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Objectives To compare the features of difficult-to-treat rheumatoid arthritis (D2TRA) patients using two different definitions according to the previous failure of targeted therapies. Methods We stratified consecutive RA patients treated at Cochin Hospital into two groups, a D2TRA group and a non-D2TRA group, according to two definitions of D2TRA. Both definitions defined D2TRA as RAs failing at least two targeted therapies, with a different mechanism of action for the EULAR-D2TRA definition or without prejudging the mechanism of action and for the Alternative D2TRA definition. Results We included 320 consecutive RA patients. We identified 76 EULAR-D2TRA and 244 non-DTRA patients, and 120 Alternative D2TRA and 200 non-DTRA patients. Compared with non-D2TRA, D2TRA patients from both definitions were more likely to have lower socioeconomic level, positive rheumatoid factor, interstitial lung disease, higher DAS28-CRP and were more likely to respond to rituximab and Janus kinase inhibitors. Although EULAR and Alternative D2TRA patients displayed similar clinical and biological features, they were characterized by different therapeutic profiles. We observed fewer patients receiving methotrexate in the Alternative D2TRA group (53% vs 64%, P = 0.046). Patients with Alternative D2TRA not fulfilling the EULAR definition (n = 44) had all received two successive first-line TNF inhibitors, a monoclonal antibody and a soluble receptor, and were comparable to EULAR-D2TRA patients with regards to all other characteristics. Conclusion Low socioeconomic status, diabetes, interstitial lung disease and absence of combination with methotrexate allow identification of D2TRA. In addition, the inclusion as ‘early-D2TRA’ of patients failing two TNF inhibitors in the EULAR definition of D2TRA would facilitate the rapid identification of D2TRA patients.

Spondyloarthropathies (SpA) are common systemic inflammatory rheumatic diseases, in which, as in other rheumatic diseases, levels of markers of bone resorption are elevated, leading to bone loss and elevated risk of vertebral fractures. However, the diseases are also associated with new bone formation in the spine, the so-called syndesmophytes. We tried to unravel the pathogenesis of formation and growth of syndesmophytes and evaluated new diagnostic and treatment options. After a successful meeting of the Working Group on Rheumatic Diseases at the ECTS 2020, we (WL and CR) were excited about the quality of the speakers (CM, JH, AG, and GL) and their complimentary lectures. Given the relative lack of reviews on spondyloarthropathies and bone, we decided to work together on a comprehensive review that might be interesting for basic scientists and clinically relevant for clinicians. Radiographic progression in axSpA is linked to several risk factors, like male sex, smoking, HLA-B-27, increased levels of CRP, presence of syndesmophytes, and marked inflammation on MRI. The potential role of mechanical stress in the context of physically demanding jobs has been also suggested to promote structural damages. Different treatment options from NSAIDs to biologic agents like TNF inhibitors (TNFi) or IL-17inhibitors (IL-17i) result in a reduction of inflammation and symptoms. However, all these different treatment options failed to show clear and reproducible results on inhibition on syndesmophyte formation. The majority of data are available on TNFi, and some studies suggested an effect in subgroups of patients with ankylosing spondylitis. Less information is available on NSAIDs and IL-17i. Since IL-17i have been introduced quite recently, more studies are expected. IL-17 inhibitors (Il-17i) potently reduce signs and symptoms, but serum level of IL-17 is not elevated, therefore, IL-17 probably has mainly a local effect. The failure of anti-IL-23 in axSpA suggests that IL-17A production could be independent from IL-23. It may be upregulated by TNFα, resulting in lower expression of DKK1 and RANKL and an increase in osteogenesis. In active AS markers of bone resorption are increased, while bone formation markers can be increased or decreased. Bone Turnover markers and additional markers related to Wnt such as DKK1, sclerostin, and RANKL are valuable for elucidating bone metabolism on a group level and they are not (yet) able to predict individual patient outcomes. The gold standard for detection of structural lesions in clinical practice is the use of conventional radiographics. However, the resolution is low compared to the change over time and the interval for detecting changes are 2 years or more. Modern techniques offer substantial advantages such as the early detection of bone marrow edema with MRI, the fivefold increased detection rate of new or growing syndesmophytes with low-dose CT, and the decrease in 18F-fluoride uptake during treatment with TNFα-inhibitors (TNFi) in a pilot study in 12 AS patients. Detection of bone involvement by new techniques, such as low-dose CT, MRI and 18-Fluoride PET-scans, and bone turnover markers, in combination with focusing on high-risk groups such as patients with early disease, elevated CRP, syndesmophytes at baseline, male patients and patients with HLA-B27 + are promising options for the near future. However, for optimal prevention of formation of syndesmophytes we need more detailed insight in the pathogenesis of bone formation in axSpA and probably more targeted therapies.

