for killing Ct in vitro. An expanded panel of IFNγ-induced and proinflammatory cytokines and chemokines also did not reveal differences between Ct clearers and non-clearers, but, rather, suggested signatures better associated with specific CSTs. Taken together, these findings suggest that BV-associated bacteria may impede Ct clearance, but a Lactobacillus spp.-dominant microbiome is not an absolute requirement to clear. Further, IFNγ may be required at lower concentrations than in vitro modeling indicates, suggesting it may act together with other factors in vivo. Data also revealed that the vaginal bacteria-driven inflammation add complexity to the genital cytokine milieu, but changes in this microbiota may contribute to, or provide cytokine biomarkers, for a shift to Ct clearance.

Based on a large body of evidence asbestos minerals have been classified as carcinogens. Despite the Italian ban on asbestos in 1992 and the subsequent remediation activities, latent sources of contamination may still represent a hazard where asbestos were particularly used. Using wild rats as sentinel animals, this study aimed at uncovering sites with the greatest potential for non-occupational exposure to asbestos in the city of Casale Monferrato (Piedmont Region, Italy), where the largest Italian manufacturing plant of asbestos-cement had been active. During the study period (2013-2015) a total of 40 wild rats were captured from 16 sampling capture points. The lungs of wild rats have been investigated by using scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS). The SEM-EDS detected the presence of asbestos fibers (tremolite/actinolite, amosite, and chrysotile) in rats' lungs from 11 sampling points. The hypothetical rats' home-range and the observed site-specific concentration of asbestos fibers per gram of dry lung tissue were used to identify areas to be targeted by additional search of latent sources of asbestos. In conclusion, our results showed that the use of wild rats as sentinel animals may effectively integrate the strategies currently in use to reduce the exposure to asbestos.

Introduction Mise en place d’un dispositif d’accompagnement de reprise d’activite physique « RAP » pour les patients ayant un rhumatisme inflammatoire chronique (RIC) au sein des hopitaux de Colmar, Mulhouse, Strasbourg depuis octobre 2020. Il se deroule en 3 phases de 3 mois, lui permettant apres une 1ere periode de pratique d’activites physiques supervisees (2 fois/semaines d’une duree de 1 h a 1h30), d’etre accompagne vers une pratique autonome. L’objectif final etant diminuer la sedentarite et augmenter le temps hebdomadaire d’activite physique chez les patients RIC. Patients et methodes Inclusion des patients majeurs avec un RIC sans contre-indication medicale a la pratique d’APA. A M0 et M3, les donnees sociodemographiques, le niveau d’activite du RIC, EVA douleur, Fatigue, la prise de traitement de fond, d’antalgique, le test de marche de6 mins, les poussees du RIC sont recueillies. Des entretiens semi directifs menes par l’enseignant en activite physique adaptee permettent de recueillir le vecu des patients. Seances d’activites physiques presentielles ou distancielles (contrainte COVID) realisees par un enseignant en activite physique adapte (EAPA) Resultats 62 patients (24 hommes et 38 femmes) beneficiaires de « RAP » en 8 mois. L’âge moyen est de 46,9 ans. 49 ont une spondyloarthrite (SA), 13 ont une polyarthrite rhumatoide (PR). A M0, BASDAI moyen a 3,92, mediane a 3,8, DAS 28 moyen a 2,22, mediane a 2,25. Moyenne de l’EVA douleur est 3,78 (0–8,5), Mediane est 4, moyenne de l’EVA fatigue est a 5,39 (0–9,5), mediane est 6. 91 % des patients ont un traitement de fond classique ou biologique. 60 % (n = 37) prennent des antalgiques ou AINS. Le test de marche de 6 min est en moyenne a 65,59 % de la valeur theorique. Le resultat moyen du questionnaire de Ricci Gagnon est de 21,86, 16 patients consideres comme inactif (score Discussion Le dispositif RAP permet d’integrer l’APA dans le parcours de soin du patient RIC. Les patients beneficiaires etaient en activite faible du rhumatisme mais avec un niveau de fatigue important. Le programme d’APA n’a pas engendre d’aggravation du rhumatisme (DAS 28, BASDAI, EVA douleur fatigue stables). Donnes superposables a la litterature scientifique. Le dispositif en distanciel a permis de « recruter » des patients habitants loin du centre hospitalier referent. Si en distanciel, le cote organisationnel semble plus simple pour les patients, ses limites sont entre autres le niveau de litteratie numerique, et le manque de lien social qui est plebiscite par les patients lors des seances presentielles. Les retours patients sont tres positifs tant sur le fond et la forme du dispositif. Ils apprecient les competences specifiques des enseignants en activite physique adapte. Conclusion Les 1ers resultats sont encourageants, le dispositif RAP distanciel ou presentiel permet aux patients RIC de reprendre une APA. Les donnees de suivi a 6 et 9 mois lors de l’autonomisation seront tres interessantes et representent le 2eme challenge de RAP.

