Sars-Cov-2 Vaccine Safety in Adolescents with Inflammatory Rheumatic and Musculoskeletal Diseases and Adults with Juvenile Idiopathic Arthritis: Data from the Eular Covax Physicianreported Registry

Introduction/Background: There is a lack of data on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination safety in children and young people (CYP) with rheumatic and musculoskeletal diseases (RMDs) as they were excluded from initial vaccine trials. Vaccination guidance is based on data from adults with or CYP without RMDs. Description/Method: Our objective was to describe the safety of SARS-COV-2 vaccination in adolescents with inflammatory RMDs and adults with JIA. We described patient characteristics, flares, and adverse events in adolescent cases under 18 with inflammatory RMDs and adult cases aged 18 or above with JIA submitted to the European Alliance of Associations for Rheumatology (EULAR) COVAX registry. Discussion/Results: Thirty-six adolescent cases were reported from 4 countries, mostly female (58%) with JIA (42%: 28% non-systemic JIA, 14% systemic JIA) and a median age of 15 [IQR: 14.5, 17]. Most were in remission (64%) or had minimal (22%) disease activity at the time of vaccination. Over half of the adolescent group (56%) reported early reactogenic-like AEs. One mild polyarthralgia flare and one serious AE of special interest (malaise) were reported. No CYP reported SARS-CoV-2 infection post-vaccination. No cases of paediatric inflammatory multi-system syndrome or myocarditis adverse events were reported. Seventy-four adult JIA cases were reported from 11 countries;73% were female with a median age of 26 [IQR: 23, 31]. Eight-five percent had ns-JIA and 15% had s-JIA. Almost two thirds (62%) reported early reactogenic-like AEs and two flares were reported (mild polyarthralgia and moderate uveitis). No serious AEs of special interest were reported among adults with JIA. Three 20-30 year old females were diagnosed with SARS-CoV-2 post-vaccination;all fully recovered. Key learning points/Conclusion: In this observational registry dataset, SARS-CoV-2 vaccines appeared safe in adolescents with RMDs and adults with JIA, with a low frequency of disease flares, serious AEs, and SARS-CoV-2 re-infection seen in both populations.

Sars-Cov-2 Infection in 898 Patients with Sjogren's Syndrome: Characteristics Associated with Poor Outcomes

Objectives. To determine characteristics associated with a more severe COVID-19 outcome in people with Sjogren's disease (SJD). Methods. People with SJD and COVID-19 reported to two international registries (Sjogren Big Data Consortium and COVID-19 Global Rheumatology Alliance) from March 2020 to October 2021 were included. An ordinal COVID-19 severity scale was defined: (1) not hospitalized, (2) hospitalized with no ventilation, (3) hospitalized requiring non-invasive ventilation, (4) hospitalized requiring invasive ventilation, and (5) death. Odds ratios (OR) were estimated using a multivariable ordinal logistic regression model adjusted for age, sex, comorbidities and anti-rheumatic medications included as covariates. Results. A total of 898 people with SJD were included (825 (91.8%) women, mean age SARS-CoV-2 infection diagnosis: 55.5 years), including 652 patients with primary SJD and 246 with other associated systemic rheumatic diseases. 33.9% were hospitalized, 14.5% required ventilation, and 4.3% died. In the multivariable model, older age (OR 1.03, 95% CI 1.02 to 1.05), male sex (OR 1.81, 95% CI 1.10 to 2.92), two or more comorbidities (OR 2.99, 95% CI 1.92 to 4.67;vs none), baseline therapy with corticosteroids (OR 2.04, 95% CI 1.20 to 3.46), immunosuppressive agents (OR 2.09, 95% CI 1.30 to 3.38) and B-cell depleting agents (OR 5.38, 95% CI 2.77 to 10.47) were associated with worse outcomes (reference for all medications: hydroxychloroquine only). Conclusions. More severe COVID-19 outcomes in individuals with Sjogren's are largely driven by demographic factors and baseline comorbidities. Patients using immunosuppressants, especially rituximab, also experienced more severe outcomes.

