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Introduction: Combining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo. Methods: Endpoints at week 16 included proportions of responders (C 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, IntroductionCombining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo.MethodsEndpoints at week 16 included proportions of responders (≥ 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, and sustained weekly average pain responders.ResultsPooled population comprised 1545 patients. Of patients who had a ≥ 30% improvement in WOMAC Pain and/or WOMAC Physical Function, 88.5% were WOMAC Pain/Function composite responders, 7.0% were WOMAC Pain (but not Function) responders, and 4.4% were WOMAC Function (but not Pain) responders. Of weekly average pain responders, 43.1% were PASS composite responders. Odds ratios (tanezumab 2.5 mg and 5 mg groups, respectively, vs placebo) were 1.75 and 1.86 (WOMAC Pain/Function composite responders), 1.41 and 1.65 (weekly average pain responders), 1.60 and 1.73 (PASS composite responders), 1.52 and 1.68 (MCII composite responders), 1.75 and 1.88 (OMERACT-OARSI responders), and 1.85 and 1.48 (sustained weekly average pain responders). Subgroup analyses suggested a greater magnitude of effect for patients with a knee index joint compared with hip on some endpoints.ConclusionResponders on single pain endpoints were in many cases also responders on function or composite endpoints. Separation of tanezumab from placebo was similar and consistent across single and composite endpoints.

Objective To report the 10-year outcome of an inception cohort of patients with early rheumatoid arthritis (RA), the ESPOIR cohort, and predictors of outcome. Methods From 2003 to 2005, 813 patients were included if they had early arthritis ( Results In total, 521 (64.1%) RA patients were followed up for 10 years; 35 (4.3%) died, which appears to be similar to the French general population. Overall, 480 (92.1%) patients received a DMARD; 174 (33.4%) received at least one biologic DMARD, 13.6% within 2 years. At year 10, 273 (52.4%) patients were in DAS28 remission, 40.1% in sustained remission, 14.1% in drug-free remission, 39.7% in CDAI remission. Half of the patients achieved a health assessment questionnaire-disability index (HAQ-DI) < 0.5. SF-36 physical component and pain were well controlled. Structural progression was weak, with a mean change from baseline in modified Sharp score of 11.0 (17.9). Only 34 (6.5%) patients required major joint surgery. A substantial number of patients showed new comorbidities over 10 years. Positivity for anti-citrullinated peptides antibodies (ACPA) was confirmed as a robust predictor of long-term outcome. Conclusions We report a very mild 10-year outcome of a large cohort of patients with early RA diagnosed in the early 2000s, which was much better than results for a previous cohort of patients who were recruited in 1993. This current favourable outcome may be related to more intensive care for real-life patients.

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 …

International audience; Objective. To evaluate the impact of telemedicine use during the coronavirus disease 2019 (COVID-19) pandemic on rheumatology trainees. Methods. A voluntary, anonymous, web-based survey was administered in English, Spanish, or French from August 19 to October 5, 2020. Adult and pediatric rheumatology trainees were invited to participate via social media and email. Using multiple-choice questions and Likert scales, the survey assessed prior and current telemedicine use, impact on training, and supervision after COVID-19 prompted rapid telemedicine implementation. Results. Surveys were received from 302 trainees from 33 countries, with 83% in adult rheumatology training programs. Reported telemedicine use increased from 13% before the pandemic to 82% during the pandemic. United States trainees predominantly used video visits, whereas outside the United States telemedicine was predominantly audio only. Most (65%) evaluated new patients using telemedicine. More respondents were comfortable using telemedicine for follow-up patients (69%) than for new patients (25%). Only 39% of respondents reported receiving telemedicine-focused training, including instruction on software, clinical skills, and billing, whereas more than half of United States trainees (59%) had training. Postconsultation verbal discussion was the most frequent form of supervision; 24% reported no supervision. Trainees found that telemedicine negatively impacted supervision (50%) and the quality of clinical teaching received (70%), with only 9% reporting a positive impact. Conclusions. Despite widespread uptake of telemedicine, a low proportion of trainees received telemedicine training, and many lacked comfort in evaluating patients, particularly new patients. Inadequate supervision and clinical teaching were areas of concern. If telemedicine remains in widespread use, ensuring appropriate trainee supervision and teaching should be prioritized. No funding was received for this study. The views expressed here are those of the authors and participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology, the European League Against Rheumatism, or any other organization.

AIM To assess the impact of pre-specified patient characteristics on efficacy and safety of subcutaneous tanezumab in patients with osteoarthritis (OA). METHODS Data were pooled from two (efficacy; N = 1545) or three (safety; N = 1754) phase 3 placebo-controlled trials. Change from baseline to week 16 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function and patient global assessment of OA (PGA-OA) scores was compared between tanezumab (2.5 and 5 mg) and placebo groups via analysis of covariance. Treatment-emergent adverse events (TEAEs) were summarised descriptively. Analyses were done in patient subgroups (men or women; age

BackgroundWe describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine.MethodsFrom 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination.ResultsWe analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%.ConclusionAmong adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.

Objective: Despite its prevalence, there are few worldwide hand osteoarthritis (HOA) cohorts. The main objective of DIGItal COhort Design (DIGICOD) cohort is to investigate prognostic clinical, biological, genetic and imaging factors of clinical worsening after 6 years follow-up.Methods: DIGICOD is a hospital-based prospective cohort including patients > 35 years-old with symptomatic HOA fulfilling: (i) ACR criteria for HOA with > 2 symptomatic joints among proximal/distal interphalangeal joints or 1st interphalangeal joint with Kellgren-Lawrence (KL) > 2; or (ii) symptomatic thumb base OA with KL > 2. Main exclusion criteria were inflammatory arthritis and crystal arthropathies. Annual clinical evaluations were scheduled with imaging (X-rays of the hands and of other OA symptomatic joints) and biological sampling every 3 years. Hand radiographs are scored using KL and anatomical Verbruggen-Veys scores. Follow-up visits are ongoing. Cohort methodology and baseline characteristics are presented.Results: Between April 2013 and June 2017, from the 436 HOA included patients, 426 have been analysed of whom 357 (84%) are women. Mean age +/- standard deviation was 66.7 +/- 7.3 years and mean disease duration was 12.6 +/- 9.6 years. Metabolic syndrome affected 151 (36.5%) patients. Mean Visual Analog Scale (VAS) hand pain (0-100 mm) was 44.4 +/- 26.7 mm at activity. Mean FIHOA (0-100) was 19.9 + 18.6. Elevated serum CRP level (>= 5 mg/L) involved 10% patients. Mean KL score (0-128) was 46.7 +/- 18 and the mean number ofjoint with KL >= 2 was 15.1 +/- 6.3. Erosive HOA (defined as >= 1 Erosive or Remodeling phase joint according to Verbruggen-Veys score) involved 195/426 (45.8%) patients and the median number (interquartile range) of erosive joints in erosive patients was 3.0 (1.0-5.0).Conclusion: DIGICOD is a unique prospective HOA cohort with a long-term 6 years standardized assessment and has included severe radiologically HOA patients with a high prevalence of erosive disease. 2021 Societe francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

Background: The impact and consequences of the COVID-19 pandemic on people with rheumatic disease are unclear. We developed the COVID-19 Global Rheumatology Alliance Patient Experience Survey to assess the effects of the COVID-19 pandemic on people with rheumatic disease worldwide. Methods: Survey questions were developed by key stakeholder groups and disseminated worldwide through social media, websites, and patient support organisations. Questions included demographics, rheumatic disease diagnosis, COVID-19 diagnosis, adoption of protective behaviours to mitigate COVID-19 exposure, medication access and changes, health-care access and communication with rheumatologists, and changes in employment or schooling. Adults age 18 years and older with inflammatory or autoimmune rheumatic diseases were eligible for inclusion. We included participants with and without a COVID-19 diagnosis. We excluded participants reporting only non-inflammatory rheumatic diseases such as fibromyalgia or osteoarthritis. Findings: 12 117 responses to the survey were received between April 3 and May 8, 2020, and of these, 10 407 respondents had included appropriate age data. We included complete responses from 9300 adults with rheumatic disease (mean age 46·1 years; 8375 [90·1%] women, 893 [9·6%] men, and 32 [0·3%] participants who identified as non-binary). 6273 (67·5%) of respondents identified as White, 1565 (16·8%) as Latin American, 198 (2·1%) as Black, 190 (2·0%) as Asian, and 42 (0·5%) as Native American or Aboriginal or First Nation. The most common rheumatic disease diagnoses included rheumatoid arthritis (3636 [39·1%] of 9300), systemic lupus erythematosus (2882 [31·0%]), and Sjogren's syndrome (1290 [13·9%]). Most respondents (6921 [82·0%] of 8441) continued their antirheumatic medications as prescribed. Almost all (9266 [99·7%] of 9297) respondents adopted protective behaviours to limit SARS-CoV-2 exposure. A change in employment status occurred in 2524 (27·1%) of 9300) of respondents, with a 13·6% decrease in the number in full-time employment (from 4066 to 3514). Interpretation: People with rheumatic disease maintained therapy and followed public health advice to mitigate the risks of COVID-19. Substantial employment status changes occurred, with potential implications for health-care access, medication affordability, mental health, and rheumatic disease activity. Funding: American College of Rheumatology.

International audience; The cholinergic system has been proposed as a potential regulator of COVID-19-induced hypercytokinemia. We investigated whole-blood expression of cholinergic system members and correlated it with COVID-19 severity. Patients with confirmed SARS-CoV-2 infection and healthy aged-matched controls were included in this non-interventional study. A whole blood sample was drawn between 9-11 days after symptoms onset, and peripheral leukocyte phenotyping, cytokines measurement, RNA expression and plasma viral load were determined. Additionally, whole-blood expression of native alpha-7 nicotinic subunit and its negative dominant duplicate (CHRFAM7A), choline acetyltransferase and acetylcholine esterase (AchE) were determined. Thirty-seven patients with COVID-19 (10 moderate, 11 severe and 16 with critical disease) and 14 controls were included. Expression of CHRFAM7A was significantly lower in critical COVID-19 patients compared to controls. COVID-19 patients not expressing CHRFAM7A had higher levels of CRP, more extended pulmonary lesions and displayed more pronounced lymphopenia. COVID-19 patients without CHRFAM7A expression also showed increased TNF pathway expression in whole blood. AchE was also expressed in 30 COVID-19 patients and in all controls. COVID-19-induced hypercytokinemia is associated with decreased expression of the pro-inflammatory dominant negative duplicate CHRFAM7A. Expression of this duplicate might be considered before targeting the cholinergic system in COVID-19 with nicotine. Coronavirus disease 19 (COVID-19) is characterized by clinical heterogeneity, with severity ranging from asymptomatic patients to critical and life-threatening disease 1. Severe and critical COVID-19 are characterized by an acute respiratory distress syndrome (ARDS) driven by an exacerbated inflammatory response that can lead to multi-organ failure and death 2. This hypercytokinemia, initially named "cytokine storm", is associated with high levels of circulating tumor necrosis factor (TNF) and interleukin-6 (IL-6), profound peripheral blood lymphopenia and chemoattraction of mononuclear cells within the lungs 3-5. Overall, this imbalanced inflammatory response is responsible for tissue damage and disease severity.

Objective: To assess the efficacy and safety of the anti–interleukin‐1α/β (anti–IL‐1α/β) dual variable domain immunoglobulin lutikizumab (ABT‐981) in patients with knee osteoarthritis (OA) and evidence of synovitis. Methods: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2–3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI‐assessed synovitis at week 26. Results: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab‐treated and placebo‐treated patients. Changes from baseline in MRI‐assessed synovitis at week 26 and other key symptom‐ and most structure‐related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high‐sensitivity C‐reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations. Conclusion: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL‐1 inhibitors, suggest that IL‐1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.

ObjectiveTo assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1α/β dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA).MethodsPatients with ≥1 erosive and ≥3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates.ResultsOf 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI –1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1α and IL-1β levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67).ConclusionDespite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo.