ObjectivesTo investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA).MethodsDemographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression.ResultsOf 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25–2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39–2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42–0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19.ConclusionOlder age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics.

Objective To identify which factors influence humoral response to coronavirus disease 2019 (COVID-19) vaccination in rituximab (RTX)-treated patients. Methods This was an observational, prospective, usual care study including consecutive patients with inflammatory rheumatic diseases in maintenance therapy with RTX. All patients received a two-dose regimen COVID-19 vaccination. Serum IgG antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins were measured at the time of the new RTX infusion. Results From the recruited patients, 16/45 (36%) produced antibodies reaching the assay cut-off value of 15 AU/ml and 29/45 (64%) had a negative serology. Within RTX-treated patients, 25 (56%) had undetectable B cells. Negative serology was associated with undetectable B cells (24/25 vs 5/20, P Conclusions B cell depletion is the main independent contributing factor of antibody response to SARS-CoV-2 vaccination in RTX-treated patients. Monitoring CD19 may be of interest to identify the most appropriate period to perform vaccination.

International audience

ObjectiveTo assess whether gut microbiota composition is associated with patient characteristics and may have predictive value on the response to TNF inhibitor (TNFi) treatment in axial spondyloarthritis (AxSpA).MethodsThe study involved 61 patients fulfilling the Assessment of SpondyloArthritis International Society classification criteria for AxSpA. All patients had active disease despite non-steroidal anti-inflammatory drugs intake and were eligible for treatment with a TNFi. At baseline, the mean Ankylosing Spondylitis Disease Activity Score was 2.9±1 and mean C reactive protein (CRP) level 9.7±11.4 mg/L. Bacterial 16S ribosomal RNA gene sequencing was performed on stool samples collected at baseline (month 0 (M0)) and 3 months after TNFi initiation (month 3 (M3)). Alpha and beta diversity metrics were calculated on the relative abundance of core operational taxonomic units (OTUs).ResultsThe HLA-B27 status affected at least in part the global composition of faecal microbiota at M0 as well as the abundance/prevalence of several anaerobic bacteria in the familiesOscillospiraceae,LachnospiraceaeandBifidobacteriaceae. In contrast, smoking affected the global composition of faecal microbiota at both M0 and M3. The prevalence/abundance of seven bacterial OTUs at M0 was associated with response to TNFi treatment. One of the candidates, present only in non-responders, is the genusSutterella, and the other six candidates are in the classClostridia.ConclusionsSeveral SpA patients’ characteristics modulate the composition of gut microbiota as did TNFi treatment. Moreover, the abundance/prevalence of seven OTUs at baseline may be used as a novel non-invasive index that predicts the response to TNFi with greater accuracy than HLA-B27 status, CRP level and measures of disease activity.

Objective The hallmark of advanced axial SpA (axSpA) is spine ankylosis due to excessive ectopic bone formation. This prospective study aimed to describe the changes in serum levels of different regulators [sclerostin, dickkopf-1 (DKK-1)] and markers of bone formation [bone morphogenetic protein 7 (BMP-7)] over 5 years in early axSpA patients and to assess determinants of such changes. Methods The DEvenir des Spondyloarthropathies Indifférenciées Récentes cohort is a prospective, multicentre French study of 708 patients with early (>3 months– Results Serum BMP-7 significantly increased over time, with a median relative change of 223.7% [interquartile range (IQR) 0–10 700 (0.17 pg/ml/month), P Conclusion Serum BMP-7 change over 5 years was related with inflammation; it was increased in active disease, but the increase was low with TNFi use. Serum sclerostin levels significantly increased over time, but to a lesser degree than for serum BMP-7. Clinical trial registration https://clinicaltrials.gov/, NCT01648907.