FACTORS ASSOCIATED with SEVERE COVID-19 OUTCOMES in PATIENTS with IDIOPATHIC INFLAMMATORY MYOPATHY: RESULTS from the COVID-19 GLOBAL RHEUMATOLOGY ALLIANCE PHYSICIAN-REPORTED REGISTRY

Background: There is a paucity of data in the literature about the outcome of patients with idiopathic infammatory myopathy (IIM) who have been infected with SARS-CoV-2. Objectives: To investigate factors associated with severe COVID-19 outcomes in patients with IIM. Methods: Data on demographics, number of comorbidities, region, COVID-19 time period, physician-reported disease activity, anti-rheumatic medication exposure at the clinical onset of COVID-19, and COVID-19 outcomes of IIM patients were obtained from the voluntary COVID-19 Global Rheumatology Alliance physician-reported registry of adults with rheumatic disease (from 17 March 2020 to 27 August 2021). An ordinal COVID-19 severity scale was used as primary outcome of interest, with each outcome category being mutually exclusive from the other:a) no hospital-ization, b) hospitalization (and no death), or c) death. Odds ratios (OR) were estimated using multivariable ordinal logistic regression. In ordinal logistic regression, the effect size of a categorical predictor can be interpreted as the odds of being one level higher on the ordinal COVID-19 severity scale than the reference category. Results: Complete hospitalization and death outcome data was available in 348 IIM cases. Mean age was 53 years, and 223 (64.1%) were female. Overall, 167/348 (48.0%) people were not hospitalized, 136/348 (39.1%) were hospitalized (and did not die), and 45/348 (12.9%) died. Older age (OR=1.59 per decade of life, 95%CI 1.32-1.93), male sex (OR=1.63, 95%CI 1.004-2.64;versus female), high disease activity (OR=4.05, 95%CI 1.29-12.76;versus remission), presence of two or more comorbidities (OR=2.39, 95%CI 1.22-4.68;versus none), predni-solone-equivalent dose >7.5 mg/day (OR=2.37, 95%CI 1.27-4.44;versus no gluco-corticoid intake), and exposure to rituximab (OR=2.60, 95%CI 1.23-5.47;versus csDMARDs only) were associated with worse COVID-19 outcomes (Table 1). Conclusion: These are the frst global registry data on the impact of COVID-19 on IIM patients. Older age, male gender, higher comorbidity burden, higher disease activity, higher glucocorticoid intake and rituximab exposure were associated with worse outcomes. These fndings will inform risk stratifcation and management decisions for IIM patients.

THE IMPACT of COVID-19 on MEDICATION NON-ADHERENCE in A RHEUMATOID and PSORIATIC ARTHRITIS UK COHORT

Background: In March 2020, as part of the UK's COVID-19 prevention strategy, those identifed as 'clinically extremely vulnerable,' were advised to shield. This included a number of patients prescribed anti-rheumatic drugs, who were asked to continue their current treatment unless they developed symptoms of infection. Suboptimal treatment adherence (16.0%-81.0%) has been reported in patients with arthritic diseases, and is associated with psychological factors, including anxiety (1). Previous literature in non-UK cohorts has highlighted suboptimal adherence levels in immunosuppressed patients during the pandemic, although many were single centre studies (2,3). Objectives: The aim of this multi-centre study is to investigate the impact of the COVID-19 pandemic on adherence to anti-rheumatic medications in patients with established rheumatoid (RA) and psoriatic (PsA) arthritis in the UK who had recently commenced a biologic or targeted synthetic DMARD. Methods: Between September 2020 and May 2021, RA and PsA patients prescribed biologic or targeted synthetic anti-rheumatic drugs from two multi-centre observational studies (BRAGGSS and OUTPASS) were sent a questionnaire on medication usage, adherence, and perceptions to establish the impact of COVID-19 on these parameters. Patients were asked about compliance during the COVID-19 pandemic using a 5-point Likert scale (always, often, sometimes, rarely, and never) and the reason for non-adherence. Adherence was defned as never missing or delaying a dose, unless medically advised. Descriptive summary statistics were calculated, and logistic regression and Pearson's chi-squared tests were employed to investigate variables associated with self-reported non-adherence. Results: In total 159 questionnaires were returned (81.1% RA and 18.9% PsA). Methotrexate (53.5%) was the most frequently prescribed agent, followed by etan-ercept (25.2%), sulfasalazine (22.6%), hydroxychloroquine (21.4%) and adalimumab (19.5%). Furthermore, 68.6% of patients were prescribed ≥2 drugs. During the pandemic, 42.1% of patients reported missing or delaying a treatment dose for any reason. Adherence information was available for 97.5% of patients with 25.8% reporting non-adherence which was not medically advised. Methotrexate non-adherence was 27.1%, with similar levels reported for etanercept (20.0%), sulfasalazine (27.8%), hydroxychloroquine (35.3%) and adalimumab (29.0%). No drugs had signifcantly different adherence compared to methotrexate. Furthermore, there was no association between disease type or perception of disease control and adherence. Of non-adherent patients, 17.5% reported increased anxiety, fear, and increased risk due to the COVID-19 pandemic as an influencing factor. Meanwhile, 37.5% of non-adherent patients listed non-COVID-19 intentional reasons and 45.0% reported non-intentional reasons, with forgetting and running out of treatment listed most frequently. Conclusion: In a UK cohort self-reported non-adherence was reported in 25.8% of patients during the COVID-19 pandemic, despite medical advice, with reasons including increased anxiety due to COVID-19.