Objective: To determine the prevalence, distribution and characteristics associated with radiographic metacarpophalangeal (MCP) osteoarthritis (OA). Methods: This is a cross‐sectional study of baseline data from the DIGItal Cohort Osteoarthritis Design, a French monocentric cohort including patients with symptomatic hand OA (HOA). We evaluated the prevalence of radiographic MCP OA defined as ≥2 MCP joints with a Kellgren and Lawrence score ≥2. We compared the prevalence of MCP OA in the dominant and non‐dominant hands. Associations between radiographic MCP OA and patient characteristics were studied using univariable and multivariable logistic regression. Results: Radiographic MCP OA was present in 138 of the 425 patients (32.5%) but was not severe. Patients with MCP OA had a mean age of 69.2±6.9 years, a BMI of 25±4.2 kg/m2, and 86.2% were women. MCP OA was more frequent in the dominant hand and predominated at the 1st and 2nd MCP joints. In the multivariable analysis, MCP OA was associated with older age (OR 1.05, 95%CI [1.01,1.10] for each year), manual occupation (OR 3.74, 95%CI [1.21,11.54]), scaphotrapezial OA (OR 2.18, 95%CI [1.27,3.72]), and a high number of proximal interphalangeal joints with radiographic OA. MCP OA was not associated with metabolic syndrome or HOA symptoms. Conclusion: In this cross‐sectional study using a hospital‐based HOA cohort, radiographic MCP OA was frequent and associated with structural HOA features rather than with symptom severity. Our results suggest that the involvement of MCP joints in HOA is predominantly related to mechanical rather than systemic factors in this population.

ObjectivesTo evaluate an intervention to reduce the nocebo effect (NE) when switching from the originator infliximab (OI) to the infliximab biosimilar SB2 in chronic inflammatory rheumatic disease (CIRD).MethodsAn intervention was built with healthcare professionals (HPs) and a patient representative, based on a systematic review of interventions reducing the NE in musculoskeletal diseases and semi-directed questioning of five patients. Our strategy consisted of training HPs, switch information given by the nurses, a consistent vocabulary. All CIRD patients switched from OI to SB2 were included for the intervention. The primary outcome was the SB2 retention rate (RR) at 34 weeks. Secondary outcomes were the SB2 RR at 12 months, discontinuation rates due to a possible NE and comparison with a historical cohort of CIRD patients receiving the OI and 6 published European cohorts.Results45 patients were included from March 2018 (rheumatoid arthritis, n=17, spondylarthritis, n=28). After 34 weeks, the SB2 RR was 91.2%, similar to the historical cohort RR (p=0.41) but higher than the 3 European cohort RRs (pConclusionsA tailored communication with a prominent role of nurses reduced the NE in non-medical switches from the OI to SB2 as compared to published results. The RR was similar to the historical cohort RR. The methodology used to construct this intervention may help improve the outcomes of switches with upcoming biosimilars.

Highlights • The SFR selected the most critical questions Rheumatologists must contend in the management of their patients with rheumatic diseases during COVID-19 pandemic • A group of 10 experts from SFR and CRI boards proposed responses based on the current knowledge of May 2020. • In most circumstances, there is no contraindication to the initiation or continuation of anti-inflammatory drugs as well as DMARDs. • If signs suggestive of infection (coronavirus or other) occurs, treatments should be discontinued and resumed, if necessary, after 2 weeks without any symptoms., Background: Rheumatologists must contend with COVID-19 pandemic in the management of their patients and many questions have been raised on the use of both anti-inflammatory drugs and disease-modifying anti-rheumatic drugs (DMARD). The French Society of Rheumatology (SFR) selected the most critical ones to the daily practice of a rheumatologist and a group of 10 experts from SFR and Club Rheumatism and Inflammation (CRI) boards proposed responses based on the current knowledge of May 2020. Basic procedure: Following the availability of the first 18 questions and statements, 1400 individuals consulted the frequently asked questions between the March 31, 2020 and April 12, 2020. As a result, 16 additional questions were forwarded to the SFR, and answered by the board. An additional round of review by email and video conference was organized, which included updates of the previous statements. The scientific relevance of 5 of the questions led to their inclusion in this document. Each response received a final assessment on a scale of 0–10 with 0 meaning no agreement whatsoever and 10 being in complete agreement. The mean values of these votes for each question are presented as the levels of agreement (LoA) at the end of each response. This document was last updated on April 17, 2020. Main findings: Based on current scientific literature already published, in most circumstances, there is no contraindication to the initiation or continuation of anti-inflammatory drugs as well as DMARDs. If signs suggestive of infection (coronavirus or other) occurs, treatments should be discontinued and resumed, if necessary, after 2 weeks without any symptoms. Only, some signals suggest that people taking an immunosuppressive dose of corticosteroid therapy are at greater risk of developing severe COVID-19. Intra-articular injections of glucocorticoids are allowed when there is no reasonable therapeutic alternative, and providing that precautions to protect the patient and the practitioner from viral contamination are adopted, included appropriate information to the patient. Principal conclusions: Currently available data on managing patients with rheumatic diseases during the COVID-19 pandemic are reassuring and support continuing or initiating symptomatic as well as specific treatments of these diseases, the main target of their management remaining their appropriate control, even during this pandemic.

Objective Antirheumatic disease therapies have been used to treat coronavirus disease 2019 (COVID‐19) and its complications. We conducted a systematic review and meta‐analysis to describe the current evidence. Methods A search of published and preprint databases in all languages was performed. Included studies described one or more relevant clinical outcomes in five or more people who were infected with SARS‐CoV‐2 and were treated with antirheumatic disease therapy between 01/01/2019 and 05/29/2020. Pairs of reviewers screened articles and extracted data and assessed risk of bias. A meta‐analysis of effect sizes using the random‐effects models was performed when possible. Results The search identified 3,935 articles, of which 45 were included (4 randomized controlled trials, 29 cohort studies, and 12 case series). All studies evaluated hospitalized patients and 29 out of 45 had been published in a peer‐reviewed journal. In a meta‐analysis of three cohort studies with a low risk of bias, hydroxychloroquine use was not significantly associated with mortality (pooled hazard ratio (HR) 1.41, 95% confidence interval (CI) 0.83‐2.42). In a meta‐analysis of two cohort studies with some concerns/high risk of bias, anakinra use was associated with lower mortality (pooled HR 0.2, 95% CI 0.1‐0.4). Evidence was inconclusive with regard to other antirheumatic disease therapies and the majority of other studies had a high risk of bias. Conclusion In this systematic review and meta‐analysis, hydroxychloroquine use was not associated with benefit or harm with regard to COVID‐19 mortality. The evidence supporting the effect of other antirheumatic disease therapies in COVID‐19 is currently inconclusive.

To establish recommendations for pharmacological treatment of knee osteoarthritis specific to France.On behalf of the French Society of Rheumatology (SFR), a bibliography group analyzed the literature on the efficacy and safety of each pharmacological treatment for knee osteoarthritis. This group joined a multidisciplinary working group to draw up recommendations. Strength of recommendation and quality of evidence level were assigned to each recommendation. A review committee gave its level of agreement.Five general principles were established: 1) need to combine pharmacological and non-pharmacological treatments, 2) personalization of treatment, 3) symptomatic and/or functional aim of pharmacological treatments, 4) need to regularly re-assess the treatments and 5) discussion about arthroplasty if medical treatment fails. Six recommendations involved oral treatments: 1) paracetamol should not necessarily be prescribed systematically and/or continuously, 2) NSAIDs, possibly as first-line, 3) weak opioids, 4) strong opioids, 5) symptomatic slow-acting drugs of osteoarthritis, and 6) duloxetine (off-label use). Two recommendations involved topical agents (NSAIDs and capsaicin1%). Three recommendations involved intra-articular treatments: corticosteroid or hyaluronic acid injections that can be proposed to patients. The experts did not draw a conclusion about the benefits of platelet-rich plasma injections.These are the first recommendations of the SFR on the pharmacological treatment of knee osteoarthritis.

OBJECTIVE The non-neuronal cholinergic system represents non-neuronal cells that have the biochemical machinery to synthetize de novo and/or respond to acetylcholine (ACh). We undertook this study to investigate this biochemical machinery in chondrocytes and its involvement in osteoarthritis (OA). METHODS Expression of the biochemical machinery for ACh metabolism and nicotinic ACh receptors (nAChR), particularly α7-nAChR, in human OA and murine chondrocytes was determined by polymerase chain reaction and ligand-binding. We investigated the messenger RNA expression of the human duplicate α7-nACh subunit, called CHRFAM7A, which is responsible for truncated α7-nAChR. We assessed the effect of nAChR on chondrocytes activated by interleukin-1β (IL-1β) and the involvement of α7-nAChR using chondrocytes from wild-type (WT) and α7-deficient Chrna7-/- mice. The role of α7-nAChR in OA was explored after medial meniscectomy in WT and Chrna7-/- mice. RESULTS Human and murine chondrocytes express the biochemical partners of the non-neuronal cholinergic system and a functional α7-nAChR at their cell surface (n = 5 experiments with 5 samples each). The expression of CHRFAM7A in human OA chondrocytes (n = 23 samples) correlated positively with matrix metalloproteinase 3 (MMP-3) (r = 0.38, P < 0.05) and MMP-13 (r = 0.48, P < 0.05) expression. Nicotine decreased the IL-1β-induced IL-6 and MMP expression, in a dose-dependent manner, in WT chondrocytes but not in Chrna7-/- chondrocytes. Chrna7-/- mice that underwent meniscectomy (n = 7) displayed more severe OA cartilage damage (mean ± SD Osteoarthritis Research Society International [OARSI] score 4.46 ± 1.09) compared to WT mice that underwent meniscectomy (n = 9) (mean ± SD OARSI score 3.05 ± 0.9; P < 0.05). CONCLUSION The non-neuronal cholinergic system is functionally expressed in chondrocytes. Stimulation of nAChR induces antiinflammatory and anticatabolic activity through α7-nAChR, but the anticatabolic activity may be mitigated by truncated α7-nAChR in human chondrocytes. In vivo experiments strongly suggest that α7-nAChR has a protective role in OA.

Background Considering the role of metabolic diseases in osteoarthritis (OA), we investigated whether biomarkers of adipose tissue dysfunction could be associated with OA-related pain. Design We cross-sectionally analyzed patients with knee and/or hip OA at inclusion in the KHOALA cohort. We used visual analogic scale (VAS) for pain, the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Osteoarthritis Knee and Hip Quality of Life (OAKHQOL) pain subscores. At inclusion, we measured ultra-sensitive CRP (usCRP), leptin and adiponectin for calculation of leptin:adiponectin ratio (LAR), a marker of adipose tissue dysfunction associated with central adiposity, high-molecular-weight adiponectin, visfatin and apolipoproteins. Univariate and multivariable analyses using stepwise linear regression models were performed to search for correlation between pain assessments and these biomarkers, with systematic adjustment on age. Results In 596 women with hip and/or knee OA, multivariable analyses indicated that higher pain intensity was associated with higher LAR (VAS pain: β=0.49; p = 0.0001, OAKHQOL pain: β=-0.46; p = 0.0002, WOMAC pain: β=0.30; p = 0.001) in the whole group as well as in hip or knee OA patients considered separately. Pain intensity correlated also with usCRP level (VAS pain: β= 0.27; p = 0.02, OAKHQOL pain: β =-0.30; p = 0.01) and Kellgren-Lawrence score. In 267 men, no correlation between biomarkers and pain was found. Conclusion Serum LAR and usCRP level are associated with pain level, independently of radiographic structural severity in women with hip and/or knee OA, emphasizing the role of adipose tissue dysfunction and of meta-inflammation in pain experience in the female population.