Resume Si la France dispose de nombreux atouts dans le domaine de la sante pour devenir un leader de l’innovation (l’excellence de ses equipes de recherche, la renommee de son systeme de sante et de nombreuses startups), force est de constater qu’elle cumule des freins culturels et reglementaires qui limitent une interaction agile et performante entre les industriels et les etablissements de sante. La table ronde avait pour objectif d’optimiser l’interface entre les startups/industries et les etablissements de sante universitaires ou non. Plusieurs etablissements ont mis en place avec succes des equipes et procedures afin de faciliter cette interface, tant vis-a-vis des evaluations des technologies, de prestations de service, de transfert de materiel biologique que de collaboration RD (2) fournir aux acteurs des moyens et ressources dediees a l’innovation, en sanctuarisant un temps de travail pour l’innovation, en securisant le statut de personnel implique, et en accompagnant la recherche de financements ; (3) developper et utiliser des methodologies et des outils communs, et (4) co-concevoir et co-construire des solutions de sante innovantes, en encourageant l’emergence des lieux de creation participative et interdisciplinaire. L’ensemble de ces recommandations devrait aider a rendre l’interface entre les startups/industries et les etablissements de sante plus fluide et plus attractive pour les acteurs de la filiere sante.

The importance of interleukin-17A (IL-17A) in the pathogenesis of axial spondyloarthritis (SpA) has been demonstrated by the success of IL-17A blockade. However, the nature of the cell populations that produce this important proinflammatory cytokine remains poorly defined. We undertook this study to characterize the major IL-17A-producing blood cell populations in the peripheral blood of patients with axial SpA, with a focus on mucosal-associated invariant T (MAIT) cells, a population known to be capable of producing IL-17.We evaluated IL-17A production from 5 sorted peripheral blood cell populations, namely, MAIT cells, γδ T cells, CD4+ T cells, CD8+ T cells, and neutrophils, before and after stimulation with phorbol myristate acetate, the calcium ionophore A23187, and β-1,3-glucan. Expression of IL-17A transcripts and protein were determined using nCounter and ultra-sensitive Simoa technology, respectively. MAIT cells from the axial entheses of non-axial SpA control patients (n = 5) were further characterized using flow cytometric immunophenotyping and quantitative polymerase chain reaction, and the production of IL-17 was assessed following stimulation.On a per-cell basis, MAIT cells from peripheral blood produced the most IL-17A compared to CD4+ T cells (P 0.01), CD8+ T cells (P 0.0001), and γδ T cells (P 0.0001). IL-17A was not produced by neutrophils. Gene expression analysis also revealed significantly higher expression of IL17A and IL23R in MAIT cells. Stimulation of peripheral blood MAIT cells with anti-CD3/CD28 and IL-7 and/or IL-18 induced strong expression of IL17F. MAIT cells were present in the normal, unaffected entheses of control patients who did not have axial SpA and showed elevated AHR, JAK1, STAT4, and TGFB1 transcript expression with inducible IL-17A protein. IL-18 protein expression was evident in spinal enthesis digests.Both peripheral blood MAIT cells and resident MAIT cells in normal axial entheses contribute to the production of IL-17 and may play important roles in the pathogenesis of axial SpA.

Introduction Despite of higher disease burden, lower efficacy to biologics has been reported in female compared to male patients with ankylosing spondylitis (AS). The aim of this study was to evaluate the efficacy and safety of secukinumab by sex in patients with active AS from five phase 3 studies (MEASURE 1–5) through 52 weeks. Methods Baseline demographics, disease characteristics and efficacy outcomes at Weeks 16 and 52 were summarized for males versus females. Baseline predictor analysis used multivariable logistic regression for binary outcome measures or generalized linear model for continuous outcome measures to assess the impact of sex as one of the independent variables on selected efficacy outcomes at Week 52. Results Overall, 1031 males and 396 females were included in this analysis. Smoking status, hs-CRP, prior exposure to TNF inhibitors, BASMI occiput-to-wall and tragus-to-wall distance (cm) were higher in males, whereas MASES was higher in females. Efficacy outcomes i.e., ASAS40 responses and BASDAI change from baseline at Weeks 16 and 52 were generally comparable between males and females. Response rates were found to be significantly higher in male patients when compared with female patients only for ASDAS-CRP inactive disease (ID) at Week 52. Conclusion Comparable efficacy and safety outcomes were observed between male and female patients with active AS treated with secukinumab over 52 weeks. Further, sex was not an independent predictor of treatment response to secukinumab as assessed by ASAS40 responder rates and BASDAI change from baseline; association of ASDAS-CRP ID responder rates with sex warrants further exploration. Trial registration ClinicalTrials.gov; NCT01358175, NCT01649375, NCT02008916, NCT02159053, and NCT02896127. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00380-2.