CHARACTERISTICS ASSOCIATED with POOR COVID-19 OUTCOMES in PEOPLE with PSORIASIS and SPONDYLOARTHRITIS: DATA from the COVID-19 PSOPROTECT and GLOBAL RHEUMATOLOGY ALLIANCE PHYSICIAN-REPORTED REGISTRIES

Background: Some factors associated with severe COVID-19 outcomes have been identifed in patients with psoriasis (PsO) and infammatory/autoimmune rheumatic diseases, namely older age, male sex, comorbidity burden, higher disease activity, and certain medications such as rituximab. However, information about specifcities of patients with PsO, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), including disease modifying anti-rheumatic drugs (DMARDs) specifcally licensed for these conditions, such as IL-17 inhibitors (IL-17i), IL-23/IL-12 + 23 inhibitors (IL-23/IL-12 + 23i), and apremilast, is lacking. Objectives: To determine characteristics associated with severe COVID-19 outcomes in people with PsO, PsA and axSpA. Methods: This study was a pooled analysis of data from two physician-reported registries: the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), comprising patients with PsO/PsA, and the COVID-19 Global Rheumatology Alliance (GRA) registry, comprising patients with PsA/axSpA. Data from the beginning of the pandemic up to 25 October, 2021 were included. An ordinal severity outcome was defned as: 1) not hospitalised, 2) hospitalised without death, and 3) death. A multivariable ordinal logistic regression model was constructed to assess the relationship between COVID-19 severity and demographic characteristics (age, sex, time period of infection), comorbidities (hypertension, other cardiovascular disease [CVD], chronic obstructive lung disease [COPD], asthma, other chronic lung disease, chronic kidney disease, cancer, smoking, obesity, diabetes mellitus [DM]), rheumatic/skin disease (PsO, PsA, axSpA), physician-reported disease activity, and medication exposure (methotrexate, lefunomide, sulfasalazine, TNFi, IL17i, IL-23/IL-12 + 23i, Janus kinase inhibitors (JAKi), apremilast, glucocorticoids [GC] and NSAIDs). Age-adjustment was performed employing four-knot restricted cubic splines. Country-adjustment was performed using random effects. Results: A total of 5008 individuals with PsO (n=921), PsA (n=2263) and axSpA (n=1824) were included. Mean age was 50 years (SD 13.5) and 51.8% were male. Hospitalisation (without death) was observed in 14.6% of cases and 1.8% died. In the multivariable model, the following variables were associated with severe COVID-19 outcomes: older age (Figure 1), male sex (OR 1.53, 95%CI 1.29-1.82), CVD (hypertension alone: 1.26, 1.02-1.56;other CVD alone: 1.89, 1.22-2.94;vs no hypertension and no other CVD), COPD or asthma (1.75, 1.32-2.32), other lung disease (2.56, 1.66-3.97), chronic kidney disease (2.32, 1.50-3.59), obesity and DM (obesity alone: 1.36, 1.07-1.71;DM alone: 1.85, 1.39-2.47;obesity and DM: 1.89, 1.34-2.67;vs no obesity and no DM), higher disease activity and GC intake (remission/low disease activity and GC intake: 1.96, 1.36-2.82;moderate/severe disease activity and no GC intake: 1.35, 1.05-1.72;moderate/severe disease activity and GC intake 2.30, 1.41-3.74;vs remission/low disease activity and no GC intake). Conversely, the following variables were associated with less severe COVID-19 outcomes: time period after 15 June 2020 (16 June 2020-31 December 2020: 0.42, 0.34-0.51;1 January 2021 onwards: 0.52, 0.41-0.67;vs time period until 15 June 2020), a diagnosis of PsO (without arthritis) (0.49, 0.37-0.65;vs PsA), and exposure to TNFi (0.58, 0.45-0.75;vs no DMARDs), IL17i (0.63, 0.45-0.88;vs no DMARDs), IL-23/IL-12 + 23i (0.68, 0.46-0.997;vs no DMARDs) and NSAIDs (0.77, 0.60-0.98;vs no NSAIDs). Conclusion: More severe COVID-19 outcomes in PsO, PsA and axSpA are largely driven by demographic factors (age, sex), comorbidities, and active disease. None of the DMARDs typically used in PsO, PsA and axSpA, were associated with severe COVID-19 outcomes, including IL-17i, IL-23/IL-12 + 23i, JAKi and apremilast.