Background Osteoarthritis (OA) causes pain, disability and impaired quality of life. Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the management of OA pain. Two randomised, placebo-controlled studies with a primary aim of assessing the efficacy and safety of subcutaneously administered tanezumab were recently completed as part of a phase 3 OA programme, and the data reported, separately. Here we report pooled analyses of secondary efficacy outcomes from these two trials: Outcome Measures in Rheumatology - Osteoarthritis Research Society International (OMERACT-OARSI) treatment response and EuroQol 5 Dimension (EQ-5D-5L) questionnaire. Methods Both studies enrolled patients with moderate-to-severe OA of the hip or knee, for whom standard care was inadequate or unsuitable. In study one (NCT02709486) with primary endpoint at Week 24, patients received three doses of placebo, tanezumab 2.5 mg or tanezumab 5 mg (at baseline/Week 8/Week 16). Study two was a dose-titration study (NCT02697773) with primary endpoint at Week 16, where patients received two doses of: placebo at baseline/Week 8 (pooled with study one placebo group), tanezumab 2.5 mg at baseline/Week 8 (pooled with study one tanezumab 2.5 mg group) or tanezumab 2.5 mg at baseline/tanezumab 5 mg at Week 8 (pooled with study one tanezumab 5 mg group). The current analysis assessed differences between pooled groups in OMERACT-OARSI treatment response, and EQ-5D-5L questionnaire responses and overall utility scores, at Week 16. Results A total of 1,545 patients were evaluated. At Week 16 in the pooled analyses, more patients in the tanezumab 2.5 mg (76.0%, 390/513) or tanezumab 5 mg (77.4%, 400/517) groups than the placebo group (64.7%, 332/513) met the criteria for OMERACT-OARSI response (each p < 0.0001 versus placebo). Patients in the pooled placebo, tanezumab 2.5 mg and 5 mg groups, respectively, recorded their baseline pain/discomfort (EQ-5D-5L) as none (1.8%, 1.0%, 0.6%), slight (7.6%, 9.7%, 8.9%), moderate (52.6%, 50.7%, 50.7%), severe (35.1%, 36.3%, 36.4%) or extreme (2.9%, 2.3%, 3.5%). At Week 16, patients recorded their pain/discomfort as none (12.8%, 15.4%, 15.8%), slight (37.3%, 44.3%, 44.8%), moderate (40.6%, 33.9%, 32.0%), severe (8.8%, 6.4%, 6.4%) or extreme (0.4%, 0.0%, 1.0%). Improvements in mobility, self-care, usual activities and anxiety/depression were also seen. At Week 16, the change from baseline in EQ-5D-5L utility score was greater for the pooled tanezumab 2.5 mg group (difference in least squares means [95% confidence interval], 0.03 [0.01, 0.05], p = 0.0083) or tanezumab 5 mg group (0.04 [0.01, 0.06], p = 0.0015) compared with placebo. Conclusion Together, pooled analyses from these studies show that significant improvements in the composite measure OMERACT-OARSI response are accompanied by significant improvements in overall health status as assessed by the EQ-5D-5L utility score at Week 16 for tanezumab-treated patients compared with placebo. These studies were sponsored by Pfizer and Eli Lilly and Company. Disclosures D. Walsh: Consultancies; consulting fees (non-personal, pecuniary interest) from Pfizer, Lilly, GlaxoSmithKline, AbbVie, Medscape Education, Love Productions. T.J. Schnitzer: Consultancies; TJS has received consulting fees from Pfizer, Lilly, AbbVie, Aptinyx, Genzyme, Regeneron, and Vertex. Grants/research support; TJS has engaged in clinical research for AbbVie, Grünenthal, and Radius. F. Berenbaum: Consultancies; Consulting fees/remuneration from AbbVie, Merck, Regulaxis, 4P Pharma, Bone Therapeutics, Galapagos, Peptinov, Expanscience, Flexion, Janssen, MerckSerono, Novartis, Roche, Gilead, Sanofi, GlaxoSm. S. Howland: Corporate appointments; SH is an employee of Pfizer Ltd. Shareholder/stock ownership; SH holds Pfizer stock options. S. Wilhelm: Corporate appointments; SW is a Lilly employee. Shareholder/stock ownership; SW holds Lilly stock and/or stock options. R. Junor: Corporate appointments; RJ is an employee of Pfizer Ltd. Shareholder/stock ownership; RJ holds Pfizer stock and/or stock options.

Globally, osteoarthritis (OA) is the most prevalent arthritic condition in those aged over 60 years. OA has a high impact on patient disability and is associated with a significant economic burden. Pain is the most common first sign of disease and the leading cause of disability. Data demonstrating the increasing global prevalence of OA, together with a greater understanding of the burden of the disease, have led to a reassessment of the seriousness of OA and calls for the designation of OA as a serious disease in line with the diseases impact on comorbidity, disability, and mortality. While OA was traditionally seen as a prototypical 'wear and tear' disease, it is now more accurately thought of as a disease of the whole joint involving cartilage together with subchondral bone and synovium. As more has become known of the pathophysiology of OA, it has become increasingly common for it to be described using a number of overlapping phenotypes. Patients with OA will likely experience multiple phenotypes during their disease. This review focuses on what we feel are three key phenotypes: post-trauma, metabolic, and aging. A greater understanding of OA phenotypes, particularly at the early stages of disease, may be necessary to improve treatment outcomes. In the future, non-pharmacological and pharmacological treatments could be tailored to patients based on the key features of their phenotype and disease pathway.

PurposeThe Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium intends to prospectively describe in detail, preselected patients with knee osteoarthritis (OA), using conventional and novel clinical, imaging, and biochemical markers, to support OA drug development.ParticipantsAPPROACH is a prospective cohort study including 297 patients with tibiofemoral OA, according to the American College of Rheumatology classification criteria. Patients were (pre)selected from existing cohorts using machine learning models, developed on data from the CHECK cohort, to display a high likelihood of radiographic joint space width (JSW) loss and/or knee pain progression.Findings to dateSelection appeared logistically feasible and baseline characteristics of the cohort demonstrated an OA population with more severe disease: age 66.5 (SD 7.1) vs 68.1 (7.7) years, min-JSW 2.5 (1.3) vs 2.1 (1.0) mm and Knee injury and Osteoarthritis Outcome Score pain 31.3 (19.7) vs 17.7 (14.6), except for age, all: pFuture plansPatients will visit the hospital again at 6, 12 and 24 months for physical examination, pain and general health questionnaires, collection of blood and urine, MRI scans, radiographs of knees and hands, CT scan of the knee, low radiation whole-body CT, HandScan, motion analysis and performance-based tests.After two years, data will show whether those patients with the highest probabilities for progression experienced disease progression as compared to those wit lower probabilities (model validation) and whether phenotypes/endotypes can be identified and predicted to facilitate targeted drug therapy.Trial registration numberNCT03883568

Objectives Further knowledge about typical hand osteoarthritis (OA) characteristics is needed for the development of new classification criteria for hand OA. Methods In a cross-sectional multi-centre international study, a convenience sample of patients from primary and secondary/tertiary care with a physician-based hand OA diagnosis (n = 128) were compared with controls with hand complaints due to inflammatory or non-inflammatory conditions (n = 70). We examined whether self-reported, clinical, radiographic and laboratory findings were associated with hand OA using logistic regression analyses. Discrimination between groups was assessed by calculating the area under receiver operating curves (AUC). Results Strong associations with hand OA were observed for radiographic osteophytes (OR = 1.62, 95 CI 1.40 to 1.88) and joint space narrowing (JSN) (OR = 1.57, 95 CI 1.36 to 1.82) in the distal interphalangeal (DIP) joints with excellent discrimination (AUC = 0.82 for both). For osteophytes and JSN, we found acceptable discrimination between groups in the proximal interphalangeal joints (AUC = 0.77 and 0.78, respectively), but poorer discrimination in the first carpometacarpal joints (AUC = 0.67 and 0.63, respectively). Painful DIP joints were associated with hand OA, but were less able to discriminate between groups (AUC = 0.67). Age and family history of OA were positively associated with hand OA, whereas negative associations were found for pain, stiffness and soft tissue swelling in metacarpophalangeal joints, pain and marginal erosions in wrists, longer morning stiffness, inflammatory biomarkers and autoantibodies. Conclusions Differences in symptoms, clinical findings, radiographic changes and laboratory tests were found in patients with hand OA versus controls. Radiographic OA features, especially in DIP joints, were best suited to discriminate between groups., The project on the development of new classification criteria for hand OA is funded by EULAR

Hydroxychloroquine, an essential treatment for many patients with rheumatologic conditions, has garnered widespread attention as a potential treatment for COVID-19 infection. The authors appraise t...

Osteoarticular involvement in systemic sclerosis (SSc) is frequent and varied. Data are scarce on the prevalence and risk factors of osteoporosis (OP). We aimed to assess clinical parameters, radiological parameters, US articular involvements, and the frequency of OP and evaluate SSc-specific risk factors. In a prospective cohort of 54 patients with SSc, data of OP risk factors, SSc organ involvements, tender and swollen joint counts, DAS28-CRP, hand US sonographies, X-ray hand views, and bone mineral density (BMD) were assessed. BMD values were compared to those from a healthy female population (OFELY cohort). Nineteen patients (40%) had OP. SSc was a risk factor of lower BMD in the patient group than in the control group. OP was associated with SSc-related risk factors and not with conventional OP risk factors. Nine patients had clinical synovitis (16%), and 23 (68%) patients had at least one US synovitis. No correlation was found with articular destruction, disease severity, autoantibody profile, or other organ impairment.

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Background:ESPOIR is a longitudinal prospective cohort of adults with possible early RA (ClinicalTrials.gov: NCT03666091). Patients were referred by rheumatologists and general practitioners to one of the 14 regional centers in France. The objective and design of the cohort are described elsewhere (1). Patients received standard of care by their rheumatologists and were followed without predefined therapeutic strategiesObjectives:To report the current 10-year outcome of patients with early rheumatoid arthritis (RA) in the ESPOIR cohort, and predictors of outcome.Methods:From 2003 to 2005, 813 patients were included if they had early arthritis (< 6 months) with a high probability of RA developing and had never been prescribed disease modifying anti-rheumatic drugs (DMARDs). Multivariate logistic regression analysis was used to evaluate predictors of outcome.Results:In total, 521 (64.1%) RA patients were followed up for 10 years and 35 (4.3%) died, which appears similar to the French general population. Overall, 480 (92.1%) patients received a DMARD; 174/521 (33.4%) received at least one biologic DMARD, 13.6 and 23.4% within 2 and 5 years. At year 10 (Table), mean DAS28 ESR was 2.5 ± 1.3; 273 (52.4%) patients were in DAS28 remission, 39.7% in CDAI remission, 40.1% in DAS28 sustained remission, and 14.1% in drug-free remission. Disability was well controlled overtime (Figure) and half of the patients achieved a HAQ Disability Index < 0.5; the SF-36 physical component and pain were well controlled. Structural progression was weak, with a mean change from baseline in modified Sharp score of 11.0 ± 17.9. A total of 82 (16.5%) patients required joint surgery including arthroplasty or arthrodesis in only 6.5% of the cases. A substantial number of patients showed new comorbidities, mainly cardiovascular or metabolic diseases over 10 years. Finally, positivity for anti-citrullinated protein antibodies was confirmed as a robust predictor of long-term outcome in patients with early RA.Table 1.Outcome in ESPOIR cohort and 1993 cohort at 10 yearsESPOIR cohort n=5211993 cohort n=112DAS28 ESR2.5 ± 1.3DAS44-2.2 ± 0.9SDAI7.5 ± 8.7CDAI6.8 ±8.3DAS28 ESR remission (n (%)273 (52.4)CDAI remission207 (39.7)DAS28 sustained remission, n (%)209 (40.1)DAS28 drug-free remission, n (%)75 (14.1)DAS28 ESR LDA336 (64.5)Rheumatoid nodules39 (7.5)Sicca syndrome314 (60.3)Patient global assessment24.0 ± 24.0HAQ DI score0.5 ± 0.60.75 ± 0.71HAQ DI < 0.5, n (%)280 (54.5)SF36 MCS46.7 ± 10.5SF36 PCS44.6 ± 9.2Pain (mm, VAS)16.6 ± 20.6Fatigue (mm, VAS)31.4 ± 27.023.2 ± 23.0ESR (mm/hr)14.4 ± 13.818.4 ± 16.5CRP level (mg/l)6.4 ± 16.59.3 ± 11.7Normal CRP (< 5 mg/l), n (%)336 (67.6)Total mSharp score*13.8 ± 19.635.4 ± 46.1Erosion score4.9 ± 9.418.4 ± 26.5)Joint narrowing score8.9 ± 12.132.1 ±23.2Joint surgery82 (16.5)26 (23.2)Joint arthroplasty/arthrodesis34 (6.5)20 (17.9)Data are mean (SD)DAS28, disease activity in 28 joints; HAQ DI, Health Assessment Questionnaire Disability Index; SF36 MCS, Medial Outcomes Study 36-item Short Form mental component summary; SF36 PCS, Medical Outcomes Study 36-item Short Form physical component summary; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; VAS, visual analog scale; CDAI, Clinical Disease Activity Index; SDAI, Simple Disease Activity Index; *van der Heijde-modified Total Sharp scoreFigure 1.Health Assessment Questionnaire Disability Index (HAQ-DI) over 10 years Data are mean (SD).Conclusion:We report a very mild 10-year outcome of a large inception cohort of patients with early RA diagnosed in the early 2000s, which was much better than results for a previous cohort of early RA patients who were recruited in 1993. This current favourable outcome may be related to more intensive care for real-life patients than previously.References:[1]Combe B et al. Jt Bone Spine Rev Rhum. 2007;74:440–5Acknowledgements:We thank MC Boissier, G Falgaronne and F. Lioté for help in patient recruitment. An unrestricted grant from Merck Sharp and Dohme (MSD) was allocated for the first 5 years of the cohort study. Two additional grants from INSERM supported part of the biological database. The French Society of Rheumatology, Abbvie, Pfizer, Lilly and more recently Fresenius and Biogen supported the ESPOIR cohort.Disclosure of Interests:Bernard Combe Speakers bureau: AbbVie; BMS; Gilead; Lilly; Merck; Pfizer; Roche-Chugai;, Consultant of: AbbVie; BMS; Gilead; Janssen; Lilly; Merck; Novartis; Pfizer; Roche-Chugai; and Sanofi;, Grant/research support from: Fresenius, Novartis, Pfizer, and Roche-Chugai., Nathalie Rincheval: None declared, Francis Berenbaum Speakers bureau: Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4Moving Biotech, 4P Pharma, Consultant of: Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4Moving Biotech, 4P Pharma, Patrick BOUMIER: None declared, Alain Cantagrel Speakers bureau: AbbVie; Amgen, Bristol-Myers Squibb; Grunenthal; Lilly; Medac; MSD France; Novartis; Pfizer; Roche-Chugai; Sanofi;, Consultant of: AbbVie; Amgen, Bristol-Myers Squibb; Grunenthal; Lilly; Medac; MSD France; Novartis; Pfizer; Roche-Chugai; Sanofi;, Grant/research support from: Abbvie, Fresenius, MSD France, Novartis, Pfizer, and UCB, Philippe Dieudé Speakers bureau: Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, Medac, Novartis Roche-Genentech, Sanofi, Consultant of: Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, Medac, Novartis Roche-Genentech, Sanofi, Grant/research support from: Bristol-Myers Squibb, GlaxoSmithKline, Pfizer., Maxime Dougados Speakers bureau: Pfizer, Abbvie, Lilly, UCB, Merck, BMS, Roche, Biogen, Sanofi, Novartis, and Sandoz, Consultant of: Pfizer, Abbvie, Lilly, UCB, Merck, BMS, Roche, Biogen, Sanofi, Novartis, and Sandoz, Grant/research support from: Pfizer, Abbvie, Lilly, UCB, Merck, BMS, Roche, Biogen, Sanofi, Novartis, and Sandoz, Bruno Fautrel Speakers bureau: AbbVie, Amgen, Biogen, BMS, Celgene, Celltrion, Fresenius Kabi, Gilead, Janssen, Lilly, Medac, MSD, Mylan, NORDIC Pharma, Novartis, Pfizer, Roche, Sandoz, Sanofi-Genzyme, SOBI, UCB, Consultant of: AbbVie, Amgen, Biogen, BMS, Celgene, Celltrion, Fresenius Kabi, Gilead, Janssen, Lilly, Medac, MSD, Mylan, NORDIC Pharma, Novartis, Pfizer, Roche, Sandoz, Sanofi-Genzyme, SOBI, UCB, Grant/research support from: AbbVie, Lilly, MSD and Pfizer, René-Marc Flipo Speakers bureau: Abbvie, Biogen, BMS, Janssen, MSD, Nordic, Novartis, Pfizer, Roche-Chugai and Sanofi-Genzyme, Consultant of: Abbvie, Biogen, BMS, Janssen, MSD, Nordic, Novartis, Pfizer, Roche-Chugai and Sanofi-Genzyme, Grant/research support from: Abbvie, Janssen, Novartis, Pfizer and Roche-Chugai, Philippe Goupille Speakers bureau: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Janssen, Lilly, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB., Consultant of: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Janssen, Lilly, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB., Grant/research support from: Abbvie, Biogen, MSD, Pfizer, Xavier Mariette Speakers bureau: BMS, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Servier, and UCB., Consultant of: BMS, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Servier, and UCB., Grant/research support from: Servier, Alain Saraux Speakers bureau: AbbVie, Bristol-Myers Squibb, Lilly, Nordic, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Lilly, Nordic, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB, Grant/research support from: Roche-Chugai, Thierry Schaeverbeke Speakers bureau: AbbVie, BMS, Lilly, Novartis, Nordic Pharma, Pfizer, Roche, UCB, Consultant of: AbbVie, BMS, Lilly, Novartis, Nordic Pharma, Pfizer, Roche, UCB, Grant/research support from: Pfizer, AbbVie, BMS, Roche, UCB, Astra, MSD, Rigel, AB-sciences, Jean Sibilia Speakers bureau: AbbVie, Lilly, MSD, Amgen, Pfizer, BMS, Janssen, Roche, Sandoz, Sanofi-Genzyme, SOBI, UCB, Novartis., Consultant of: AbbVie, Lilly, MSD, Amgen, Pfizer, BMS, Janssen, Roche, Sandoz, Sanofi-Genzyme, SOBI, UCB, Novartis., Grant/research support from: AbbVie, Lilly, Pfizer, Roche, Olivier VITTECOQ Speakers bureau: AbbVie, Bristol-Myers Squibb, Gilead, Lilly, Merck, Novartis, Pfizer; Roche-Chugai, Mylan and Sanofi, Consultant of: AbbVie, Bristol-Myers Squibb, Gilead, Lilly, Merck, Novartis, Pfizer; Roche-Chugai, Mylan and Sanofi, Grant/research support from: Novartis, Pfizer, Merck, and Bristol-Myers Squibb, Jean-Pierre Daures: None declared