Objectives To evaluate the characteristics of patients (pts) with PsA treated by ustekinumab (UST) or secukinumab (SEK) and to compare real-world persistence of UST and SEK in PsA. Methods In this retrospective, national, multicentre cohort study, pts with PsA (CASPAR criteria or diagnosis confirmed by the rheumatologist) initiating UST or SEK with a follow-up ≥6 months were included from January 2011 to April 2019. The persistence between SEK and UST was assessed after considering the potential confounding factors by using pre-specified propensity-score methods. Causes of discontinuation and tolerance were also collected. Results A total of 406 pts were included: 245 with UST and 161 with SEK. The persistence rate was lower in the UST group compared with the SEK group [median persistence 9.4 vs 14.7 months; 26.4% vs 38.0% at 2 years; weighted hazard ratio (HR) = 1.42; 95% CI: 1.07, 1.92; P =0.015]. In subgroup analysis, the persistence rate of SEK associated with MTX was significantly higher than that of UST associated with MTX: HR = 2.20; 95% CI: 1.30, 3.51; P =0.001, in contrast to SEK vs UST monotherapy: HR = 1.06; 95% CI: 0.74, 1.53; P =0.75. Discontinuation due to inefficacy was reported in 91.7% (SEK) and 82.4% (UST) of pts. Discontinuation due to an adverse event was reported in 12.2% (SEK) and 7.7% (UST) of pts. Conclusion In this first study comparing UST and SEK, the persistence of SEK was higher than that of UST in PsA. In subgroup analysis, this difference was only found in association with MTX.

Objective To describe which variables were collected by rheumatologists to monitor patients with rheumatoid arthritis (RA) during teleconsultation and identify which ones have more impact on clinician intervention. Methods Retrospective monocentric, routine care cross-sectional study including patients with RA seen in teleconsultation between March and September 2020. Available variables assessing disease status were collected in teleconsultation files. Clinician intervention was defined by treatment escalation and/or the need for a rapid face-to-face consultation or day hospitalization. Results One hundred forty-three patients with RA were included (116 females, mean age of 58 [SD 16] yrs, mean disease duration of 14 [SD 11] yrs). The presence or absence of patient self-reported RA flares was mentioned in all medical files, followed by the presence and/or the number of tender joints (76%), the duration of morning stiffness (66%), the number of pain-related nocturnal awakenings (66%) and the C-reactive protein (CRP) value (54%). Teleconsultation led to a clinician intervention in 22/143 patients (15%), representing 51% of patients with self-reported flares (22/43 patients). Therapeutic escalation was necessary in 13 patients and/or face-to-face consultation or day hospitalization were organized for 10 patients. Multivariate analysis identified RA flares (odds ratio [OR] 15.6, 95% CI 3.37-68.28) and CRP values > 10 mg/L (OR 3.32, 95% CI % 1.12-13.27) as the variables independently associated with clinician intervention. Conclusion Our study identified patient-reported RA flares and increased CRP values as 2 red flags in teleconsultation, independently associated with therapeutic modification and/or the need for a rapid face-to-face consultation. These indicators may help clinicians' decision making in teleconsultation.

Summary Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases. Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609. Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53). Interpretation Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases. Funding None.

International audience; Objective: Update the French Society for Rheumatology (SFR) recommendations on the everyday management of patients with spondyloarthritis, including psoriatic arthritis.Methods: Following standardized procedures, a systematic literature review was done by four supervised rheumatology residents based on questions defined by a task force of 16 attending rheumatologists. The findings were reviewed during three working meetings that culminated in each recommendation receiving a grade and the level of agreement among experts being determined.Results: Five general principles and 15 recommendations were developed. They take into account pharmacological and non-pharmacological measures along with treatment methods based on the dominant phenotype present (axial, articular, enthesitis/dactylitis) and the extra-articular manifestations (psoriasis, inflammatory bowel disease, uveitis). NSAIDs are the first-line pharmacological treatment in the various presentations. Conventional synthetic disease modifying antirheumatic drugs (csDMARDs) are not indicated in the axial and isolated entheseal forms. If the response to conventional treatment is not adequate, targeted therapies (biologics, synthetics) should be considered; the indications depend on the clinical phenotype and presence of extra-articular manifestations.Conclusion: This update incorporates recent data (published since the prior update in 2018) and the predominant clinical phenotype concept. It aims to help physicians with the everyday management of patients affected by spondyloarthritis, including psoriatic arthritis.