SYSTEMATIC LITERATURE REVIEW on the SCREENING and PROPHYLAXIS of CHRONIC and OPPORTUNISTIC INFECTIONS

Background: Opportunistic and chronic infections can arise in the context of treatment used for Autoimmune Rheumatic Diseases (ARDs). Although it is recognized that screening procedures and prophylactic measures must be followed, clinical practice is largely heterogeneous, with relevant recommendations not currently developed or disparately located across the literature. Objectives: To conduct a systematic literature review (SLR) focusing on the screening and prophylaxis of opportunistic and chronic infections in ARDs. This is preparatory work done by members of the respective EULAR task force (TF). Methods: Following the EULAR standardised operating procedures, we conducted an SLR with the following 5 search domains;1) Infection: infectious agents identifed by a scoping review and expert opinion (TF members), 2) Rheumatic Diseases: all ARDs, 3) Immunosuppression: all immunosuppressives/immunomodulators used in rheumatology, 4) Screening: general and specifc (e.g mantoux test) terms, 5) Prophylaxis: general and specifc (e.g trimethop-rim) terms. Articles were retrieved having the terms from domains 1 AND 2 AND 3, plus terms from domains 4 OR 5. Databases searched: Pubmed, Embase, Cochrane. Exclusion criteria: post-operative infections, pediatric ARDs, not ARDs (e.g septic arthritis), not concerning screening or prophylaxis, Covid-19 studies, articles concerning vaccinations and non-Εnglish literature. Quality of studies included was assessed as follows: Newcastle Ottawa scale for non-randomized controlled trials (RCTs), RoB-Cochrane tool for RCTs, AMSTAR2 for SLRs. Results: 5641 studies were initially retrieved (Figure 1). After title and screening and removal of duplicates, 568 full-text articles were assessed for eligibility. Finally, 293 articles were included in the SLR. Most studies were of medium quality. Reasons for exclusion are shown in Figure 1. Results categorized as per type of microbe, are as follows: For Tuberculosis;evidence suggests that tuberculin skin test (TST) is affected by treatment with glucocorticoids and conventional synthetic DMARDs (csDMARDs) and its performance is inferior to interferon gamma release assay (IGRA). Agreement between TST and IGRA is moderate to low. Conversion of TST/IGRA occurs in about 10-15% of patients treated with biologic DMARDs (bDMARDs). Various prophylactic schemes have been used for latent TB, including isoniazide for 9 months, rifampicin for 4 months, isoniazide/rifampicin for 3-4 months. For hepatitis B (HBV): there is evidence that risk of reactivation is increased in patients positive for hepatitis B surface antigen. These patients should be referred for HBV treatment. Patients who are positive for anti-HBcore antibodies, are at low risk for reactivation when treated with glucocorticoids, cDMARDs and bDMARDs but should be monitored periodically with liver function tests and HBV-viral load. Patients treated with rituximab display higher risk for HBV reactivation especially when anti-HBs titers are low. Risk for reactivation in hepatitis C RNA positive patients, treated with bDMARDs is low. However, all patients should be referred for antiviral treatment and monitored periodically. For pneumocystis jirovecii: prophylaxis with trimeth-oprim/sulfamethoxazole (alternatively with atovaquone or pentamidine) should be considered in patients treated with prednisolone: 15-30mg/day for more than 4 weeks. Few data exist for screening and prophylaxis from viruses like E B V, CMV and Varicella Zoster Virus. Expert opinion supports the screening of rare bugs like histoplasma and trypanosoma in patients considered to be at high risk (e.g living in endemic areas). Conclusion: The risk of chronic and opportunistic infections should be considered in all patients prior to treatment with immunosuppressives/immunomod-ulators. Different screening and prophylaxis approaches are described in the literature, partly determined by individual patient and disease characteristics. Collaboration between different disciplines is important.