Introduction Les études vaccinales de grande ampleur et les registres apportent des résultats précieux mais souvent de manière retardée par rapport à l’urgence pandémique. Les perfusions de biologiques intraveineux en hôpital de jour (HDJ) permettent de garantir un recueil de données fiables en temps réel. C’est ainsi que nous avions mis en évidence le surrisque d’une forme grave de COVID-19 sous rituximab. Nous avons souhaité étudier l’impact des bDMARDs sur la réponse vaccinale humorale des patients suivis en HDJ. Patients et méthodes Nous avons étudié la réponse vaccinale après un schéma vaccinale complet, 2 ou 3 doses de vaccin, suivis en hôpital de jour dans 5 centres hospitaliers français et traités par un biomédicament intraveineux entre septembre 2019 et août 2021. Après information et consentement des patients, nous avons inclus ceux disposant ou acceptant de réaliser une sérologie anti-SARS-CoV-2. Les patients étaient considérés comme non-répondeurs si le taux d’anticorps détecté était inférieur au seuil de positivé du kit utilisé. Résultats Sur les 925 patients suivis en HDJ dans les 5 centres, les données préliminaires de 205 patients sont disponibles (148 F/57 H). L’âge médian était de 64 ans (Interquartile Range [IQR] 56–71). 25 étaient traités par tocilizumab (TCZ), 36 par abatacept (ABA), 53 par infliximab (IFX) et 91 par rituximab (RTX). 156 étaient traités pour une PR, 33 pour une spondyloarthrite et 16 pour une autre pathologie (connectivite n = 5, myosite n = 3, vascularite n = 2, arthrite juvénile idiopathique n = 2, autres n = 4). 25 patients étaient co-traités par corticoïdes, 126 par csDMARDs et 2 par d’autres immunossuppresseurs (aziathioprine). Trois quarts des patients traités par RTX ont débuté leur schéma vaccinal plus de 4 mois après leur dernier cycle de traitement. Un total de 23 patients avaient un antécédent de COVID-19 confirmé (par PCR ou sérologie). Un total de 169 patients ont été vaccinés par Pfizer, 16 par Astra-Zeneca, 14 par Moderna, 5 par Janssen et un par Astra-Zeneca puis Pfizer. Un total de 167 patients ont bénéficié d’une sérologie après 2 doses de vaccin (ou un schéma vaccinal complet en cas de COVID-19 préalable). Parmi eux, 28 (16,8 %) étaient non-répondeurs. Il n’y avait pas de différence en fonction de l’âge (p = 0,24) ou du sexe des patients (p = 0,51), du type de pathologie ou du co-traitement par corticoïdes ou csDMARD. La réponse vaccinale était différente en fonction du bDMARD utilisé (p = 0,0003) : aucun patient traité par IFX (0/42) n’était non-répondeur, un seul sous TCZ (1/25, 4 %) contre 25 % sous ABA (8/32) et 27,9 % sous RTX (19/68). Un total de 94 % des non répondeurs après 2 ou 3 doses de vaccin avaient été traités par RTX ou ABA. Chez les patients traités par rituximab, le délai entre la dernière perfusion et la première dose de vaccin était significativement plus courte chez les non-répondeurs (médiane 4,3 IQR [2,9–6,1] mois chez les non-répondeurs versus 8,4 IQR [5,7–14,5] chez les répondeurs, p = 0,0007). La diminution de réponse vaccinale post-ABA ou RTX étaient similaires après 3 doses de vaccin (56 patients), 25 % de non répondeurs sous ABA (1/4), 25 % sous RTX (10/40) contre 19 % sous IFX (9/11) et aucun sous TCZ (0/1). 18 des 56 patients ont bénéficié d’une sérologie après 2 doses et également après 3 doses de vaccin. 7 étaient non-répondeurs après 2 doses (6 RTX et 1 TCZ). Parmi eux, 5 sont restés non-répondeurs après leur 3e dose, tous traités par RTX. Conclusion L’ABA et le RTX altèrent la réponse vaccinale anti-SARS-CoV-2 : associés à 94 % des non-réponses vaccinales. La réponse vaccinale est altérée si un délai suffisant n’est pas respecté entre la perfusion de RTX, permettant une repopulation lymphocytaire B, et la vaccination.

The endocervix, the primary site ofChlamydia trachomatis(Ct) infection in women, has a unique repertoire of locally synthesized IgG and secretory IgA (SIgA) with contributions from serum IgG. Here, we assessed the ability of genital and serum-derived IgG and IgA from women with a recent positive Ct test to neutralize Ct elementary bodies (EBs) and inhibit inclusion formationin vitroin human endocervical epithelial cells. We also determined if neutralization was influenced by the major outer membrane protein (MOMP) of the infecting strain, as indicated byompAgene sequencing and genotyping. At equivalent low concentrations of Ct EB (D/UW-3/Cx + E/UW-5/Cx)-specific antibody, genital-derived IgG and IgA and serum IgA, but not serum IgG, significantly inhibited inclusion formation, with genital IgA being most effective, followed by genital IgG, then serum IgA. The well-characterized Ct genotype D strain, D/UW-3/Cx, was neutralized by serum-derived IgG from patients infected with genotype D strains, genital IgG from patients infected with genotype D or E strains, and by genital IgA from patients infected with genotype D, E, or F strains. Additionally, inhibition of D/UW-3/Cx infection by whole serum, rather than purified immunoglobulin, was associated with levels of serum EB-specific IgG rather than the genotype of infecting strain. In contrast, a Ct genotype Ia clinical isolate, Ia/LSU-56/Cx, was neutralized by whole serum in a genotype and genogroup-specific manner, and inhibition also correlated with EB-specific IgG concentrations in serum. Taken together, these data suggest that (i) genital IgA most effectively inhibits Ct infectionin vitro, (ii) human antibody-mediated inhibition of Ct infection is significantly influenced by theompAgenotype of the infecting strain, (iii) the genital antibody repertoire develops or matures differently compared to systemic antibody, and (iv)ompAgenotype-specificity of inhibition of infection by whole serum can be overcome by high concentrations of Ct-specific IgG.