• Objectives: to estimate the seroprevalence of SARS-CoV-2 infection in patients with rheumatic diseases and to specify the proportion of asymptomatic and symptomatic forms of COVID-19. • Methods: we screened for SARS-CoV-2 infection among spondyloarthritis (SpA, n=143) or rheumatoid arthritis (RA, n=140) patients in our outpatient clinic at Cochin Hospital in Paris between June and August 2020. We performed a qualitative SARS-CoV-2 serological test which detects IgG directed against the N nucleocapsid protein (anti-N) and, for some patients, against the Spike protein (anti-S). Descriptive analyses were managed. • Results: during June–August 2020, the SARS-CoV-2 seroprevalence rate in our population was 2.83% (8/283 patients) without significant difference between RA and SpA patients (2.14% and 3.5% respectively). We report 11 out of 283 patients (3.8%) with a diagnosis of SARS-CoV-2 infection. Among these 11 patients, 1 patient was asymptomatic (9%) with a confirmed diagnosis of COVID-19 by anti-S serology. Of the 283 patients, 85% were under bDMARDs, mainly on rituximab (RTX) (n=44) and infliximab (IFX) (n= 136). • Conclusions: the seroprevalence of SARS-CoV-2 in patients with rheumatic diseases, mainly under bDMARDs treatments, was 2.83%. Among infected patients, 9% were asymptomatic. Detecting SARS-CoV-2 infections could be based on the strategy using patients’ interview and anti-N serology.

To describe the switch to biosimilar etanercept (bETN), evaluate factors associated with this switch, and evaluate the efficacy of this switch in a real-life setting METHODS: We included patients, from October 2016 to April 2017, with rheumatoid arthritis (RA) and spondyloarthritis (SpA) who received innovator ETN (iETN) for at least 6 months. After receiving information on biosimilars, all physicians were invited to propose a switch from iETN to bETN. Factors associated with bETN discontinuation were explored by univariate and multivariate analyses. We estimated the proportion of patients still on bETN over time by Kaplan-Meier survival analysis. We assessed serum trough concentrations of iETN and bETN and anti-drug antibodies to ETN.Overall, 183 outpatients were eligible for a potential switch; 94 (51.6%) switched from iETN to bETN. The probability of a switch was greater with an older than younger aged physician (mean [SD] age 50.4 [14.3] with a switch vs 44.8 [11.3] with no switch, p = 0.005) and the physician having a full-time academic position than other position (56.4% with a switch vs 13.5% with no switch, p 0.001). After a 6-month follow-up, bETN retention rate was 83% (95% CI: 0.76-0.92). The first cause of bETN discontinuation was inefficacy (50%). On multivariate analysis, no factor was independently associated with a bETN switch or discontinuation. Drug trough levels did not significantly differ by discontinuation or continuation of bETN. No patient showed anti-drug antibodies.The probability of switching from iETN to bETN was likely related to physician characteristics.

Although France has numerous assets in the realm of health care, such as the excellence of its research teams, the reputation of its healthcare system, and the presence of many startups, all of which are necessary to become a leader in innovation, it also has combined cultural and regulatory barriers that limit the flexibility and efficiency of interactions between companies/startups and public health institutions. Therefore, the aim of the roundtable discussion was to optimize the interface between those businesses and institutions. Several institutions have successfully implemented teams and procedures which aim to facilitate this interface, with regard to assessments of technology, services provided, the transfer of biological material, RD collaboration, and licensing agreements. However, there is still a notable absence of entrepreneurial culture among hospital and academic research practitioners; their training regarding innovation remains insufficient and business-related value-creation is non-existent in their career evolution. Pharmaceutical companies, and particularly startups, often lack knowledge about hospital environments and their constraints. As a result, the recommendations of the roundtable participants are as follows: (1) promote reciprocal acculturation between public health institutions and startups through multidisciplinary training in innovation, promoting project development and staff recognition within the institution, and improving pharmaceutical companies' understanding regarding the health care system; (2) provide those involved with means and resources dedicated to innovation by reserving time for innovation at work, securing the status of the staff involved, and aiding in the search for funding; (3) develop and use standard methodologies and tools; and (4) co-design and co-construct innovative health solutions, encouraging the emergence of participatory and interdisciplinary creative spaces. All of these recommendations should help to make the interface between startups/companies and public health institutions more fluid and attractive for those in the health sector.