SARS-COV-2 VACCINE SAFETY in ADOLESCENTS with INFLAMMATORY RHEUMATIC and MUSCULOSKELETAL DISEASES and ADULTS with JUVENILE IDIOPATHIC ARTHRITIS

Background: There is a lack of data on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination safety in children and young people (CYP) with rheumatic and musculoskeletal diseases (RMDs). Current vaccination guidance is based on data from adults with RMDs or CYP without RMDs. Objectives: To describe the characteristics and outcomes of adolescents with infammatory RMDs and adults with juvenile idiopathic arthritis (JIA) vaccinated against SARS-CoV-2. Methods: We described patient characteristics, fares, and adverse events in adolescent cases under 18 with infammatory RMDs and adult cases aged 18 or above with JIA submitted to the European Alliance of Associations for Rheumatology (EULAR) COVAX registry. Results: Thirty-six adolescent cases were reported from 4 countries, the most frequent diagnosis was JIA (42%). Over half (56%) reported early reactogen-ic-like adverse events (AEs) experienced within 7 days of vaccination. One mild polyarthralgia fare and one serious AE (malaise) were reported. No CYP reported SARS-CoV-2 infection post-vaccination. In addition to the adolescent cases, eleven countries reported 74 adult JIA cases. Among these, 62% reported early reactogenic-like AEs and two fares were reported (mild polyarthralgia and moderate uveitis). No serious AEs of special interest were reported among adults with JIA. Three 20-30 year old females were diagnosed with SARS-CoV-2 post-vaccination;all fully recovered. Conclusion: In this observational registry dataset, SARS-CoV-2 vaccines appeared safe in adolescents with RMDs and adults with JIA, with a low frequency of disease fares, serious AEs, and SARS-CoV-2 re-infection seen in both populations.

MONITORING OF METHOTREXATE BLOOD TOXICITY DURING THE COVID-19 PANDEMIC FOR PATIENTS WITH RHEUMATOID ARTHRITIS: DATA FROM THE GREATER MANCHESTER CARE RECORD

Background/Aims Current British Society for Rheumatology guidance suggests 3- monthly blood monitoring for patients prescribed methotrexate whose disease, drug dosage and blood results are stable, although evidence for this recommendation is limited. Anecdotal reports suggest monitoring may have reduced during the pandemic. The study aims were, in patients with rheumatoid arthritis (RA) prescribed methotrexate, to determine: 1) interval length between blood tests during the pandemic, and 2) whether prolonged intervals were associated with abnormal blood test results. Methods Data came from the Greater Manchester Care Record, a database containing electronic health records from both primary and secondary care for people across Greater Manchester. Inclusion criteria were: a diagnosis of RA;regular blood monitoring (<=91 days between blood tests) and regular methotrexate prescriptions in the year prior to the pandemic (01/03/2019-01/03/2020). Blood test intervals during the pandemic were determined, a prolonged interval was defined as>91 days. Cytopenia and transaminitis events were identified between March-December 2020 and March-December 2019 (as a comparator). Proportions of events are presented for each time-period and stratified by whether the interval was prolonged. Results 1011 patients met the inclusion criteria, with a median of 5 blood tests (interquartile range (IQR): 3-7) during the pandemic and a median interval of 57 days (IQR: 34-84). 612 (61%) patients had at least one prolonged interval, with 241 (23.8%) having multiple. Prolonged intervals had a median length of 112 days (IQR: 99-135). 115 (11.4%) people had a prolonged interval but no subsequent blood test before the study end date (median 120 days [IQR: 104-150]). The proportion of cytopenia and transaminitis events was low and similar across time-periods and when stratified by interval length (Table 1). Conclusion Nearly two-thirds of patients on stable methotrexate had at least one prolonged interval and 1 in 10 had a prolonged interval with no subsequent blood test. Initial analyses of test results do not indicate increased occurrence of methotrexate blood toxicity in those with prolonged blood test intervals during the pandemic. Further work is required to determine whether those with prolonged intervals represent a group at lower risk where less frequent blood tests would be appropriate.