Objective Knee osteoarthritis (OA) is a frequent degenerative disease representing an important health and economic burden. Symptomatic medical treatments available include intra-articular (IA) injections of corticosteroids (GC) but their efficacy and safety profile are debated. Methods We performed a systematic literature review (SLR) and a meta-analysis (MA) of randomized controlled trials (RCTs) assessing the effect of IA GC injections for knee OA. The effect of the interventions on pain and function was extracted from the single studies and pooled. Standardized mean differences (SMD) are reported. Results Of 520 studies screened, 23 were included in the SLR and 15 subsequently included in the MA. IA GC showed a trend towards a superior effect compared to control on both pain (SMD −0.61 (95% CI: −1.25, 0.03)) and function (SMD −1.02 (95% CI: −2.14, 0.10)) in short term follow-up (≤ 6 weeks), while long term follow-up (≥ 24 weeks) analysis showed a trend towards superiority of controls (IA HA, IA NSAID, physiotherapy) for pain (SMD 0.68 (95% CI: −0.11, 1.47)) and function (SMD 0.88 (95% CI: −0.36, 2.12). There were no differences between interventions in medium term (> 6 weeks & Conclusion In this work, IA GC injections reduced pain and improved function early after administration (≤ 6 weeks) compared to placebo; while this result was no longer statistically significant with other comparators (IA hyaluronic acid or physiotherapy). Other interventions seem to be more efficient in the long term (≥ 24 weeks) but this effect was largely driven by single studies with large effect sizes.

[Asbtract] Epidemiological findings support the hypothesis that type 2 diabetes mellitus (T2DM) is a risk factor for osteoarthritis (OA). Moreover, OA cartilage from patients with T2DM exhibits a greater response to inflammatory stress, but the molecular mechanism is unclear. To investigate whether the antioxidant defense system participates in this response, we examined here the expression of nuclear factor-erythroid 2-related factor (Nrf-2), a master antioxidant transcription factor, and of heme oxygenase-1 (HO-1), one of its main target genes, in OA cartilage from T2DM and non-T2DM patients as well as in murine chondrocytes exposed to high glucose (HG). Ex vivo experiments indicated that Nrf-2 and HO-1 expression is reduced in T2DM versus non-T2DM OA cartilage (0.57-fold Nrf-2 and 0.34-fold HO-1), and prostaglandin E2 (PGE2) release was increased in samples with low HO-1 expression. HG-exposed, IL-1β-stimulated chondrocytes had lower Nrf-2 levels in vitro, particularly in the nuclear fraction, than chondrocytes exposed to normal glucose (NG). Accordingly, HO-1 levels were also decreased (0.49-fold) in these cells. The HO-1 inducer cobalt protoporphyrin IX more efficiently attenuated PGE2 and IL-6 release in HG+IL-1β-treated cells than in NG+IL-1β-treated cells. Greater reductions in HO-1 expression and increase in PGE2/IL-6 production were observed in HG+IL-1β-stimulated chondrocytes from Nrf-2−/− mice than in chondrocytes from wild-type mice. We conclude that the Nrf-2/HO-1 axis is a critical pathway in the hyperglucidic-mediated dysregulation of chondrocytes. Impairments in this antioxidant system may explain the greater inflammatory responsiveness of OA cartilage from T2DM patients and may inform treatments of such patients. Agence Nationale de la Recherche (France); ANR-11-IDEX-0004-02

Background Nocebo effect (NE) defines any declared negative side effect of a drug that is non-specific, non-explained by its pharmacokinetic, and non-dose dependant. Recently, it has been pointed out as the main factor that reduces the retention rate of switches from a biologic originator (BO) to biosimilars (BS) in rheumatology. Objectives To identify the risk factors (RFs) and interventions strategies to reduce the NE in rheumatism and musculoskeletal diseases (RMDs), and more specifically in BS switches. Methods MEDLINE, Embase and Cochrane databases were systematically searched (inception to 15th November 2018) using relevant keywords: search1: “musculoskeletal diseases” and “nocebo” or “non-specific side effect” (NS-SE); search2: “biosimilars” and “nocebo” or “non-specific side effect”. Inclusion criteria were: studies on pharmacological treatments, studies investigating RFs for NE or NS-SEs, studies specifically describing an intervention aimed to reduce NE. Studies on non-RMDs and fibromyalgia were excluded. Results Of 212 and 639 references screened respectively in search1 and search2, 151 duplications were deleted, 32 mentioning NE or equivalent were read in full text by 2 independent investigators and consensually selected. No study met inclusion criteria for NE risk factors: 6 studies investigated the RFs of discontinuation after switch to BS, 3 with etanercept (ETN), 3 with infliximab (IFX), one investigated risk factors of back switch (meaning return from BS ETN to BO ETN), one study analyzed a genetic factor of intolerance to methotrexate (MTX) in juvenile idiopathic arthritis (JIA) and one study assessed the RFs for overall discontinuation of biologics. Although contextual factors were mentioned, no study tested RFs on NE responders only. RFs for a negative outcome were low self-efficacy, small-size rheumatology department, early start of IFX BS after its introduction on the market. Only 5 studies met the inclusion criteria for specific interventions to reduce NE. One was about countermeasures used to reduce MTX intolerance in children with JIA: including covert dosing and taste masking, with no significant results. The other four studies aimed to reduce NE related to a switch: by a shared decision-making method (ETN, one study), another by a structured communication strategy (ETN, one study) and two by a standardized information (ETN, one study; IFX, one study). Rate of NS-SE was mentioned in 3 studies, and the outcome (NS-SE rate compared to NE-SE rate of control group) was mentioned in only 2 studies. However, the assessment of intervention efficacy was not possible, since comparison was performed with historical cohorts. Conclusion Although nocebo effect is an important issue in rheumatology, especially as an explicative factor for limiting the retention rate when switching from biologic originators to biosimilars, its risk factors and intervention strategies to prevent it are poorly known. Our results encourage studies to better understand the risk factors associated with nocebo effect and the means to reduce it, particularly in the context of switches from bio-originators to biosimilars. Disclosure of Interests None declared

Background Tanezumab, a monoclonal antibody against nerve growth factor, is in development for treatment of osteoarthritis (OA) pain. Objectives To assess efficacy and safety of tanezumab in patients with moderate to severe OA pain who have not responded to or cannot tolerate standard of care analgesics. Methods A randomized, double-blind, placebo-controlled study (24 week treatment; 24 week follow-up) was conducted in patients in Europe and Japan with moderate to severe OA pain of the knee or hip and history of insufficient pain relief or intolerance to acetaminophen, oral nonsteroidal anti-inflammatory drug, and either tramadol or opioids (or unwilling to take opioids). Patients received subcutaneous tanezumab (2.5 or 5 mg) or placebo at baseline, week 8, and week 16. Co-primary endpoints were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, and Patient Global Assessment of OA (PGA-OA) scores at week 24. Safety, including independent adjudication of joint safety events, was assessed. Results Tanezumab 5 mg met all co-primary endpoints (Fig. 1). Tanezumab 2.5 mg met WOMAC Pain and Physical Function endpoints but not the PGA-OA endpoint; thus, this dose did not meet pre-specified efficacy criteria. The occurrence of adverse events (AEs) and discontinuations due to AEs were similar across groups, though serious AEs occurred more frequently in both tanezumab groups relative to placebo. Two deaths in the 5 mg tanezumab group were deemed unrelated to treatment. The only AE occurring in =3% of patients in any group, and more frequently (>1% difference) in both tanezumab groups relative to placebo, was OA. Total joint replacements (TJR) occurred in 6.7%, 7.8%, and 7.0% of patients in the placebo, tanezumab 2.5 mg, and tanezumab 5 mg groups, respectively. Joint safety events, including TJRs, were mostly adjudicated as normal progression of OA (58/79; 73.4%). Pre-specified joint safety events occurred in 0% and 2.5% (n = 14) of patients in the placebo and tanezumab (2.5 mg = 1.8%; 5 mg = 3.2%) groups, respectively. These 14 events in the tanezumab groups included rapidly progressive OA (2.5 mg n = 4; 5 mg n = 8), subchondral insufficiency fracture (2.5 mg n = 1), and primary osteonecrosis (5 mg n = 1). Conclusion Tanezumab 5 mg significantly improved all co-primary endpoints of pain, physical function, and PGA-OA. Tanezumab 2.5 mg significantly improved pain and physical function, but did not reach significance on PGA-OA. AEs are consistent with previous studies of tanezumab in OA. A similar number of TJRs were reported across groups, though overall joint safety events were more frequent with tanezumab than placebo. Disclosure of Interests Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (throughinstitution), Consultant for: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Francisco J. Blanco Grant/research support from: Galapagos NV, Abbvie, Sanofi, Bristol MS, UCB, Novartis, Genentech Inc., Regeneron, Lilly, Celgene, Amgen, Janssen, kiniksa Pharmaceuticals, Ltd., Tedec Meiji., Consultant for: Pfizer, Gebro, Bioiberica, Sanofi., Ali Guermazi Consultant for: AstraZeneca, Pfizer, TissueGene, Galapagos, Roche and MerckSerono., Eric Vignon Consultant for: Pfizer/Eli Lilly, Kenji Miki Speakers bureau: Pfizer, Janssen, Ayumi, Hisamitsu, Takaharu Yamabe Shareholder of: Pfizer, Employee of: Pfizer, Lars Viktrup Shareholder of: Eli Lilly & Company, Grant/research support from: Astella, Lundbeck, Coloplast, Employee of: Ciba Geigy, Eli Lilly and Company (currently), Rod Junor Shareholder of: Pfizer, Employee of: Pfizer, William Carey Shareholder of: Pfizer, Employee of: J&J, Pfizer (currently), Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ken Verburg Shareholder of: Pfizer, Employee of: Pfizer, Christine West Shareholder of: Pfizer, Employee of: Pfizer