International audience; Introduction: IgA nephropathy (IgAN) can be associated with spondyloarthritis (SpA). The course of SpA-associated IgAN remains largely unknown due to the absence of large cohorts.Methods: This retrospective study included patients with biopsy-proven IgAN and definite SpA. Kidney biopsies were centrally examined and scored according to the IgAN Oxford Classification. Thirty-two patients fulfilled the inclusion criteria, with a male:female ratio of 9:1 and median age of 27 and 37 years at SpA and IgAN diagnosis, respectively. HLA-B27 was positive in 90% of cases, and most patients (60%) presented with ankylosing spondylitis. The mean baseline estimated glomerular filtration rate (eGFR) was 84 ± 26 ml/min per 1.73 m2, and the urine protein-to-creatinine ratio was 0.19 g/mmol.Results: Renal biopsy revealed frequent presence of crescents (33%) and interstitial inflammation (18%). Despite almost constant use of renin-angiotensin system inhibitors, combined with steroids in 13 of 32 patients, renal outcome was particularly poor. After a median follow-up of 5.9 years, 4 patients (12.5%) reached end-stage renal disease and 41% of patients experienced a >50% decrease of eGFR. The mean annual eGFR decline rate was -4.3 ± 6.7 ml/min per 1.73 m2. The risk of reaching class IV or V chronic kidney disease (CKD) stage during follow-up was associated with the presence of hypertension, level of proteinuria, and baseline S- and T-scores of the Oxford.Conclusion: SpA-associated IgAN is associated with a poor renal outcome, despite frequent use of steroids. Tumor necrosis factor (TNF)-α blockade did not appear to influence the rate of eGFR decline in this setting.

To study in daily practice the risk of immunogenicity of patients treated with the biosimilar rituximab (RTX) GP2013 used for chronic inflammatory rheumatic disorders.A prospective monocentric routine care study was carried out between September 2018 and May 2021, including consecutive patients treated with the biosimilar RTX GP2013. Biosamples were taken before each infusion to quantify anti-RTX antibodies (ADAbs) and serum RTX trough levels by ELISA (Lisa Tracker Duo Rituximab, LTR005, Theradiag).168 GP2013-treated patients were included (129 who switched from originator RTX and 39 originator RTX naïve). The analysis of 602 samples identified 15 patients (8%) with positive ADAbs including 6 and 9 with transient and persistent ADAbs, respectively. The switch from originator RTX to GP2013 did not increase the risk of immunogenicity, with an incidence rate of 0.8 for 100 patient years. The frequency of persistent ADAs was higher in non-RA patients (5/56, 9% vs. 4/112, 3.5%). Patients with positive persistent ADAbs were more frequently non-caucasian (7/9, 78%, vs. 56/159, 35%, p0.01) and all had detectable circulating B cells (vs. 40% in ADAb-negative patients, P0.001). ADAb positivity was not associated with disease activity or RTX discontinuation but patients with ADAb titers100 ng/mL experienced reduced treatment efficacy or severe infusion-related reaction.Within the study duration, the immunogenicity of GP2013 is a rare event affecting the pharmacodynamics of RTX. Although development of ADAbs had no impact on treatment discontinuation, possible harmful consequences may be observed in patients with high antibody levels.