Background:At a time when vaccines are being prioritized for individuals most at risk, there is currently no clear evidence that risk of SARS-CoV-2 infection is higher for patients with than without inflammatory arthritides (IA). Biologic use was not associated with worse COVID-19 outcomes for yet but the case of rituximab (RTX) remains an issue, given its immunological long term effect, the role of humoral response against SARS-CoV-2 and its indirect effect on T-cell response. A potential association between rituximab and worse COVID-19 outcomes was raised by case reports and retrospective, declarative studies (with few data on the total number of patients exposed).Objectives:To address differently the issue of the risk of COVID-19 related to RTX and limit biases, we examined the occurrence of severe COVID-19 in all patients receiving intravenous biologic agents at day-hospitals during the pandemic in France.Methods:From 1st September 2019 to 1st January 2021, we analyzed patients with IA prospectively treated with intravenous biologic agents (RTX, abatacept, infliximab or tocilizumab) in 7 clinical centers in France. We obtained the list of patients receiving intravenous biologic agents in each center from the pharmacist of the hospitals. Therefore, all consecutive patients receiving 1 of the 4 drugs at the time of the study were included in each center. Patients with no follow-up after September 2020 were systematically contacted by phone. The occurrence of a severe COVID -19 (i.e. resulting in death, hospitalization or increase in length of hospitalization related to COVID-19) was the primary outcome criteria.Results:In total, 1116 patients receiving intravenous biologic agents were included: 449 with infliximab, 392 RTX, 170 tocilizumab and 105 abatacept. From 1st September 2019, the median follow-up time was 15 months (interquartile range 14-16). In total, 10 cases of severe COVID-19 occurred, 9 treated with RTX and 1 with infliximab (supplementary Table 1). Four deaths occurred in our cohort during follow-up but none was related to COVID-19 (1 patient treated by tocilizumab, 1 by RTX and 2 by infliximab). In univariate analysis, the proportion of severe COVID-19 was significantly higher for patients receiving RTX than other biologic agents (9/392 vs 1/724, p=0.0003, OR [95%CI] 17.0 [2.1-134.6]). To take into account potential confounders, we performed multivariate analysis accounting for baseline parameters that differed between RTX and other biologic groups. RTX remained significantly associated with risk of severe COVID-19 (p=0.019) (Table 1).Patient characteristicsRituximab (n= 392)Other bDMARDs (n= 724)Univariate analysis, p-valueMultivariate analysis, p-valueMedian age (years), — [IQR]64 [56-71]57.3 [47.0-67.0]< 0.00010.51Female — n (%)285 (72.7)426 (58.8)< 0.00010.58IA diagnosis< 0.00010.12Median follow-up from 1st September to last news14 [13-15]15 [14-16]< 0.00010.86Confirmed severe COVID-19 cases —n (%)9 (2.3)1 (0.1)0.00030.019Comorbidities** (history of) — n (%) Cardiovascular disease60 (15.4)167 (23.1)0.00250.77 Chronic lung disease,92 (23.5)84 (11.6)0.00010.88Median BMI (kg/m2) — [IQR]25.8 [23.2-29.4]27.3 [23.4-31.2]0.0150.80Treatments — n (%) Methotrexate179 (45.8)322 (44.5)0.71 Leflunomide41 (10.5)39 (5.4)0.00230.43 Hydroxychloroquine35 (8.9)24 (3.3)0.00010.15 Glucocorticoids127 (41.8)100 (19.4)< 0.00010.36 Median dose (mg/day) — [IQR]1 [0-5]0 [0-0]< 0.0001No significant difference in terms of baseline gammaglobulins (p=0.46) or number of previous RTX infusions (p=0.57) was observed among patients receiving RTX with or without a severe COVID-19.Conclusion:The present results highly indicate increased risk of severe COVID-19 with RTX. Among patients with inflammatory arthritides, those receiving RTX should be prioritized for vaccination against SARS-CoV-2, sufficiently long before infusion/reinfusion and the immunization checked, or an alternative targeted therapy proposed.Acknowledgements:We thank Dr. Karine Demesmay and all the pharmacists who helped us for this study.Disclosure of Interests:Renaud FELTEN Speakers bureau: Abbvie, Biogen, BMS, Lilly, Novartis, Pfizer, Pierre-Marie Duret: None declared, Elodie BAUER: None declared, Marc Ardizzone: None declared, H Julien Djossou: None declared, Jean-Hugues Salmon: None declared, Cassandre Fabre: None declared, Julia Walther: None declared, Isabelle CHARY VALCKENAERE: None declared, marion geoffroy: None declared, Laurent Messer: None declared, Francis Berenbaum: None declared, Martin SOUBRIER: None declared, Jérémie SELLAM Speakers bureau: MSD, Pfizer, Abbvie, Roche, BMS, Lilly, Janssen, Novartis, Galapagos, Sandoz, Fresenius Kabi, Grant/research support from: Roche, MSD, Pfizer, Jacques-Eric Gottenberg: None declared

Background:Objectives:To describe current management and outcome of septic arthritis on native joint in French rheumatology departments.Methods:Retrospective, nation-wide multicentric study. 127 French rheumatology departments were contacted to report 10 successive cases of septic arthritis on native joint that occurred between the 01/01/16 to 31/12/17 (excluding mycobacteria). Characteristics, diagnosis procedure, therapeutic management and outcome were recorded.Results:52 centers included 363 patients (mean age 64± 18.7 years, mean Charlson comorbidity index 4±3). 28.3% patients had a preexisting arthropathy on affected joint. Monoarthritis was observed in 89.6% patients, knee was the most frequent site (38.9%). The most frequent pathogens wereStaphylococcus sp(50.7%) andStreptococcus sp.(23.3%). Bacteremia was found in 156 (45.1%) patients and endocarditis in only 12 (3.0%). Management was heterogeneous. All patients received antibiotics for a mean duration of 46.7±22 days (including intravenous route: 17.3±15.4 d). An initial monotherapy was administered in 42.3% of patients. Surgical procedure (mostly lavage 70.6%) was performed in 171 (48.3%), joint immobilization in 128 (35.3%) (median duration of 21.7±14.1 days). 94 (29.2%) patients have had serious complications including 29 (9.5%) death. Factors associated with death are reported in the table.Conclusion:This study shows that management of septic arthritis is very heterogenous with a still high rate of morbidity and mortality. We identified age, comorbidities, bacteremia and recent antibiotherapy were associated with mortality. Of note, duration of antibiotics was not. Thus, new guidelines are needed in order to facilitate septic arthritis management.Table:FactorsSurvivor(N=276)Dead(N=29)Univariate analysispAdjusted Odds ratio (95%IC)Multivariate analysispAge65 (16-97)82 (32-98)1,07 (1,03-1,12)< 0.001Charlson’s index1 (0-12)2 (0-9)0,00011,3 (1,05-1,63)0,018Delay before antibiotic initiation8,5 (0-310)5 (0-75)0,04840,99 (0,96-1,02)0,562Corticosteroid in the previous 3 months13,9%33,3%0,01842,56 (0,75-8,74)0,133Bacteriemia42,4%71,4%0,00615,07 (1,4-18,370,013Antibiotics in the previous 3 months26,6%56,6%0,00566,7 (2,04-22,01)0,002Disclosure of Interests:Pauline Richebé: None declared, Sophie Godot: None declared, Guillaume Coiffier: None declared, Pascal GUGGENBUHL: None declared, Denis Mulleman: None declared, Marion Couderc: None declared, Emmanuelle Dernis Speakers bureau: Lilly, Novartis, Valentine Deprez: None declared, Carine Salliot: None declared, Saik Urien: None declared, Rachel Brault: None declared, Adeline Ruyssen-Witrand Grant/research support from: Abbvie, Pfizer, Consultant of: Abbvie, BMS, Lilly, Mylan, Novartis, Pfizer, Sandoz, Sanofi-Genzyme, Emmanuel Hoppe: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Christian Roux: None declared, Sebastien Ottaviani: None declared, Maxime Breban: None declared, Marie Beaufrere: None declared, Alexia Michaut: None declared, Loic Pauvele: None declared, Christelle Darrieutort: None declared, Daniel Wendling: None declared, Pascal COQUERELLE: None declared, Géraldine Bart: None declared, Elisabeth Gervais: None declared, Vincent Goeb: None declared, Marc Ardizzone: None declared, Edouard Pertuiset: None declared, Sophie Derolez: None declared, Jean Marc Ziza: None declared, René-Marc Flipo Consultant of: Johnson and Johnson, MSD France, Novartis, Sanofi, Speakers bureau: Johnson and Johnson, MSD France, Novartis, Sanofi, Raphaèle Seror Consultant of: BMS UCB Pfizer Roche