Background: Biologic Disease Modifying Anti-Rheumatic Drugs (bDMARD) tapering is possible in rheumatoid arthritis (RA) patients in sustained remission. However, only minimal data are available on progressive tapering of non-TNF bDMARD such as tocilizumab (TCZ) or abatacept (ABA). Objectives: The TOLEDO (Towards the Lowest Efficacious Dose) trial aimed to assess the impact on disease activity of progressive spacing of TCZ or ABA in RA patients in sustained remission compared to their maintenance at full dose. Methods: In this multicenter open-label non-inferiority randomized controlled trial, patients fulfilling ACR-EULAR 2010 criteria for RA were included if they were 1) treated with ABA or TCZ for ≥ 1 year (monotherapy or in combination with csDMARD, corticosteroid allowed at a dose ≤ 5 mg/day), 2) in DAS28VS remission (DAS28 3.2, and DAS28 >3.2 not recovered at the following visit despite bDMARD escalation at previous step) were also compared between the 2 arms. Analysis were done per protocol (PP) according to a non-inferiority hypothesis (non-inferiority margin at 0.25 for DAS44 and 0.07 for relapse rates). Results: 117 patients were randomized in Spacing arm and 116 in Maintenance arm (90 and 112 respectively for PP analysis). 165 (72.4%) patients were treated with TCZ and 63 (27.6%) with ABA. At the end of the follow-up in the Spacing arm, 12.4% of patients were able to discontinue their bDMARD (step 4), 38.9% had tapered them (step 1 to 3) and 23.9% needed to go back to initial step (step 0). In terms of disease activity, the non-inferiority of the Spacing strategy in terms of disease activity (DAS44) was not demonstrated for the whole population and the ABA subgroups: slope difference of 11% (95% CI: -9%, 32%) and 37% (95% CI: -4%, 77%) respectively. However, it was satisfied for the TCZ subgroup: slope difference 3% (95% CI: -21%, 27%) (Figure 1). Relapses (Figure 2) were more frequent in the Spacing arm: +45% (95% CI: 32%, 57%), +48% (95% CI: 24%, 71%) and +43% (95%CI: 29%, 58%) in the whole population, ABA and TCZ subgroups respectively. Durable relapses were more frequent in the Spacing arm: +10% (95%CI: 0%, 19%), 16% (95%CI: -5%, 37%) and 7% (95%CI: -3%, 16%) in the whole population, ABA and TCZ subgroups respectively, compared with Maintenance arm. Conclusion: The TOLEDO trial generally failed to demonstrate the non-inferiority of the proposed tapering strategy in comparison to maintenance at full dose. However, the non-inferiority was satisfied in terms of disease activity for the TCZ subgroup. Disclosure of Interests: Joanna KEDRA: None declared, Philippe Dieude: None declared, Hubert MAROTTE: None declared, Alexandre Lafourcade: None declared, Emilie Ducourau Speakers bureau: BMS and Abbvie, Thierry Schaeverbeke: None declared, Aleth Perdriger: None declared, Martin SOUBRIER: None declared, Jacques Morel: None declared, Arnaud Constantin: None declared, Emmanuelle Dernis: None declared, Valerie Royant: None declared, Jean-Hugues Salmon Speakers bureau: Janssen Novartis, Thao Pham Speakers bureau: Lilly, Novartis, Jacques-Eric Gottenberg Grant/research support from: Bristol-Myers Squibb, Grant/research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Lilly, Pfizer, Sanofi-Genzyme, UCB Pharma, Consultant for: Bristol-Myers Squibb, Eli Lilly, UCB, Sanofi-Genzyme, Pfizer, Edouard Pertuiset: None declared, maxime dougados Grant/research support from: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Valerie Devauchelle-Pensec Grant/research support from: Roche-Chugai, Speakers bureau: MSD, BMS, UCB, Roche, Philippe Gaudin Speakers bureau: Roche, Chugai, BMS, Abbvie, Servier, Pfizer, MSD, UCB, ESAOTE, Genevrier, Janssen, Novartis, Lilly, Biogen, Amge, Gregoire CORMIER: None declared, Philippe Goupille: None declared, Xavier Mariette Grant/research support from: Servier, Consultant for: AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, UCB Pharma, Francis Berenbaum: None declared, Didier Alcaix: None declared, SID AHMED ROUIDI: None declared, Jean-Marie Berthelot: None declared, Agnes Monnier: None declared, Christine Piroth: None declared, Frederic Liote Grant/research support from: institutional grants from Grunenthal, Ipsen Pharma/Menarini, Novartis, SOBI for the European Crystal Network Workshops, Consultant for: Grunenthal, Novartis, Vincent Goeb: None declared, Cecile Gaujoux-Viala Consultant for: Speaking and/or consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Merck-Serono, Medac, Nordic Pharma, Novartis, Pfizer, Roche, Sandoz, Sanofi and UCB Pharma., Speakers bureau: Speaking and/or consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Merck-Serono, Medac, Nordic Pharma, Novartis, Pfizer, Roche, Sandoz, Sanofi and UCB Pharma., Isabelle CHARY VALCKENAERE: None declared, David Hajage: None declared, Florence Tubach Grant/research support from: Financial compensation received from MSD on a pro-rota basis for participation in Scientific Committee meetings and functions for this study, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant for: AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, Medac, MSD, NORDIC Pharma, Novartis, Pfizer, Roche, Sanofi-Aventis, Sanofi Genzyme, SOBI, UCB

Background Accumulation of advanced glycation end-products (AGEs) is involved in age-related osteoarthritis (OA). Glyoxalase (Glo)-1 is the main enzyme involved in the removal of AGE precursors, especially carboxymethyl-lysine (CML). We aimed to investigate the expression of several AGEs and Glo-1 in human OA cartilage and to study chondrocytic Glo-1 regulation by inflammation, mediated by interleukin (IL)-1β. Methods Ex vivo, we quantified AGEs (pentosidine, CML, methylglyoxal-hydroimidazolone-1) in knee cartilage from 30 OA patients. Explants were also incubated with and without IL-1β, and we assessed Glo-1 protein expression and enzymatic activity. In vitro, primary cultured murine chondrocytes were stimulated with increasing concentrations of IL-1β to assess Glo-1 enzymatic activity and expression. To investigate the role of oxidative stress in the IL-1β effect, cells were also treated with inhibitors of mitochondrial oxidative stress or nitric oxide synthase. Results Ex vivo, only the human cartilage CML content was correlated with patient age (r = 0.78, p = 0.0031). No statistically significant correlation was found between Glo-1 protein expression and enzymatic activity in human cartilage and patient age. We observed that cartilage explant stimulation with IL-1β decreased Glo-1 protein expression and enzymatic activity. In vitro, we observed a dose-dependent decrease in Glo-1 mRNA, protein quantity, and enzymatic activity in response to IL-1β in murine chondrocytes. Inhibitors of oxidative stress blunted this downregulation. Conclusion Glo-1 is impaired by inflammation mediated by IL-1β in chondrocytes through oxidative stress pathways and may explain age-dependent accumulation of the AGE CML in OA cartilage. Electronic supplementary material The online version of this article (10.1186/s13075-018-1801-y) contains supplementary material, which is available to authorized users.

Objective.To evaluate the association of baseline serum level of vitamin D with disease activity, disability, and radiographic damage over the first year in early rheumatoid arthritis (RA).Methods.Among early arthritis patients included in the ESPOIR cohort, patients with early RA were evaluated. Levels of 25-hydroxy vitamin D2 and D3 were measured at baseline. Baseline associations between vitamin D level and 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR), Health Assessment Questionnaire–Disability Index (HAQ-DI), and van der Heijde modified total Sharp score (mTSS) were assessed. Bivariate analysis was used to assess the association between vitamin D level and radiographic progression (mTSS increased by ≥ 1 point) or disability (HAQ-DI ≥ 0.5) over 12 months. Forward stepwise multiple logistic regression was used to evaluate the independent association of baseline variables and outcomes.Results.Among 813 patients with early arthritis, data for 645 patients with RA were analyzed. Vitamin D level was < 10 ng/mL (deficiency, group 1), 10–29.9 ng/mL (low level, group 2), and ≥ 30 ng/mL (normal, group 3) for 114 (17.7%), 415 (64.54%), and 114 (17.7%) patients, respectively. At baseline, DAS28-ESR and HAQ-DI were higher with vitamin D deficiency compared with groups 2 and 3 combined (P = 0.007 and P = 0.001, respectively), as was mean mTSS, but not significantly (p = 0.076). On multivariate analysis, baseline vitamin D deficiency was associated with HAQ-DI at 6 months (OR 1.70) and mTSS at 12 months (OR 1.76).Conclusion.Vitamin D deficiency was associated with more active and severe disease at baseline and may predict disability and radiographic progression over 1 year in early RA patients. [ClinicalTrials.gov: NCT03666091]

Background Intra-articular adipose tissues (IAATs) are involved in osteoarthritis (OA) pathophysiology. We hypothesize that mesenchymal cells residing in IAATs may account for the specific inflammatory and metabolic patterns in OA patients. Methods Adipocyte precursors (preadipocytes and dedifferentiated fat cells (DFATc)) from IAATs (infrapatellar and suprapatellar fat pads) and autologous subcutaneous adipose tissues (SCATs) were isolated from knee OA patients. The ability of these precursors to differentiate into adipocytes was assessed by oil red O staining after 14 days of culture in adipogenic medium. The gene expression of adipocyte-related transcription factors (C/EBP-α and PPAR-γ) and development-related factors (EN1 and SFRP2) were analyzed. The inflammatory pattern was assessed by RT-qPCR and ELISA (interleukin 6 (IL-6), IL-8, Cox2, and prostaglandin E2 (PGE2)) after a 24-h stimulation by IL-1β (1 ng/mL) and by conditioned medium from OA synovium. Results IAAT preadipocytes displayed a significantly higher ability to differentiate into adipocytes and expressed significantly more C/EBP-α mRNA than SCAT preadipocytes. IAAT preadipocytes expressed significantly less EN-1 and SFRP2 mRNA than SCAT preadipocytes. Unstimulated IAAT preadipocytes displayed a less inflammatory pattern (IL-6, IL-8, and Cox2/PGE2) than SCAT preadipocytes. In contrast, the response of IAAT preadipocytes to an inflammatory stimulus (IL-1β and conditioned media of OA synovium) was exacerbated compared to that of SCAT preadipocytes. Similar results were obtained with DFATc. Conclusion IAAT adipocyte precursors from OA patients have a specific phenotype, which may account for the unique phenotype of OA IAATs. The exacerbated response of IAAT preadipocytes to inflammatory stimulation may contribute to OA pathophysiology.