Resume Objectif L’immunogenicite du tocilizumab (TCZ) a ete peu etudiee. Nous avons evalue l’immunogenicite du TCZ et les taux seriques residuels de TCZ chez des patients atteints de polyarthrite rhumatoide (PR), ainsi que le repertoire de cellules T CD4 specifiques du TCZ preexistantes chez des sujets sains. Methodes Les anticorps (Ac) anti-TCZ et les taux seriques residuels de TCZ ont ete quantifies par Elisa chez des patients atteints de PR a differents temps. La frequence de cellules T CD4+ naives anti-TCZ a ete etudiee chez des sujets sains. Resultats Au total, 91 echantillons provenant de 40 patients atteints de PR ont ete analyses : pour 21 patients dans les 6 premiers mois apres le debut du traitement et pour 19 patients au cours du suivi, apres une duree moyenne de traitement par le TCZ de 21 ± 13 mois. Aucun des 91 patients ne presentait d’Ac anti-TCZ persistant. Seuls 3 patients atteints de PR presentaient des titres transitoires et faibles d’Ac anti-TCZ. Les concentrations residuelles seriques de TCZ n’etaient associees ni aux caracteristiques des patients (sexe, indice de masse corporelle), ni a l’activite de la maladie, et etaient identiques que les patients aient recu ou non un co-traitement avec du methotrexate. Des cellules T CD4+ preexistantes specifiques du TZC etaient detectees chez 3 des 9 sujets sains, a un faible taux. Conclusion Les taux seriques residuels de TCZ ne dependent pas des caracteristiques des patients. L’apparition d’Ac anti-TCZ etait rare. Les frequences de precurseurs de cellules T CD4+ specifiques du TZC ou specifiques de l’infliximab etant comparables chez les donneurs sains. Des lors, il est possible que la faible prevalence d’Ac anti-TCZ resulte du blocage de l’interleukine-6.

Objective.Spondyloarthritis (SpA) and Takayasu arteritis (TA) are 2 chronic inflammatory diseases; their coexistence in a single patient is uncommon. The aims of our study were to describe clinical features of patients having SpA associated with TA and to identify some characteristics of the types of patients with SpA associated with TA. We also analyzed treatments used in this context.Methods.This French multicenter retrospective survey called for observations on behalf of the Club Rhumatismes et Inflammations, with a standardized questionnaire established by the investigators.Results.We included 14 patients (women: 10/14; median age at SpA diagnosis: 43.5 yrs, ranging from 19 to 63). Subtypes of SpA were ankylosing spondylitis (n = 11), psoriatic arthritis (n = 2), and synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome (n = 1). HLA-B27 was positive in 3 cases, negative in 9, and unknown in 2. SpA was diagnosed before TA in 13 cases. Imaging findings compatible with the diagnosis of TA were found with computed tomography (11/14) and/or Doppler ultrasound (10/14). Laboratory tests showed increased acute-phase reactants in all cases (C-reactive protein ≥ 25 mg/l in 71% of the cases). All patients except 1 received corticosteroids and 7 were treated with anti–tumor necrosis factor (anti-TNF).Conclusion.Association of SpA and TA is rare but probably not coincidental. Peripheral pulse palpation and vascular auscultation should be systematic and are the first indicators of TA in patients with SpA. Moreover, increased acute-phase reactants during SpA followup should lead to search for TA. Finally, there are therapeutic implications because anti-TNF are efficient in SpA and might be efficient in TA.

Item does not contain fulltext OBJECTIVE: In many rheumatoid arthritis (RA) patients, disease is controlled with anti-tumor necrosis factor (anti-TNF) biologic therapies. However, in a significant number of patients, the disease fails to respond to anti-TNF therapy. We undertook the present study to examine the hypothesis that rare and low-frequency genetic variants might influence response to anti-TNF treatment. METHODS: We sequenced the coding region of 750 genes in 1,094 RA patients of European ancestry who were treated with anti-TNF. After quality control, 690 genes were included in the analysis. We applied single-variant association and gene-based association tests to identify variants associated with anti-TNF treatment response. In addition, given the key mechanistic role of TNF, we performed gene set analyses of 27 TNF pathway genes. RESULTS: We identified 14,420 functional variants, of which 6,934 were predicted as nonsynonymous 2,136 of which were further predicted to be "damaging." Despite the fact that the study was well powered, no single variant or gene showed study-wide significant association with change in the outcome measures disease activity or European League Against Rheumatism response. Intriguingly, we observed 3 genes, of 27 with nominal signals of association (P < 0.05), that were involved in the TNF signaling pathway. However, when we performed a rigorous gene set enrichment analysis based on association P value ranking, we observed no evidence of enrichment of association at genes involved in the TNF pathway (Penrichment = 0.15, based on phenotype permutations). CONCLUSION: Our findings suggest that rare and low-frequency protein-coding variants in TNF signaling pathway genes or other genes do not contribute substantially to anti-TNF treatment response in patients with RA.