Outcomes of COVID-19 infection among children and young people with pre-existing rheumatic and musculoskeletal diseases

Introduction: It remains unknown whether children and young people with rheumatic and musculoskeletal diseases (RMD) who acquire COVID-19 infection have a more severe COVID-19 course, due to either underlying disease or immunosuppressive treatments. Objectives: To describe outcomes among children and young people with underlying RMD who acquire COVID-19 infection. Methods: All children and young people <19 years of age with COVID-19 (presumptive or confirmed) reported to the EULAR COVID- 19 Database, which collects details regarding RMD diagnosis and treatment, COVID infection and outcomes, between 27 March 2020 and 9 April 2021 (cut-off date for this analysis) were included. Patient characteristics and COVID-19 outcomes are presented. Results: A total of 364 children and young people (age range 2-18 years;table) have been reported to the database from 17 countries;mostly France (N=71), Germany (N=71), Czechia (N=59), Spain (N= 50), Israel (N=60), and UK (N=25). Most patients had a diagnosis of juvenile idiopathic arthritis (JIA;N=244;67%). There were 20 (5%) hospitalisations and 1 death reported due to COVID-19. The most commonly reported symptoms were fever (40%) and cough (30%). Only 42 (12%) patients reported glucocorticoid use. Any DMARD therapy was used by 251 (69%) patients;161 (44%) were on csDMARDs, 119 (33%) on anti-TNF. 40% were in remission at time of COVID-19 infection, 28% in low, and 9% in moderate/high disease activity. Among those with hospitalisation data [N=290], patients on any DMARD therapy (cs/b/tsDMARDs) had similar odds for hospitalisation compared with those not on therapy, adjusted for age, sex, rheumatic disease, and disease severity (odds ratio 1.3;95% CI 0.3, 4.6). Conclusion: These initial data on outcomes of COVID-19 infection in paediatric RMDs are very reassuring, only one-in-twenty patients were reported to be hospitalised. Due to the database design and inherent reporting bias, this is likely an overestimate, suggesting that overall outcomes among this population appear to be generally good, with mild infection. Increasing case reports to the database will allow further exploration of drug- and disease-specific outcomes.

Tolérance de la vaccination contre le SRAS-CoV-2 chez les patients atteints de maladies rhumatologiques inflammatoires/auto-immunes : résultats du registre EULAR-COVAX chez 5121 patients