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:Interstitial lung disease (ILD) is an extra-articular manifestation of rheumatoid arthritis (RA) detected in 20% to 60% of patients with RA on high-resolution computed-tomography (HRCT) chest scan and is clinically significant in near 10%. Despite a high morbi-mortality rate, a definite strategy for preclinical ILD screening in patients with RA remains to be determined. To date, several factors have been reported to increase the risk of RA-ILD occurrence (i.e. older age at RA onset, ACPA positivity, male sex, RA disease activity, the MUC5B rs35705950 promoter variant...). However, none of these risk factors has been validated in a prospective cohort of patients with RA. The ESPOIR prospective cohort includes patients aged 18 to 70 years with recent arthritis (less than 6 months) and a definite or probable diagnosis of RA.Objectives:To identify in the ESPOIR cohort factors associated with ILD after at least 10 years of RA duration in order to develop a predictive score to identify patients with preclinical RA-ILD.Methods:An ILD detection by chest HRCT scan was systematically offered to every patient with definite RA after at least 10 years-follow-up. Chest HRCT scans were centrally reviewed by an experienced radiologist. Potential predictors of ILD were prospectively collected from baseline to the date of the HRCT scan, and all included patients were genotyped for MUC5B rs35705950. To take into account repeated measures, trajectories were determined for disease activity, C reactive protein, smoking, treatment exposure (i.e. prednisone, methotrexate [MTX] and biological disease modifying anti-rheumatic drugs [bDMARDs]). A logistic model was used to identify independent predictors for the occurrence of ILD on HRCT scans. Confidence intervals were estimated using sampling methods. A predictive score for preclinical ILD occurrence was developed based on the identified predictors.Results:163 RA patients according to 2010 ACR/EULAR classification criteria, none of whom had pulmonary symptoms, were investigated with a chest HRCT scan (128 women (78.5%), mean RA duration 13.7 ± 1.1 years, age at inclusion 47.6 y/o ± 10.4, mean disease activity score [DAS]-28 during follow up was 3.1 ± 1.0). ILD was detected in 31 patients (19.0%). The MUC5B rs35705950 minor allele frequency (MAF) was 22.2% and 10.0% in the RA-ILD and RA-noILD populations, respectively (OR univariate=2.6 CI95% [1.2-5.5], P=0.01). After logistic regression, independent predictors for preclinical RA-ILD were male sex (OR=3.9 CI95% [1.4-11.4]), older age at RA onset (OR=1.1 per year CI95% [1.0-1.2]), mean DAS-28 score during the follow-up (OR=2.0 CI95% [1.2-3.4]) and MUC5B rs35705950 T risk allele (OR=3.7 CI95% [1.4-10.4]) (Figure 1). No influence of the use of RA-related drugs (prednisone, MTX or bDMARDs) was identified as risk factor. The logistic model could predict preclinical ILD occurrence after 13 years of RA duration with an AUC=0.82 CI95% (0.72-0.91). A predictive score for preclinical RA-ILD based on the 4 identified predictive risk factors was developed (Sensitivity 80%, Specificity 56%).Figure 1.Factors independently associated with preclinical ILD after 13 years of RA durationConclusion:In this cross-sectional study of the prospective ESPOIR cohort, we identified clinical and genetic predictors for ILD after 13 years of RA duration. We developed a predictive score that could improve risk stratification for preclinical RA-ILD and help physicians identify patients with RA in whom a HRCT scan should be performed.Disclosure of Interests:Pierre-Antoine Juge Consultant of: BMS, Benjamin Granger: None declared, Marie-Pierre Debray: None declared, Esther Ebstein: None declared, Fabienne Louis Sidney: None declared, Joanna KEDRA: None declared, Raphael Borie: None declared, Arnaud Constantin Consultant of: Bristol-Meyers Squibb, Chugai, Roche, Abbvie, MSD, Pfizer, and UCB, Bernard Combe Consultant of: Abbvie, Bristol-Meyers Squibb, Lilly, MSD, Janssen, Pfizer, Roche, Chigai, and Sanofi, Grant/research support from: Abbvie, Bristol-Meyers Squibb, Lilly, MSD, Janssen, Pfizer, Roche, Chugai, and Sanofi, René-Marc Flipo Consultant of: Bristol-Meyers Squibb, Roche, Chugai, Abbvie, and Pfizer, Grant/research support from: Roche, Chugai, Abbvie, and Pfizer, Xavier Mariette Consultant of: Bristol-Meyers Squibb, GSK, Janssen, Pfizer, and UCB, Olivier VITTECOQ Consultant of: Bristol Myers Squibb, Roche, Chugai, MSD, Novartis, Pfizer, Abbvie, and Lilly, Alain Saraux Consultant of: Roche, Chugai, and Bristol-Meyers Squibb, Grant/research support from: Roche, Chugai, and Bristol-Meyers Squibb, Guillermo CARVAJAL ALEGRIA: None declared, Jean Sibilia Consultant of: Roche, Chugai, Bristol-Meyers Squibb, UCB, GSK, LFB, Actelion, Pfizer, MSD, Novartis, Amgen, Hospira, AbbVie, Sandoz, Gilead, Lilly, Sanofi, Janssen, and Mylan, Francis Berenbaum Consultant of: Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Elli Lilly, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4P Pharma, Caroline Kannengiesser: None declared, Catherine Boileau: None declared, Bruno Crestani Consultant of: Boehringer Ingelheim, Roche, Sanofi, Apellis, Astra-Zeneca, Grant/research support from: MedImmune, Boehringer Ingelheim, Bruno Fautrel Consultant of: AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, Medac, MSD, NORDIC Pharma, Novartis, Pfizer, Roche, Sanofi-Aventis, SOBI, UCB, Grant/research support from: AbbVie, MSD, Pfizer, Philippe Dieudé: None declared

Background:Knee osteoarthritis (OA) is a frequent degenerative disease representing an important health and economic burden. Symptomatic medical treatments available include intra-articular (IA) injections of corticosteroids (GC) but their efficacy is debated. In addition, safety signals regarding cartilage damage with IA GC have been highlighted in a few studies.Objectives:To perform a meta-analysis of studies assessing IA GC efficacy and safety in knee OA.Methods:A systematic literature review and a meta-analysis of randomized controlled trials (RCTs) assessing the effect of GC IA injections versus other interventions (IA Hyaluronic Acid, IA placebo, IA NSAID, oral NSAID or physiotherapy) in knee OA was performed. The effect of the interventions on pain and function were extracted from the single studies and pooled and are presented as short term (24 weeks) follow-up period. Standardized mean differences (SMD) are reported.Results:Of 520 studies screened, 23 were included in the SLR and 14 subsequently included in the MA. While IA GC showed a superior effect compared to control on both pain (SMD -0.61 (95% CI -1,25, 0.03)) and function (SMD -1.02 (95% CI -2.14, 0.10)) in short term follow-up; long term follow-up analysis favored controls (IA HA, IA NSAID, physiotherapy) for both pain (SMD 0.68 (95% CI -0.11, 1.47)) and function (SMD 0.88 (95% CI -0.36, 2.12) outcomes (Figure 1). No difference was found between interventions in the medium term. Safety data were reported in 18/23 studies (n= 1936/2314 patients); and side effects were reported as follows: arthralgia (69 IA GC patients, 146 IA HA patients, and 20 saline patients); site injection pain (7 in the IA GC group, 2 in the IA saline group, 14 in the IA HA group); 16 post injection knee swelling without signs of septic arthritis in the IA GC group and 24 in the IA HA group. In one study assessing cartilage effects of GCs, the rate of cartilage loss was greater in the GC group with a reduction of cartilage thickness at 2 year compared to placebo group. No difference was observed in the progression of cartilage denudation or bone marrow lesion. On the contrary, another study showed no effect of injections on the cartilage structure.Conclusion:We demonstrate in this work that IA GC injections reduce pain and improve function in the early phase (≤6 weeks) of treatment. In the long term (≥24 weeks), other intervention such as IA HA injections or physiotherapy seem to be more efficient, but this effect was largely driven by single studies with large effect sizes and the comparators were heterogeneous.Figure 1.Knee pain outcome at short term (≤6weeks) (A), medium term (>6 & Disclosure of Interests:None declared.

Background:The COVID-19 pandemic has disrupted healthcare delivery and education of physicians, including rheumatology trainees.Objectives:To assess the impact of the COVID-19 pandemic on the clinical experiences, research opportunities, and well-being of rheumatology trainees.Methods:A voluntary, anonymous, web-based survey was administered in English, Spanish, or French from 19/08/2020 to 05/10/2020. Adult and paediatric rheumatology trainees worldwide in training in 2020 were invited to participate via social media and email. Using multiple choice questions, Likert scales, and free text answers, we assessed trainee patient care activities, redeployment, research, and well-being.Results:The 302 respondents were from 33 countries, with most (83%, 252/302) in adult rheumatology training. Many trainees (45%, 135/300) reported an increase in non-rheumatology clinical work (e.g. care of COVID-19 patients), with 52% of these (70/135) also continuing rheumatology clinical work. COVID-19 redeployment was not optional for 68% (91/134).Trainees reported a negative impact of the pandemic in their growth in rheumatology (Figure 1). They also reported a substantial impact on several training areas: outpatient clinics (79%, 238/302), inpatient consultations (59%, 177/302), formal teaching (55%, 167/302), procedures (53%, 147/302), teaching opportunities (52%, 157/302), and ultrasonography (36%, 110/302), with 87-96% perceiving a negative impact on these areas. Only 54% (159/294) reported feeling comfortable with their level of clinical supervision during the pandemic (Figure 1).Many trainees (46%, 128/280) reported changes in research experiences during the pandemic; 39% (110/285) reported that COVID-19 negatively affected their ability to continue their pre-pandemic research and 50% (142/285) reported difficulty maintaining research goals (Figure 1).Some rheumatology trainees reported having health condition(s) putting them at high risk for COVID-19 (10%, 30/302) and 14% of trainees (41/302) reported having had COVID-19 (Table 1). Only 53% (160/302) reported feeling physically safe in the workplace while 25% (76/302) reported not feeling physically safe; reasons included lack of training about COVID-19, lack of comfort in the clinical setting, insufficient personal protective equipment, immunocompromised state, and pregnancy. Half (151/302) reported burnout and 68% (204/302) an increase in stress from work during the pandemic (Figure 1), whilst 25% (75/302) reported that changes to their training programme negatively impacted their physical health.Conclusion:The COVID-19 pandemic has negatively impacted the experience of rheumatology training as well as the well-being of trainees globally. Our data highlight concerns for rheumatology trainees including research opportunities and clinical care which should be a focus for curriculum planning.Figure 1.Rheumatology trainee perceptions of pandemic impact and changes in training programme.Table 1.Estimated hazard ratios, adjusted for age and gender, for individuals with rheumatoid arthritisEuropen = 89ROWn = 213Combinedn = 302Disability1 (1)9 (4)10 (3)High risk7 (8)23 (11)30 (10)Pregnant4 (5)15 (7)19 (6)Shielding/Quarantining12 (13)70 (33)82 (27)Acquired COVID-1920 (22)21 (10)41 (14)Disclosure of Interests:Kristen Young: None declared, Su-Ann Yeoh: None declared, Michael Putman: None declared, Elizabeth Graef: None declared, Francis Berenbaum: None declared, Richard Conway: None declared, Rebecca Grainger Speakers bureau: Speaker fees from Abbvie, Janssen, Novartis, Pfizer, Cornerstones, all not related to this work, Consultant of: Consultancy fees from Abbvie, Janssen, Novartis, Pfizer, Cornerstones, all not related to this work, Grant/research support from: Travel assistance from Pfizer, not related to this work, Adam Kilian: None declared, Maximilian Konig: None declared, Jean Liew Grant/research support from: Research grant from Pfizer unrelated to this manuscript, Pedro M Machado Speakers bureau: Speaker fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, Consultant of: Consulting fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, Sebastian E. Sattui: None declared, Jeffrey Sparks Consultant of: Consultancy for Bristol-Myers Squibb, Gilead, Inova Diagnostics, Optum, and Pfizer unrelated to this manuscript, Grant/research support from: Research support from Bristol-Myers Squibb unrelated to this manuscript, Paul Sufka: None declared, Manuel Ugarte-Gil Grant/research support from: Research grants from Janssen and Pfizer unrelated to this manuscript, Laura Upton: None declared, Zachary Wallace: None declared, Jinoos Yazdany Consultant of: Consultancy for Astra Zeneca, Eli Lilly, and Pfizer, not related to this work, Grant/research support from: Research grants from Gilead and Pfizer, not related to this work, Arundathi Jayatilleke: None declared.