Background Patients treated with biologic DMARDs have to be aware of the specific adverse events and have to be able to manage their treatments in case of infectious disease. Therapeutic Patient Education aims to enable patient to acquire these safety skills. Objectives To assess the impact of Therapeutic Patient Education on safety skills and management of infectious events in patients treated with biologic DMARDs in rheumatology. Methods Bi-centric analytical study comparing safety skills and infectious events between two cohorts of patients (TPE and TPE-naive). Safety skills were assessed by an auto-assessment called “Biosecure”, rated on a scale from 0 to 100. This assessment explores several dimensions of treatment management and was validated for assessment of safety skills in patients treated with biologic DMARDs in rheumatology in a preliminary study. Infectious events and their management were self-reported by patients. A cluster analysis aimed to separate patients into working group based on their shortcomings (on the basis of their answers to the Biosecure Assessment). Results 414 patients answered the assessment. The median Biosecure Score was 70.98/100 (Q1Q3: 60.97–84.63) 47% attended Therapeutic Patient Education. The median Biosecure Score was significantly higher in the TPE group than in the TPE-naive group (74.88 versus 67.20/100; p Cluster analysis based on Biosecure assessment separated patients into 3 level groups but failed to identify specific patient profiles. Conclusions Therapeutic Patient Education could provide better safety skills and better treatment management in patients treated with biologic DMARDs in rheumatology. Prospective studies may confirm the impact of TPE on treatment management during infectious events. Further studies may assess the impact of TPE on incidence of serious infectious events. References [1] Orefice D, Beauvais C, Gossec L, Flipon E, Fautrel B, Marguerie L, et al. Cross-sectional study of self-care safety skills in 677 patients on biodrugs for inflammatory joint disease. Jt Bone Spine Rev Rhum. dec 2014;81(6):502. [2] Rat A-C, Fautrel B, Flipon E, Gossec L, Marguerie L, Nataf H, et al. Factors associated with knowledge and safety skills of arthritis patients receiving biologics: A survey of 677 patients. Joint Bone Spine. Disclosure of Interest None declared

Resume Introduction Le tocilizumab (TCZ) est un anticorps anti-recepteur de l’IL-6 humanise, indique dans le traitement de la polyarthrite rhumatoide (PR) active, moderee a severe, la maladie de Still de l’adulte, la maladie de Castleman et, de facon plus recente, l’arthrite juvenile idiopathique dans sa forme systemique. De meme que les anti-TNFα, le rituximab et plus rarement l’abatacept, le TCZ est capable d’induire des reactions cutanees paradoxales de type psoriasique essentiellement a type de pustulose palmo-plantaire. Observation Nous rapportons l’observation d’une patiente suivie pour un rhumatisme psoriasique qui developpait sous anti-TNFα puis sous tocilizumab une eruption psoriasiforme palmo-plantaire. Conclusion Le mecanisme de ces reactions reste imparfaitement compris, mais des reactions croisees avec d’autres biotherapies sont observees.

The polyethers yessotoxin (YTX) and okadaic acid (OA) are two marine algal toxins frequently associated as edible shellfish contaminants. Seafood contamination by these compounds, also at low concentrations and for a long period of time, can increase the possibility of their simultaneous and repeated ingestion, with possible synergistic toxic effects. Thus, in vivo toxicity by repeated oral exposure to a combination of fixed doses of YTX and OA (1 mg YTX/kg and 0.185 mg OA/kg, daily for 7 days) was investigated in mice, in comparison to that of each toxin alone. No mortality, signs of toxicity, diarrhea or hematological changes was induced by the toxins co-administration or by the single toxins. Light microscopy revealed changes at gastric level (multifocal subacute inflammation, erosions and epithelial hyperplasia) in 2/5 mice co-administered with the toxins. In animals dosed only with OA, epithelial hyperplasia of forestomach and slight focal subacute inflammation of its submucosa were noted. No changes were induced by the treatment with YTX. Ultrastructural analysis of the heart revealed some cardiomyocytes with “loose packing” of myofibrils and aggregated rounded mitochondria in mice co-administered with the toxins or with YTX; OA-treated mice showed only occasional mitochondrial assemblage and dilated sarcomeres. Thus, the combined oral doses of YTX (1 mg/kg/day) and OA (0.185 mg/kg/day) did not exert cumulative or additive toxic effects in mice, in comparison to the single toxins.