Background The burden of ankylosing spondylitis (AS) is reported to be higher in female patients (pts). In addition, females show less improvement in AS outcome measures as compared to males when treated with tumour necrosis factor (TNF) inhibitors.1,2 Currently, there are no data available on the efficacy of secukinumab (SEC) in males versus females. Objectives To compare the efficacy of SEC in pts with active AS by gender (male vs female) from data pooled from four phase 3 studies (MEASURE 1-4). Methods This post hoc analysis pooled data from the MEASURE 1-4 trials. Baseline (BL) demographics and disease characteristics were summarized across genders. Efficacy outcomes assessed at Week (Wk) 16 and 52 were ASAS20, ASAS40, ASDAS-ID, BASDAI, BASMI, BASFI, SF-36 PCS and FACIT-F. BL predictor analysis used multivariable logistic regression (binary variables) or generalized linear model (continuous variables) to assess the impact of gender as an independent variable on ASAS40, ASDAS-ID, and BASDAI at Wk 52, after adjusting for treatment group and other baseline factors in a pooled analysis across studies and treatment groups. Results Overall, 647 males and 322 females who received SEC 300mg IV load (LD) (n=76), 150mg IV LD (n=199), 150mg s.c. LD (n=188), 150mg no LD (n=117), and placebo (n=389), respectively, were included in the analysis. At BL, significant differences in TNFi, HLA-B27, and smoking status were observed between genders. MASES scores were significantly higher in females; hs-CRP, BASMI-occiput to wall, and BASMI tragus to wall distance scores were significantly higher in males. Efficacy outcomes were generally similar in males and females (Figure 1). There was no significant impact of gender as an independent predictor of SEC efficacy at Wk 52 as measured by ASAS40 (Odds ratio [OR] 1.1; P=0.50), ASDAS-ID (OR 1.32; P=0.16) or change in BASDAI (treatment effect, -0.17; P=0.82). Conclusion Similar efficacy outcomes were observed in male and female patients with active ankylosing spondylitis treated with secukinumab over 52 weeks. References [1] Rusman Tet al, Int J Rheum Dis. 2018; 21: 836–42. [2] van der Horst-Bruinsma IEet al, Ann Rheum Dis. 2013;72:1221–4. Disclosure of Interests Irene van der Horst-Bruinsma Grant/research support from: MSD, Pfizer, AbbVie, Consultant for: Abbvie, UCB, MSD, Novartis, Speakers bureau: BMS, AbbVie, Pfizer, MSD, Corinne Miceli Richard Grant/research support from: MSD, Pfizer, AbbVie, Biogen, UCB, Novartis, Consultant for: Abbvie, Novartis, BMS, Juergen Braun Shareholder of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Grant/research support from: Abbott, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Johnson & Johnson, MSD, Novartis, Pfizer, Roche, UCB Pharma, Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Grant/research support from: Abbvie (Abbott), Amgen, Baxter, Biogen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Hexal, Janssen, Lilly, Medac, MSD (Schering-Plough), Mylan, Mundipharma, Novartis, Pfizer (Wyeth, Hospira), Roche, Sanofi-Aventis and UCB, Consultant for: Abbvie (Abbott), Amgen, Baxter, Biogen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Hexal, Janssen, Lilly, Medac, MSD (Schering-Plough), Mylan, Mundipharma, Novartis, Pfizer (Wyeth, Hospira), Roche, Sanofi-Aventis and UCB, Consultant for: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Consultant for: Abbott, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Johnson & Johnson, MSD, Novartis, Pfizer, Roche, UCB Pharma, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Speakers bureau: Abbvie (Abbott), Amgen, Baxter, Biogen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Hexal, Janssen, Lilly, Medac, MSD (Schering-Plough), Mylan, Mundipharma, Novartis, Pfizer (Wyeth, Hospira), Roche, Sanofi-Aventis and UCB, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB, Weibin Bao Employee of: Novartis, Brian Porter Shareholder of: Novartis, Employee of: Novartis, Effie Pournara Shareholder of: Novartis, Employee of: Novartis