Background Previous studies suggested that obesity could negatively affect the response to antitumour necrosis factor-α (TNFα) agents in rheumatoid arthritis (RA). However, data are lacking on whether obesity affects the response to abatacept (ABA). We aimed to determine whether body mass index (BMI) affects the response to ABA in RA. Materials and methods In this multicenter retrospective study, we included RA patients who received ABA. BMI was calculated at the initiation of treatment. After 6 months of treatment, change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate and C-reactive protein level, tender and swollen joint count were analysed. The primary endpoint was decrease in DAS28 ≥ 1·2. Secondary outcomes were good response and remission by EULAR criteria. Results At baseline, among 141 RA patients included, the median [interquartile range] BMI was 26·0 [22·9–30·8] kg/m². The number of patients with normal weight, overweight and obesity was 64 (45·4%), 38 (27%) and 39 (27·6%), respectively. Baseline characteristics did not differ among the three BMI subgroups. Univariate analysis revealed no difference in BMI between responders and nonresponders: DAS28 decrease ≥ 1·2 (25·0 [23·4–31·3] vs. 26·3 [22·9–30·2], P = 0·95), EULAR good response (26·4 [23·5–30·9] vs. 26·0 [22·9–30·6], P = 0·96) and remission (26·7 [21·7–30·3] vs. 26·0 [23·0–30·1], P = 0·83). Conclusion In our real-life study, BMI did not affect the response to ABA in RA. If confirmed, these results suggest that obesity is not a limitation of ABA use in RA.

Osteoarthritis (OA) is a prevalent and debilitating joint disease for which ageing, obesity and chronic inflammation are known risk factors. The central, peripheral and autonomic nervous systems are essential in all metabolic systems, and emerging evidence suggests a role for these systems in OA. In the past few years, metabolic diseases, such as obesity or diabetes, have been linked to disruption of circadian rhythms that are tightly regulated by the nervous system, whereas inflammatory and autoimmune diseases are known to be linked to disruption of the cholinergic vagus nerve reflex. Interestingly, metabolism, inflammation and circadian rhythms have all been linked to the development and progression of OA. This article reviews current knowledge of the direct and indirect roles of the nervous system and circadian system in the initiation and/or progression of OA, and highlights the directions for future research in this emerging field.

Several studies have suggested that obesity could have a negative effect on response to anti-tumor necrosis factor α (anti-TNFα) in rheumatoid arthritis (RA). Little is known about the impact of body mass index (BMI) on other biologic agents. We aimed to evaluate the effect of BMI on response to tocilizumab (TCZ) in RA. RA patients treated with TCZ were included in this multicenter retrospective study. BMI was calculated at the initiation of treatment. After 6 months of treatment, change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate and C-reactive protein level, and tender and swollen joints were analyzed. The primary endpoint was decrease in DAS28 ≥ 1.2. Secondary outcomes were good response and remission by EULAR criteria. At baseline, among 115 RA patients included, the median (interquartile range) BMI was 25.4 (22.0-28.8) kg/m(2). The number of patients with normal weight, overweight, and obesity was 53 (46 %), 37 (32 %), and 25 (22 %), respectively. Baseline characteristics did not differ between the three subgroups of BMI. The median BMI did not differ between responders and non-responders for DAS28 decrease ≥1.2 (25.7 [22.1-29.9] vs 24.9 [22.0-27.1], P = 0.38), EULAR good response (25.9 [22.8-30.0] vs 25.4 [22.0-28.4], P = 0.61), and remission (25.1 [22.5-28.6] vs 25.4 [22.0-28.9], P = 0.76). BMI did not affect the response to TCZ in RA. If confirmed, these results could be helpful for the selection of a biologic agent in obese RA patients.

Background:Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential for any autoimmune or inflammatory disease (AIID). We performed a disease-finding “basket trial” (TRANSREGNCT01988506) in patients affected by one of 11 different AIID and reported the outcome of the first 46 patients (Rosenzwajg et al, ARD 2019).Objectives:Here we analyzed and discussed results from deep immunophenotyping, of 78 patients, to comprehensively study the effect of ld-IL2 on the immune system of patients affected by various AIIDMethods:We performed a prospective, open label, phase I-IIa study in 78 patients with a mild to moderate form of one of 13 selected AIID. All patients received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Deep immunophenotyping was performed before and after 5 days of ld-IL2.Results:ld-IL2 significantly expands both memory Tregs as well as naïve Tregs, including recent thymic emigrant Tregs. It also activates Tregs as demonstrated by the significantly increased expression of HLA-DR, CD39, CD73, GITR, CTLA-4. Similar results were observed across the different AIID.Conclusion:ld-IL2 “universally” improves Treg fitness across 13 autoimmune and inflammatory disease.References:[1]Rosenzwajg M#, Lorenzon R#, Cacoub P, Pham HP, Pitoiset F, El Soufi K, RIbet C, Bernard C, Aractingi S, Banneville B, Beaugerie L, Berenbaum F, Champey J, Chazouilleres O, Corpechot C, Fautrel B, Mekinian A, Regnier E, Saadoun D, Salem JE, Sellam J, Seksik P, Daguenel-Nguyen A, Doppler V, Mariau J, Vicaut E, Klatzmann D. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis. 2019 Feb;78(2):209-217. doi: 10.1136/annrheumdis-2018-214229. Epub 2018 Nov 24.Disclosure of Interests:Michelle Rosenzwajg: None declared, Roberta Lorenzon: None declared, Patrice cacoub: None declared, Fabien Pitoiset: None declared, Selim Aractingi: None declared, Beatrice Banneville Speakers bureau: Lilly, Novartis, Laurent Beaugerie: None declared, Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Julien Champey: None declared, Olivier Chazouilleres: None declared, Christophe Corpechot: None declared, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant of: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Medac MSD France, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi Aventis, SOBI and UCB, Arsene Mekinian: None declared, Elodie Regnier: None declared, david Saadoun: None declared, Joe-Elie Salem: None declared, Jérémie SELLAM: None declared, Philippe Seksik: None declared, David Klatzmann Consultant of: ILTOO Pharma

Background:Nonspecific subjective adverse effects and symptoms (NSAE/NSS), usually considered as related to a nocebo effect (NE), have been identified as a barrier to the acceptability of switches from biologic originators (BO) to biosimilars (BS) in rheumatology. A multidisciplinary team intervention with a prominent role of nurses has provided a reduction of the NE assessed in the short-term during a systematic switch from originator Infliximab (OI) to the biosimilar infliximab SB2 (ref.1).Objectives:To assess the intervention outcomes after one-year follow up in comparison with a historical cohort.Methods:The intervention was developed after a literature search and semi-directive interviews of patients, and included consensual communication towards patients, with a prominent role of nurses (Ref.1). All patients with chronic inflammatory rheumatic diseases (CIRD) treated by OI were included and followed-up in routine care. The outcomes were I) SB2 retention rate (RR) II) SB2 discontinuation rate due to a presumed NE, defined as lack of efficacy with no objective criteria for increased inflammation or non-objective and non-specific adverse event, either occurring after the switch and disappearing after back-switch or change of biologic. Criteria for NSAE/NSS in the historical cohort were the same lack of efficacy or subjective adverse events and disappearance after change of biologic BD. Medium-term (12 months) SB2 outcomes were assessed and compared with I) the data obtained in the short-term (34 weeks) II) the data from an historical cohort of CIRD patients treated by OI in the same rheumatology department, using Kaplan-Meier survival curve.Results:Forty-five patients were prospectively included for the switch from March 2018 to August 2018: 17 with rheumatoid arthritis (RA), 28 with spondylarthritis (SpA); 55% were women, mean age was 53.2 (SD: 2,1), and mean time under OI was 113.5 (SD9.3). For the historical cohort, the 52 patients treated with OI between December 2016 and January 2017 were included and their data collected at baseline and one year. Fifty-nine percent were women, mean age at inclusion was 50.25 (1.2), and mean time under OI was 94.8 (9.4).SB2 RR did not differ from the OI RR in the historical cohort: 91.2% and 96.2% respectively at 34 weeks (p = 0.41); 84.4% and 88.5% respectively at 12 months (p = 0.52) (figure 1). The SB2 RR was significantly higher than in three other European cohorts at 34 weeks (mean RR 73.6%, pSB2 and OI discontinuations due to NSAE/NSS at 34 weeks were 2,2 % and 1.9% respectively; at 12 months 6,6% and 1.9% respectively (p= 0.6).Conclusion:An intervention based on a tailored communication with a prominent role of nurses was effective in reducing the NE when switching from OI to SB2 in the short term, compared with an historical cohort and other European cohorts. The one-year follow-up showed no statistical difference in RR or NE compared with our historical cohort. The present study shows that appropriate interventions may be developed to improve the outcome of switches to biosimilars.Figure 1:Treatment withdrawal free survival curves (SB2 in switched cohort and OI in historical cohort).Kaplan Meir survival curves. Comparison with Log-Rank test between OI to SB2 cohort and historical OI cohort, p = 0.520. OI : original infliximab.References:[1] Petit J. Ann Rheum Dis, volume 78, supplement 2, year 2019, page A1447[2] Glintborg B. et al. Ann Rheum Dis 2017;76:1426–31.[3] Nikiphorou E. et al. Expert Opin Biol Ther 2015;15:1677–83.[4] Boone NW. et al. Eur J Clin Pharmacol 2018;:1–7.Acknowledgments:Dr Margaux Boisson Service de rhumatologie du Professeur Kahan, Hôpital Cochin, APHP.Disclosure of Interests:Juliette Petit: None declared, Marie Antignac: None declared, Karine Louati: None declared, Sandra Desouches: None declared, Nathalie DEPARIS: None declared, Regine Baratto: None declared, Rosemarie POILVERD: None declared, Sylvie Dartout: None declared, Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Catherine Beauvais Speakers bureau: Abbvie, MSD, Roche, UCB, Mylan, Sanofi

Background:Tanezumab, a monoclonal antibody against nerve growth factor (NGF), is in development for the treatment of osteoarthritis (OA).Objectives:To assess the effects of gender, age and body mass index (BMI) on the incidence of adverse events (AEs) in patients (pts) treated with subcutaneous (SC) tanezumab in pooled data from three phase 3 OA studies. Anti-NGF therapy has been associated with joint safety events1. Here we focus on treatment emergent AEs, including abnormalities of peripheral sensation (APS).Methods:All three randomised, double-blind, placebo-controlled studies enrolled pts with radiographically-confirmed OA of the hip or knee, who had inadequate response or could not tolerate standard of care analgesics. In the 16-week (wk) Study 1 (NCT01089725), pts received placebo, tanezumab 2.5 mg, 5 mg or 10 mg at baseline and wk 82. Due to a clinical hold on NGF antibodies, nddose at wk 8. Pts in the 16-wk Study 2 (NCT02697773), received placebo or tanezumab 2.5 mg at baseline and wk 8 or tanezumab 2.5mg at baseline and 5mg at wk 81. Pts in the 24-wk Study 3 (NCT02709486), received placebo, tanezumab 2.5 mg or 5 mg at baseline, wks 8 and 16. All treatments were given SC. AE data from the treatment period of each study were pooled for placebo, tanezumab 2.5 mg and 5 mg groups and examined by subgroups of gender, age and BMI. Data from the 10 mg group of Study 1 were not included due to the low sample size.Results:The incidence of any AE was numerically higher in females across treatment groups and in pts with a BMI ≥30 kg/m2in the tanezumab 5mg, but not 2.5 mg group, vs the overall population (Table 1). SAEs were infrequent but numerically higher across all tanezumab 5 mg subgroups vs placebo (Table 2). Paraesthesia and hypoaesthesia were the most common AEs of APS and were increased in all tanezumab groups in the overall population vs placebo. In any of the subgroups, the incidence of paraesthesia or hypoaesthesia was ≤7.8% and ≤3.9%, respectively. The difference within a patient subgroup for paraesthesia or hypoaesthesia was typically comparable with that of the overall population across treatments.Table 1.Incidence of AEs during the treatment period% of pts with an AE in each subgroupPlacebon=586Tanezumab2.5 mgn=602Tanezumab2.5 mg/5 mg n=219Tanezumab5 mgn=347Overall population51.752.347.054.8Gender Male51.149.741.346.6 Female52.053.650.459.0Age (years) 55.054.044.054.5 ≥6547.250.052.654.9BMI (kg/m2) 58.146.651.945.5 25–51.455.943.750.0 30–49.251.543.258.9 ≥3552.752.355.360.9BMI, body mass index; kg/m2, kilogram per square metreTable 2.Incidence of SAEs during the treatment period% of pts with a SAE in each subgroupPlacebon=586Tanezumab2.5 mgn=602Tanezumab2.5 mg/5 mg n=219Tanezumab5 mgn=347Overall population1.52.21.42.6Gender Male1.63.01.32.5 Female1.51.71.42.6Age (years) 1.22.61.41.9 ≥652.01.61.33.1BMI (kg/m2) 1.61.102.3 25–1.62.702.7 30–1.62.01.43.1 ≥351.32.34.31.6BMI, body mass index; kg/m2, kilogram per square metreConclusion:This pooled analysis showed that the safety profile of tanezumab in the subgroups studied is broadly similar to that of the overall study population.References:[1]Schnitzer, T. J.et al. JAMA(2019)[2]Birbara, C.et al. J Pain Res(2018)Disclosure of Interests:Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sean Donevan Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., Anne Hickman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Takaharu Yamabe Shareholder of: Pfizer, Employee of: Pfizer