Resume L’utilisation des traitements par anti-TNF se doit d’etre guidee pour en permettre une utilisation plus efficace et plus securisee. La Societe francaise de rhumatologie et le Club rhumatismes et inflammations, en partenariat avec plusieurs societes savantes francaises, ont donc sollicite la Haute Autorite de sante (HAS) afin d’etablir puis de labelliser des recommandations de bonne pratique de prescription et de suivi des traitements par anti-TNF, applicables par des medecins issus de differentes specialites. Ces recommandations, concues puis validees par deux groupes d’experts pluridisciplinaires, se sont appuyees sur un etat de la litterature recent et complet, selon les regles methodologiques de la HAS. Elles concernent la prescription initiale des anti-TNF ainsi que differents themes cliniques pratiques rencontres au cours du suivi des patients sous traitement (infections, cancers, grossesse, vaccination, effets indesirables paradoxaux, chirurgie, utilisation chez le sujet âge, vascularites).

Resume Objectifs Les arthrites induites par les cristaux de pyrophosphate de calcium surviennent plus particulierement chez les personnes âgees. Cette population a souvent une comorbidite et des traitements associes ce qui peut limiter l’utilisation des traitements conventionnels (colchicine, anti-inflammatoires non steroidiens et corticoides). Le but de cette etude est d’evaluer l’efficacite et la tolerance de l’anakinra chez les patients porteurs d’une arthrite induite par les cristaux de pyrophosphate de calcium. Methodes Nous avons effectue une revue retrospective, multicentrique, schematisee des patients ayant recu de l’anakinra pour une arthrite induite par des cristaux de pyrophosphate de calcium. Les renseignements demographiques, les comorbidites, les coprescriptions, l’evolution sous traitement a court terme, les effets secondaires, les complications et par la suite les poussees evolutives furent revues. Resultats Un total de 16 patients (12 femmes, âge moyen : 80 ± 11,1 ans) recurent de l’anakinra (100 mg/j en s.c.). Le nombre moyen d’injections d’anakinra fut de 15,5 ± 42,9 par patient (mediane 3). Tous les patients avaient une contre-indication et/ou etaient en echec des traitements conventionnels. La majorite (14 [87,5 %]) des patients ayant une arthrite induite par les cristaux de pyrophosphate de calcium manifestait une reponse favorable au traitement par l’anakinra : dix bonnes reponses et quatre reponses partielles. Une rechute survint chez six patients (37,5 %) (temps moyen de la rechute de 3,4 ± 4,9 mois). Un patient eut une pneumonie aigue bacterienne. Conclusion Nos resultats suggerent que l’anakinra est relativement bien tolere et pourrait etre une bonne option pour le traitement de l’arthrite induite par les cristaux de pyrophosphate de calcium. Cela illustre le fait que les anti-IL-1 pourraient etre utiles pour controler les poussees evolutives des patients porteurs d’une arthrite induite par les cristaux de pyrophosphate pour qui les therapeutiques conventionnelles sont soit inefficaces, soit contre-indiquees.

Objectives Calcium pyrophosphate (CPP) crystal-induced arthritis occurs particularly in elderly people. This population has frequently associated comorbidities and treatments, which could limit the use of conventional therapies (colchicine, non-steroidal anti-inflammatory drugs and corticosteroids). The aim of the study was to evaluate the efficacy and tolerance of anakinra in patients with CPP crystal-induced arthritis. Methods We performed a multicentric retrospective chart review of patients who received anakinra for CPP crystal-induced arthritis. Demographic information, comorbidities, co-prescription, short-term treatment outcomes, adverse event, complication and subsequent flares were reviewed. Results A total of 16 patients (12 females, mean age: 80.2 ± 11.1 years) received anakinra (100 mg subcutaneously per day). The mean number of anakinra injection was 15.5 ± 42.9 per patient (median: 3). All patients had contraindication and/or failure to conventional therapies. The majority (14 [87.5%]) of patients with CPP crystal-induced arthritis demonstrated a beneficial response to anakinra therapy: 10 good responses and four partial responses. A relapse occurred in six (37.5%) patients (mean time to relapse: 3.4 ± 4.9 months). One patient had an acute bacterial pneumonitis. Conclusion Our results suggest that anakinra is relatively well tolerated and could be a good option in the treatment of CPP crystal-induced arthritis, illustrating that IL-1β blockade may be helpful to control flares in patients having CPP crystal-induced arthritis for which conventional therapies are ineffective or contra-indicated.

Introduction : Les patients traites par biotherapie doivent en connaitre les complications. L'acquisition de competences de securite est l'un des objectifs des programmes d'education therapeutique (ETP) dans les rhumatismes inflammatoires chroniques (RIC). Objectifs : Evaluation de l'impact du programme ETP RHIN-RIC sur les competences de securite et d'autosoins de patients sous biotherapie pour un RIC. Methodes : Appreciation par le questionnaire Biosecure des competences de 80 patients sous biotherapie intraveineuse pour un RIC en hopital de jour de Rhumatologie du Groupe Hospitalier de la region Mulhouse-Sud-Alsace. Resultats : Parmi les patients, 10 % jugeaient l'information qui leur avait ete prodiguee insuffisante. Le score moyen etait de 65,9/100 (ecart-Type 19,15). Il variait significativement avec le niveau d'education (p = 0,009). Le score moyen etait significativement plus eleve chez les patients dont le traitement avait ete introduit recemment (p = 0,043). Parmi les patients, 37,5 % avaient integre le programme d'ETP. Le score Biosecure moyen etait significativement plus eleve dans le groupe ETP (71,87/100 contre 62,32/100 ; p = 0,038) et ce egalement dans le sous-groupe de niveau d'education moindre. Il n'y avait pas de difference significative sur le controle de la pathologie ou la survenue d'infections. Conclusion : Les programmes d'ETP permettent une meilleure maitrise des competences de securite, et une meilleure implication du patient dans la gestion de sa pathologie et de son traitement.