Introduction Les patients atteints de maladies musculosquelettiques inflammatoires/auto-immunes (I-RMD) n’ont pas été inclus dans les études de tolérance des vaccins contre le SARS-CoV-2 et sont souvent inquiets quant à la tolérance de la vaccination. Notre objectif est d’étudier la tolérance des vaccins contre le SARS-CoV-2 chez les patients atteints de maladies musculosquelettiques inflammatoires/auto-immunes (I-RMD). Patients et méthodes Pour cela, nous avons créé avec l’EULAR un registre international de cas rapportés par les médecins rhumatologues et internistes de patients atteints d’I-RMD et de RMD non inflammatoire (NI-RMD) vaccinés contre le SARS-CoV-2. Du 5 février 2021 au 27 juillet 2021, nous avons recueilli des données sur la démographie, la vaccination, le diagnostic de RMD, l’activité de la maladie, les traitements immunomodulateurs/immunosuppresseurs, les poussées, les événements indésirables (EI) et les infections COVID-19 chez les patients vaccinés. Les données ont été analysées de manière descriptive. Résultats L’étude a inclus 5121 participants de 30 pays, la majorité de France (40 %), Italie (16 %) et Portugal (14 %), 90 % avec des I-RMD (n=4604, 68 % de femmes, âge moyen 60,5 ans) et 10 % avec des NI-RMD (n=517), 77 % de femmes, âge moyen 71,4 ans. La polyarthrite rhumatoïde (33 %), les connectivites (18 %), les spondyloarthrites (11 %), le rhumatisme psoriaqique (10 %) et les vascularites (12 %) étaient les diagnostics les plus fréquents ;54 % des patients ont reçu des traitements de fond synthétiques conventionnels (csDMARD), 42 % des DMARD biologiques ou ciblés et 35 % des immunosuppresseurs. La plupart des patients ont reçu le vaccin Pfizer/BioNTech (70 %), 17 % AstraZeneca/Oxford et 8 % Moderna. Une infection COVID post-vaccination a été signalée dans 0,7 à 1,1 % des cas, selon le statut vaccinal (entièrement/partiellement vacciné) et le groupe RMD. Des poussées d’I-RMD ont été signalées dans 4,4 % des cas (0,6 % de poussées sévères), dont 1,5 % ont entraîné des changements de médicaments. Des EI ont été signalés dans 37 % des cas (37 % I-RMD, 40 % NI-RMD), des EI sévères dans 0,4 % des cas, très divers et avec une fréquence comparable et même inférieure à celle observée chez les patients atteints de NI-RMD (1,1 %). Discussion La tolérance au vaccin n’était pas différente entre les groupes I-RMD et NI-RMD. Dans les essais cliniques de vaccins à ARN contre le SRAS-CoV-2 dans la population générale, les taux d’EI graves étaient très semblables à ceux de notre étude, allant de 0,4 % à 0,6 % dans le groupe vacciné et de 0,5 % à 0,6 % dans le groupe témoin, ce qui suggère que ces EI graves ne sont pas nécessairement liés au vaccin. Conclusion Il s’agit de la plus grande étude de la tolérance des vaccins anti-SRAS-CoV-2 chez près de 5000 patients atteints de maladies inflammatoires/auto-immunes rhumatologiques. Le profil de sécurité des vaccins contre le SRAS-CoV-2 chez les patients atteints d’I-RMD était rassurant, et comparable à celui des patients atteints de NI-RMD. La majorité des patients ont bien toléré leur vaccination, avec de rares poussée d’I-RMD et de très rares EI sévères probablement non liés à la vaccination. Ces résultats devraient rassurer les rhumatologues et les personnes vaccinées, et favoriser la confiance dans la sécurité du vaccin COVID-19 chez les patients atteints de I-RMD.