Background:Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the treatment of signs and symptoms of osteoarthritis (OA).Objectives:To assess the safety and tolerability of subcutaneous (SC) tanezumab in patients with OA.Methods:Data were derived from 3 randomized placebo-controlled OA trials. SC treatment (every 8 weeks for 16–24 weeks with 8–24 week follow-up) included placebo, tanezumab 2.5 mg, tanezumab 2.5/5 mg (2.5 mg at day 1 and 5 mg at week 8), and tanezumab 5 mg. Overall treatment-emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation were pooled from all 3 trials (placebo N = 586; tanezumab: 2.5 mg N = 602, 2.5/5 mg N = 219, 5 mg N = 347). Pre-specified TEAEs potentially associated with sympathetic neuropathy (anhidrosis, bradycardia, hypohidrosis, orthostatic hypotension, or syncope) and pre-specified joint events (primary osteonecrosis, rapidly progressive OA [RPOA] type 1 or type 2, subchondral insufficiency fracture, or pathological fracture; adjudicated by an independent committee of experts) were pooled from the 2 trials that included prospective evaluation of sympathetic and joint safety (placebo N = 514; tanezumab: 2.5 mg N = 528, 2.5/5 mg N = 219, 5 mg N = 284). TEAEs are presented for the treatment period; joint safety is presented for the full study (treatment plus follow up) period.Results:Patient demographics (80.7% white, 66.8% female, mean age ≈ 63 years) and clinical characteristics were similar across groups. TEAE rates were: placebo = 51.7%, tanezumab 2.5 mg = 52.3%, tanezumab 2.5/5 mg = 47.0%, and tanezumab 5 mg = 54.8%. Of TEAEs occurring in ≥2% of patients in any group, only oedema peripheral, joint stiffness, and paraesthesia had a higher incidence (95% confidence interval excluded 0) in any tanezumab group relative to placebo. Serious TEAE rates were: placebo = 1.5%, tanezumab 2.5 mg = 2.2%, tanezumab 2.5/5 mg = 1.4%, and tanezumab 5 mg = 2.6%. Rates of treatment and/or study discontinuation due to TEAEs were: placebo = 2.2%, tanezumab 2.5 mg = 1.8%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 1.4%. Only arthralgia and OA led to discontinuation in >1 patient in any group. TEAEs of abnormal peripheral sensation rates were: placebo = 2.2%, tanezumab 2.5 mg = 5.1%, tanezumab 2.5/5 mg = 3.2%, and tanezumab 5 mg = 6.1%. Paraesthesia and hypoaesthesia were the most common events. Potential sympathetic neuropathy TEAE rates were: placebo = 0.8%, tanezumab 2.5 mg = 1.5%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 2.8%; exposure-adjusted rates were not statistically different between any tanezumab group and placebo. Bradycardia and orthostatic hypotension were the most common events. No patient was considered to have a sympathetic neuropathy. TEAEs of abnormal peripheral sensation and potential sympathetic neuropathy were mostly mild and resolved. Joint safety event rates were statistically different for tanezumab 5mg (3.2%), but not 2.5mg (1.9%) or 2.5/5mg (0.5%), compared to placebo (0%). RPOA type-1 was the most common event. Total joint replacement rates were: placebo = 4.5%, tanezumab 2.5 mg = 5.9%, tanezumab 2.5/5 mg = 6.8%, and tanezumab 5 mg = 7.0%; rates were not statistically different between any tanezumab group and placebo.Conclusion:Tanezumab was generally safe and well tolerated in most patients, with rates of overall TEAEs and treatment/study discontinuations similar to placebo and no evidence of a sympathetic safety signal. TEAEs of abnormal peripheral sensation and joint safety events were infrequent but more common with tanezumab than placebo.Disclosure of Interests:Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Anne Hickman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Glenn Pixton Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Isabelle Davignon Shareholder of: Pfizer, Employee of: Pfizer, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Animal studies suggested that inhibiting IL-1α/β with lutikizumab (formerly, ABT-981) may reduce pain and slow structural progression in OA. Objectives This study (NCT02087904; ILLUSTRATE-K) assessed the safety and efficacy of lutikizumab in subjects with knee OA. Methods Subjects (n=350; 347 analysed) with Kellgren-Lawrence (KL) grade 2–3 knee OA, synovitis on MRI or US, and visual analogue scale knee pain score 4–8 (range, 0–10) were randomised to receive placebo (PBO) or lutikizumab 25, 100, or 200 mg subcutaneously (sc) every 2 wk (E2W) for 50 wk. The primary endpoints were change from baseline (BL) in WOMAC pain at wk 16 and change from BL in MRI synovitis at wk 26. Other endpoints included WOMAC function and OMERACT/OARSI response (wk 16, 26, and 52) MRI cartilage volume (wk 26 and 52), and x-ray joint space narrowing (JSN) (wk 52). Results BL demographics and disease characteristics were balanced (KL grade 3, 36.0%%–38.8%; mean WOMAC pain (scale 0–50), 26.2–28.4). The primary endpoint of WOMAC pain at wk 16 improved significantly, compared with PBO, with lutikizumab 100 mg (p=0.050;), but not 25 mg (p=0.834) or 200 mg (p=0.415). WOMAC pain reduction in all lutikizumab groups was sustained from wk 16 to 52, but differences between lutikizumab and PBO for WOMAC pain and other key signs and symptoms were not significant (table 1). Synovitis-related imaging, cartilage volume endpoints, and JSN were similar between lutikizumab and PBO groups at wk 26 and 52. lutikizumab was well tolerated; serious adverse events (SAEs), treatment-related SAEs, and infections and serious infections were similar with lutikizumab vs PBO. Injection site reactions, grade 2/3 neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab vs PBO. Lutikizumab exposures reached steady state after wk 6 and were stable through wk 52. Pharmacodynamic responses (neutrophil and high-sensitivity CRP levels) plateaued at the 100 mg dose and data were similar at 200 mg. The low immunogenicity to lutikizumab did not meaningfully affect outcomes. Conclusions Lutikizumab was generally well tolerated and met the primary endpoint of reduction in WOMAC pain at wk 16 compared with placebo at a dose of 100 mg, but not at 25 mg or 200 mg; cartilage thickness, synovitis, and other structural endpoints were similar between lutikizumab and PBO. Acknowledgements AbbVie funded the study (NCT02087904), contributed to its design and participated in data collection, analysis and interpretation of the data, and in writing, review, and approval of the publication. Medical writing (funded by AbbVie): Richard M. Edwards, PhD, and Michael J. Theisen, PhD of CPS. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Consultant for: AbbVie, H. Bliddal Consultant for: AbbVie Inc., Roche, Pfizer, Lilly, F. Blanco Consultant for: AbbVie Inc., Pfizer, UCB, Bristol, Roche, Bioiberica, Sanofi, Grunenthal, GlaxoSmithKline, Lilly, Janssen, Regeneron, TRB Chemedica (DISSCO), T. Schnitzer Grant/research support from: AbbVie, Consultant for: AbbVie, C. Peterfy Shareholder of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), Employee of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), S. Chen Shareholder of: AbbVie, Employee of: AbbVie, L. Wang Shareholder of: AbbVie, Employee of: AbbVie, P. Conaghan Consultant for: AbbVie Inc., Medivir, Merck Serono, Novartis, Pfizer, Speakers bureau: AbbVie, F. Berenbaum Consultant for: AbbVie, Pfizer, Regeneron, J.-P. Pelletier Consultant for: AbbVie, J. Martel-Pelletier Consultant for: AbbVie, O. Vaeterlein Employee of: Bioclinica, W. Liu Shareholder of: AbbVie, Employee of: AbbVie, G. Levy Shareholder of: AbbVie, Employee of: AbbVie, L. Zhang Shareholder of: AbbVie, Employee of: AbbVie, J. Medema Shareholder of: AbbVie, Employee of: AbbVie, M. Levesque Shareholder of: AbbVie, Employee of: AbbVie

Background Calprotectin (S100A8/A9), a protein secreted by activated neutrophils and monocytes in inflammatory conditions, is upregulated in active spondyloarthritis1 and associated with radiographic spinal progression in axial spondyloarthritis (axSpA)2 Objectives To determine if serum calprotectin level at baseline can predict the radiographic progression of structural damage in spine at 2 years in the early axSpA cohort DESIR (DEvenir des Spondyloarthrites Indifferenciees Recentes) and to compare the association with spine and sacroiliac joint (SIJ) inflammation on magnetic resonance imaging (MRI). Methods Patients presenting with inflammatory back pain suggestive of axSpA for less than 3 years from the DESIR cohort were analysed. axSpA patient were defined as patients who fulfilled the Assessment in SpondyloArthritis Society (ASAS) criteria for axSpA at baseline. Calprotectin was assessed in the serum at baseline with ELISA kit (Hycult Biotech, the Netherlands). Spine radiographs, SIJ and spine MRI were centrally scored. Radiographic spinal progression was defined as worsening by ≥2 units of the mSASSS 2 years after the inclusion. Level of MRI spine and SIJ inflammation at baseline and 2 years was evaluated with BERLIN and SPARCC score. The associations between calprotectin level and mSASSS worsening were tested with Wilcoxon test, Berlin and SPARCC score were tested by Spearman’s correlation tests. Results Of all, 426 had a calprotectin dosage and an early axSpA according to the ASAS criteria. Among them, 211patients have had a mSASSS scoring at baseline and M24. A total of 399 patients have had spinal and SIJ MRI scoring at baseline. Only 15 patients had a radiographic progression with a variation of mSASSS ≥2. We showed a correlation between baseline calprotectin and MRI inflammation in SIJ or spine (Berlin score (r=0.15, p=0.003), SPARCC Sacroiliac score (r=0.12, p=0.012) and SPARCC Spine score (r=0.16, p=0.002)). Calprotectin baseline level was significantly higher in patients who fulfilled axSpA ASAS sacroiliitis arm criteria versus those who fulfilled ASAS HLA B27 arm criteria without any signs of sacroiliitis or versus patients did not fulfil ASAS criteria (respectively p Conclusions Calprotectin do not seem to be a helpful biomarker predicting clinically relevant radiographic progression at 2 years although calprotectin levels at baseline are moderately correlated with disease activity in early axSpA. References [1] Gupta L, et al. Clinical Rheumatology2016. [2] Turina MC, et al. Ann Rheum Dis2014. Disclosure of Interest None declared

Biologic therapies have vastly improved clinical outcomes for patients with axial spondyloarthritis (axSpA). Consequently, targeting clinical remission/inactive disease is now a major treatment goal as outlined in current treat-to-target recommendations1,2. In March 2016, the current status of treating to target and aiming for remission in axSpA was reviewed by 7 expert rheumatologists and 1 patient representative at an industry-sponsored roundtable discussion. This editorial summarizes the key findings from the meeting and recommendations for future research. At present, there is no clear, universally accepted definition of remission in axSpA for both clinical trials and routine practice. Clinical remission/inactive disease is defined by the absence of clinical and laboratory evidence of significant inflammatory disease activity in current treat-to-target recommendations1,2; however, it remains unclear how to precisely assess this in practice. Various criteria to measure low disease activity (LDA) and clinical remission have been proposed that while potentially serving as realistic treatment goals in a treat-to-target strategy, require further validation in the clinical setting3,4. In 2001, the Assessment of Spondyloarthritis international Society (ASAS) developed a preliminary definition of clinical remission—ASAS partial remission (ASAS PR), which includes assessment of 4 domains: patient global, spinal pain, physical function, and “inflammation” (a proxy for true inflammation, based on morning stiffness)5. In clinical trials, 12–15%5,6 of patients with ankylosing spondylitis (AS) receiving nonsteroidal antiinflammatory drugs (NSAID) achieve partial remission; a ceiling of ∼15–40% at 6 months also exists with biologic therapies, including tumor necrosis factor (TNF) inhibitors and secukinumab7,8 (Table 19–20). Treating patients with short symptom duration may increase the proportion of patients reaching clinical remission to ∼50%9,21,22. View this table: Table 1. Achievement of ASAS partial remission and ASDAS inactive disease with … Address correspondence to Dr. X. Baraliakos, Associate Professor, Rheumazentrum Ruhrgebiet, Ruhr-University Bochum, Claudiusstr. 45, 44649 Herne, Germany. E-mail: xenofon.baraliakos{at}elisabethgruppe.de