OBJECTIVES: When Sj�gren's syndrome (SS) is secondary to rheumatoid arthritis, the sicca syndrome is less serious and anti-SSA/SSB antibodies are found less frequently than in primary SS (pSS). When SS is associated with systemic lupus erythematosus, clinical and serological patterns are similar to those of pSS. We aimed to determine whether SS, accompanying systemic sclerosis (SSc), could be considered secondary to or associated with SSc and whether the coexistence of both modifies the severity and the outcome of each disease. PATIENTS AND METHODS: A retrospective multicentric study was conducted to compare (i) characteristics and complications of SS between 27 patients with SS and SSc (SS-SSc) and 202 patients with pSS, and (ii) the characteristics of SSc and complications between the SS-SSc group and 94 patients with SSc alone. RESULTS: SS features were similar in both SS-SSc and pSS patients, except for peripheral neuropathy and arthritis, which was more common in SS-SSc than in the pSS patients (P = 0.02 and 0.05, respectively). SSc appears to be less severe in patients with SS-SSc than SSc alone with a lower frequency of lung fibrosis (P = 0.05). Compared with patients with pSS or SSc alone, SS-SSc patients were more likely to have another autoimmune disorder and other autoantibodies (SS-SSc vs pSS, P = 0.02 and P = 0.03, respectively). CONCLUSION: SS seems to be associated with and not secondary to SSc. SS associated with SSc has the same features as pSS, but SSc seems to be less serious. Moreover, the association of SS and SSc is frequently accompanied by a spreading of autoimmunity.

Resume Propos. – La spondylarthrite ankylosante (SA) est un rhumatisme inflammatoire caracterise par une evolution par poussee pouvant aboutir a une ankylose progressive du rachis liee a une ossification des structures ligamentaires et discales paravertebrales. Lors de l'evolution de la SA, les patients ont significativement plus de fractures vertebrales que la population temoin. Ces fractures sont dues soit a un defaut de compliance du rachis lie a l'ankylose soit a une osteoporose secondaire a la SA. Actualites et points forts. – La physiopathologie de cette osteoporose est multifactorielle mais en rapport essentiellement avec les phenomenes inflammatoires lies a la SA. Elle se caracterise par une masse osseuse diminuee a la densitometrie osseuse (au rachis lombaire et au col femoral), un hyperremodelage osseux avec une augmentation des marqueurs urinaires du remodelage osseux (telopeptides du collagene), mais sans modification significative des parametres sanguins du bilan phosphocalcique. Sur le plan histologique, on observe une depression de la formation osseuse avec une resorption conservee ou augmentee. Perspectives. – Le depistage de cette osteoporose repose sur l'identification des sujets a risque (SA inflammatoire evolutive) grâce a l'absorptiometrie osseuse biphotonique et au dosage des marqueurs du remodelage osseux. Le traitement repose sur une modulation des phenomenes inflammatoires et du remodelage osseux grâce aux bisphosphonates et aux anti-TNF alpha.

Gene expression analysis of target organs might help provide new insights into the pathogenesis of autoimmune diseases. We used global gene expression profiling of minor salivary glands to identify patterns of gene expression in patients with primary Sjögren’s syndrome (pSS), a common and prototypic systemic autoimmune disease. Gene expression analysis allowed for differentiating most patients with pSS from controls. The expression of 23 genes in the IFN pathways, including two Toll-like receptors (TLR8 and TLR9), was significantly different between patients and controls. Furthermore, the increased expression of IFN-inducible genes, BAFF and IFN-induced transmembrane protein 1, was also demonstrated in ocular epithelial cells by quantitative RT-PCR.In vitroactivation showed that these genes were effectively modulated by IFNs in salivary gland epithelial cells, the target cells of autoimmunity in pSS. The activation of IFN pathways led us to investigate whether plasmacytoid dendritic cells were recruited in salivary glands. These IFN-producing cells were detected by immunohistochemistry in all patients with pSS, whereas none was observed in controls. In conclusion, our results support the pathogenic interaction between the innate and adaptive immune system in pSS. The persistence of the IFN signature might be related to a vicious circle, in which the environment interacts with genetic factors to drive the stimulation of salivary TLRs.

The acute oral toxicity of palytoxin (PLTX), a highly toxic compound associated with seafood intoxication in tropical and subtropical areas, was investigated in mice. After gavage administration (300-1697 microg/kg) to groups of five female CD-1 mice, signs of toxicity and lethality were recorded for 24 h. The LD(50) was 767 microg/kg (95% confidence limits: 549-1039 microg/kg) and the main symptoms observed were scratching, jumping, respiratory distress and paralysis. Hematoclinical analyses showed increased levels of creatine phosphokinase and lactate dehydrogenase at doses of 600 microg/kg and above, and aspartate transaminase at 848 microg/kg and above. Histological analysis revealed acute inflammation of the forestomach in mice surviving up to 24h after administration (424-1200 microg/kg). Other histological alterations were observed in the liver and pancreas, while cardiac and skeletal muscle cells revealed only ultrastructural alterations visible by transmission electron microscopy. Ultrastructural and hematoclinical findings suggest an involvement of skeletal and/or cardiac muscle as targets of PLTX, according to the observed human symptoms. A NOEL of 300 microg/kg can be estimated from this acute oral toxicity study.

Yessotoxin (YTX), an algal toxin contaminating edible shellfish, was previously shown to induce ultrastructural changes in some cardiac muscle cells of mice after acute (1 and 2 mg/kg) or daily repeated oral exposure (1 and 2 mg/kg/day, for 7 days). Therefore, the temporal evolution of the ultrastructural myocardial alterations and the development of other signs of toxicity induced by a repeated daily oral administration of YTX (1 mg/kg/day, for 7 days) to mice were evaluated within 3 months after the treatment. Symptoms, food consumption, body weight, gross pathology and histopathology of the main organs and tissues were observed, and plasma levels of transaminases, lactate dehydrogenase, creatinine and creatinine phosphokinase were measured. Heart, liver, kidneys and cerebellum were also analysed by transmission electron microscopy. In addition, the blood concentration of YTX was determined by a direct enzyme linked immunosorbent assay (ELISA) 24 h after the last toxin administration. No mortality or other treatment-related changes, including histological or hematoclinical parameters, were recorded in mice administered with YTX. Similarly, electron microscopy did not reveal any ultrastructural alteration in the liver, kidneys, and cerebellum associated with YTX treatment. In contrast, changes in cardiac muscle cells near to the capillaries (clusters of rounded mitochondria and disorganization of myofibrils) were observed 24 h after the treatment. These changes were also noted 30 days after the toxin administration, while after 90 days no differences in cardiac muscle cells between control and YTX-treated mice were observed, which indicated a recovery of the ultrastructural alterations induced by the toxin.

Tocilizumab (TCZ) is a humanized antihuman interleukin (IL)-6 receptor antibody recommended for the treatment of moderate to severe active rheumatoid arthritis, adult-onset Still disease, Castleman disease and more recently, systemic juvenile idiopathic arthritis. Like anti-TNFα, rituximab and less frequently abatacept, TCZ can induce paradoxical cutaneous eruption like psoriasis with predominantly palmoplantar presentation.We report a 47-year-old woman with psoriastic arthritis who developed under anti-TNFα therapy and later under tocilizumab a paradoxical palmoplantar eruption.The specific underlying mechanisms of this side effect are unclear but relapse of these lesions seems to be observed with certain biological agents.

Importance One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists. Objective To compare the efficacy of a non–TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor. Design, Setting, and Participants A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints–erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013. Interventions Patients were randomly assigned (1:1) to receive a non–TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician. Main Outcomes and Measures The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections. Results Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, −0.43; 95% CI, −0.72 to −0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003). Conclusions and Relevance Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication. Trial Registration clinicaltrials.gov Identifier:NCT01000441

The use of biological therapies for treating autoimmune diseases is increasing. These therapies are sometimes administered to pregnant women as part of a planned therapeutic regimen or to women with unexpected or unplanned pregnancies. The safety of biological therapies in this setting is a major issue. Here, we describe three young pregnant patients with autoimmune disorders: two patients with rheumatoid arthritis and one with idiopathic thrombotic thrombocytopenic purpura. These patients were exposed to rituximab (anti-CD20 monoclonal antibody) or abatacept (fusion protein CTLA4Ig) during the first trimester of their pregnancies. No significant adverse effects or complications were observed during the pregnancies, and all three patients delivered healthy newborns. In the rituximab cases, this result might be explained in part by the very low transplacental maternofetal transfer of rituximab during the first trimester of pregnancy. Despite these favorable outcomes, the use of these two biological agents must follow international recommendations. Their use is not currently allowed during pregnancy except in cases where the potential benefit to the mother justifies the potential risk to the fetus. In the case of exposure to the single agent rituximab during the first trimester, current data suggest that the low risk to the fetus may be outweighed by the potential benefit to the mother.

Non-conventional MHC class I MIC molecules interact not with the TCR, but with NKG2D, a C-type lectin activatory receptor present on most NK, gammadelta and CD8(+) alphabeta T cells. While this interaction is critical in triggering/calibrating the cytotoxic activity of these cells, the actual extent of its in vivo involvement, in man, in infection, cancer or autoimmunity, needs further assessment. The latter has gained momentum along with the reported expansion of peripheral CD4(+)CD28(-)NKG2D(+) T cells in rheumatoid arthritis (RA). We first initiated to extend this report to a larger cohort of not only RA patients, but also those affected by systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). In RA and SS, this initial observation was further tested in target tissues: the joint and the salivary glands, respectively. In conclusion and despite occasional and indiscriminate expansion of the previously incriminated T cell subpopulation, no correlation could be observed between the CD4(+)CD28(-)NKG2D(+) and auto-immunity. Moreover, in situ, the presence of NKG2D matched that of CD8(+), but not that of CD4(+) T cells. In parallel, a total body tissue scan of both MICA and MICB transcription clearly shows that despite original presumptions, and with the exception of the central nervous system, both genes are widely transcribed and therefore possibly translated and membrane-bound. Extending this analysis to a number of human tumors did not reveal a coherent pattern of expression vs. normal tissues. Collectively these data question previous assumptions, correlating a tissue-specific expression/induction of MIC in relevance to auto-immune or tumor processes.

Background According to the EULAR recommendations for the management of patients with rheumatoid arthritis (RA), the use of a biologic therapy should be done in combination with methotrexate (MTX) or another synthetic DMARD (csDMARD). However, in “real-life studies”, 30% of the patients are treated with biologic in monotherapy. Objectives Our objectives were to describe the characteristics of patients with RA receiving intravenous biologic therapy without csDMARD and the reasons for monotherapy. Methods We made an observational, retrospective and multicentric study in 3 rheumatology units in Alsace (France) between the 1/01/13 and the 31/01/14. Patients with a RA diagnosis according to the 2010 ACR criteria and treated with abatacept (ABA), infliximab (IXF), rituximab (RTX) or tocilizumab (TCZ) with no MTX, sulfazalazine, leflunomid or hydroxychloroquine for at least 3 months were included. Collected variables included patients9 characteristics (age, gender and comorbidities), RA characteristics, past and present antirheumatic therapies. Results 109 (27%) patients treated with an intravenous biologic were in monotherapy; 74% were women, mean (SD) age was 65 (12) years. Mean time (SD) since RA diagnosis was 15.2 years (9.4). 78% had rheumatoid factor and 72% anti-CCP antibodies, 80% had joint damage. Among the 109 patients, 20 (18.3%) were treated with ABA, 8 (7.3%) with IFX, 48 (44%) with RTX and 33 (30.3%) with TCZ. The mean (SD) DAS28 at the treatment initiation was 5 (1.4). The mean DAS28 (SD) at the last cure was 3.4 (1.4). The mean (SD) dose of oral corticosteroid at the last cure was 7.4 mg/d (5.5). The biologic was initiated in combination with 30% of patients and in monotherapy with 70% of patients. Patients had received a mean (SD) of 2.2 (1) synthetic DMARDs and 2.46 (1.3) biologics. 94% of patients previously received MTX, 58% MTX and LFN and 11% the 4 csDMARDs. About MTX, 43 patients were treated orally (57%), 25 subcutaneously (33%) and 7 had the 2 routes (9.3%). The mean dose before stopping MTX was 13.8mg ±4.4. Reasons for stopping MTX were: intolerance for 73% of patients, lack of effectiveness for 10% of patients, patient refusal (4%) and cancer (3%). Among withdrawals for intolerance, there was 35% of gastro-intestinal intolerance (abdominal pain, diarrhea, dyspepsia, nausea, loss of appetite), 30% of liver intolerance (ASAT and/or ALAT elevation superior to 2N), 11% of hematological intolerance and 8% of lung intolerance. 7 patients never had MTX: 6 because of medical contraindication and 1 refused. Conclusions Use of biologics in monotherapy is frequent though combination showed better control of disease progression and less immunogenicity. In our study, most patients previously received at least 2 csDMARDs. The most frequent reason for MTX withdrawal was gastrointestinal intolerance and only few patients received MTX in parenteral. In order to optimize the MTX, practitioners should give good information about side effects, try low dose of MTX, switch from oral to parenteral administration, assess the adherence to folic acid supplementation. Disclosure of Interest None declared

We report on a 65-year-old man who was hospitalized for polyarthritis with deterioration of his general state of health and chronic sinusitis. Clinical and biological signs led to the diagnosis of RA associated with localized Wegener's granulomatosis. Methotrexate and corticosteroids led to a distinct improvement in the patient's articular symptoms and in his general condition. One year after the start of treatment, a tumefaction of the right maxillary sinus appeared. Scans revealed a tumoral lesion in the right maxillary sinus. This proved to be a large B-cell lymphoma. The patient received chemotherapy (CHOP) and radiotherapy. This centrofacial lymphoma may be regarded as a B lymphoma of the MALT (mucosal associated lymphoma tumor) type, mimicking a relapse of Wegener's granulomatosis.

Background We recently reported the clinical efficacy and safety of anti-TNF-alpha in a cohort of 15 rhupus patients with rheumatoid arthris and systemic lupus (“rhupus”). TNF-alpha and type I interferon (IFN) were reported to be crossregulated in a gene expression study of patients with juvenile idiopathic arthritis. Treating with anti-TNF these patients could raise the concern of a potential overexpression of IFN-inducible genes and chemokines, which play a pathogenic role in SLE. Objectives To evaluate changes in levels of IFN-inducible genes and chemokines under treatment with anti-TNF for RA associated with SLE. Methods Among the 15 patients with RA and SLE, PBMCs and serum were collected before and after anti-TNF initiation (median: 8 months) in 6 patients. Total RNA was extracted from PBMC using the Nucleospin RNA II extraction kit according to the manufacturer’s instructions and reverse transcribed using the First Strand cDNA Synthesis Kit according to the manufacturer’s instructions (In Vitrogen). Real-time quantitative RT-PCR was performed in a total volume of 20 μl using SensiMix Plus SYBR kit (Quantace, Corbett Life Science)and gene specific primers for BAFF, IFTIMMX-1,PKR. Serum CXCL10, CCL2 and CCL19 levels were assessed using R&D ELISA. Results All 15 patients were women with a mean age of 51 years [20-75]. The mean duration of treatment was 34.7 and 33.7 (4-69) months with etanercept and adalimumab, respectively. 8.3 infections for 100 patient years occurred. No mycobacteria infection, no lymphoproliferation and no cancer were observed. Also, no cutaneous, renal or other systemic flare of SLE occurred. No death was observed. After 2 years of follow-up, the mean decrease of DAS 28 and SLEDAI was -3 [-0.75 to -4.89] -5.13 [0 – 6], respectively. Corticosteroid dosage significantly decreased from 10mg/d to 5mg/d. No statistical significant increase in gene expressions of 4 different IFN-inducible genes, BAFF (2.2 to 0 fold), MX1 (17.2 to 0 fold), IFITM (1.2 to 0 fold), and PKR (19.3 to 0 fold) Likewise, no significant change was observed in serum levels of 3 IFN-inducibles chemokines: CXCL10 (82 to 56.2 pg/ml, p=0.87), CCL2 (343.8 to 729.4 pg/ml, p=0.375) and CCL19 (316.3 to 335.9 pg/ml, p=0.875). Conclusions This study shows good short term tolerance and efficacy of anti-TNF in patients with SLE and RA (“rhupus”). The absence of increase in IFN-inducible genes and chemokines, which are validated prognostic markers of disease activity in SLE, might contribute to the absence of SLE flares observed in rhupus patients treated with anti-TNF. Disclosure of Interest None Declared

Background Calcium pyrophosphate (CPP) associated arthritis is common in elderly patients. Non-steroidal anti-inflammatory drugs (NSAID), colchicine, oral or local steroids are recommended (1), but in some patients these therapies are non-effective or contra-indicated and therapeutic alternatives are limited. Recently, the pivotal role of IL-1β in the crystal-induced inflammation has been demonstrated, and IL-1β inhibitors such as anakinra, has been shown to be effective in the treatment of acute gout arthritis (2). Objectives To evaluate the efficacy of anakinra on refractory CPP arthritis. Methods In a multicentric retrospective study, patients having proven acute or chronic CPP arthritis by CPP crystal demonstration in synovial fluid or typical X-rays were included. All the patients had failure or contra-indication to conventional therapies and received subcutaneous anakinra (100mg/day). All individuals provided informed written consent as approved by the recruiting site institutional review boards at each of the affiliate institutions. Ultrasonographic assessment, measure of pain by Visual Analogic Scale (0-100 mm VAS pain), CRP level and consummation of corticosteroids were assessed at baseline and at day 4. Results A total of 16 patients were included in this open study. Mean age was 80.2±11.1 year-old and mean symptoms duration was 3.9±3.8 months. Arthritis was localized to wrists (n=15, 88%), shoulders (n=12, 71%), knees (n=11, 65%), ankles (n=11, 59%), elbows (n=7, 47%), cervical spine (n=7, 41%), tarsal joints (n=6, 29%) and MCPs (n=4, 24%). Between baseline and day 4, IL-1β blockade led to a significant decrease of VAS pain (76.6±12.3 to 33.0±14.5 mm; P Conclusions Anakinra is an effective and relatively well-tolerated treatment of refractory CPP arthritis and should be an alternative in individuals having non-response or contra-indication to conventional therapies. References Zhang W, Doherty M, Pascual E, Barskova V, Guerne PA, Jansen TL, et al. EULAR recommendations for calcium pyrophosphate deposition. Part II: management. Ann Rheum Dis 2011;70(4):571-5. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007;9(2):R28. Disclosure of Interest None Declared