COVID-19 vaccine safety in patients with rheumatic and musculoskeletal disease

Background: The consequences of the COVID-19 outbreak are unprecedented and have been felt by everyone around the world, including people with rheumatic and musculoskeletal diseases (RMDs). With the development of vaccines, the future is becoming brighter. Vaccines are a key pillar of public health and have been proven to prevent many serious diseases. However, vaccination also raises questions, especially for patients with inflammatory RMDs and/or treated with drugs that influence their immune system. Objectives: Our aim was to collect safety data among RMD patients receiving COVID-19 vaccines. Methods: The EULAR COVID-19 Vaccination (COVAX) Registry is an observational registry launched on 5 February 2021. Data are entered voluntarily by clinicians or associated healthcare staff;patients are eligible for inclusion if they have an RMD and have been vaccinated against SARS-CoV-2. Descriptive statistics are presented. Results: As of 27 April 2021, 1519 patients were reported to the registry. The majority were female (68%) and above the age of 60 (57%). Mean age was 63 years (SD 16), ranging from 15 to 97 years. A total of 28 countries contributed to the registry, with France (60%) and Italy (13%) as the highest contributors. The majority (91%) had inflammatory RMDs. Inflammatory joint diseases accounted for 51% of cases, connective tissue diseases 19%, vasculitis 16%, other immune mediated inflammatory diseases 4%, and non-inflammatory/mechanical RMDs 9%. The most frequent individual diagnoses were rheumatoid arthritis (30%), axial spondyloarthritis (8%), psoriatic arthritis (8%), systemic lupus erythematosus (SLE, 7%) and polymyalgia rheumatica (6%). At the time of vaccination, 45% were taking conventional synthetic DMARDs, 36% biological DMARDs, 31% systemic glucocorticoids, 6% other immunosuppressants (azathioprine;mycophenolate;cyclosporine;cyclophosphamide;tacrolimus), and 3% targeted synthetic DMARDs. The most frequent individual DMARDs were methotrexate (29%), TNF-inhibitors (18%), antimalarials (10%) and rituximab (6%). The vaccines administered were: 78% Pfizer, 16% AstraZeneca, 5% Moderna and 1% other/unknown;66% of cases received two doses and 34% one dose. Mean time from 1st and 2nd dose to case report was 41 days (SD 26) and 26 days (SD 23), respectively. COVID-19 diagnosis after vaccination was reported in 1% (18/1519) of cases. Mean time from first vaccination until COVID-19 diagnosis was 24 days (SD 17). Disease flares were reported by 5% (73/1375) of patients with inflammatory RMDs, with 1.2% (17/1375) classified as severe flares. Mean time from closest vaccination date to inflammatory RMD flare was 5 days (SD 5). The most common flare types were arthritis (35/1375=2.5%), arthralgia (29/1375=2.1%), cutaneous flare (11/1375=0.8%) and increase in fatigue (11/1375=0.8%). Potential vaccine side effects were reported by 31% of patients (467/1519). The majority were typical early adverse events within 7 days of vaccination, namely pain at the site of injection (281/1519=19%), fatigue (171/1519=11%) and headache (103/1519=7%). Organ/system adverse events were reported by 2% (33/1519) but only 0.1% (2/1519) reported severe adverse events, namely a case of hemiparesis in a patient with systemic sclerosis/ SLE overlap syndrome (ongoing at the time of reporting), and a case of giant cell arteritis in a patient with osteoarthritis (recovered/resolved without sequelae). Conclusion: The safety profiles for COVID-19 vaccines in RMD patients was reassuring. Most adverse events were the same as in the general population, they were non-serious and involved short term local and systemic symptoms. The overwhelming majority of patients tolerated their vaccination well with rare reports of inflammatory RMD flare (5%;1.2% severe) and very rare reports of severe adverse events (0.1%). These initial findings should provide reassurance to rheumatologists and vaccine recipients, and promote confidence in COVID-19 vaccine safety in RMD patients, namely those with inflammatory RMDs and/or taking treatments that influence their immune system.

Characteristics associated with severe COVID-19 outcomes in systemic lupus erythematosus (SLE): Results from the covid-19 global rheumatology alliance (COVID-19 GRA)

Background: An increased risk of severe COVID-19 outcomes may be seen in patients with autoimmune diseases on moderate to high daily doses of glucocorticoids, as well as in those with comorbidities. However, specific information about COVID-19 outcomes in SLE is scarce. Objectives: To determine the characteristics associated with severe COVID-19 outcomes in a multi-national cross-sectional registry of COVID-19 patients with SLE. Methods: SLE adult patients from a physician-reported registry of the COVID-19 GRA were studied. Variables collected at COVID-19 diagnosis included age, sex, race/ethnicity, region, comorbidities, disease activity, time period of COVID-19 diagnosis, glucocorticoid (GC) dose, and immunomodulatory therapy. Immunomodulatory therapy was categorized as: antimalarials only, no SLE therapy, traditional immunosuppressive (IS) drug monotherapy, biologics/targeted synthetic IS drug monotherapy, and biologic and traditional IS drug combination therapy. We used an ordinal COVID-19 severity outcome defined as: not hospitalized/hospitalized without supplementary oxygen;hospitalized with non-invasive ventilation;hospitalized with mechanical ventilation/extracorporeal membrane oxygenation;and death. An ordinal logistic regression model was constructed to assess the association between demographic characteristics, comorbidities, medications, disease activity and COVID-19 severity. This assumed that the relationship between each pair of outcome groups is of the same direction and magnitude. Results: Of 1069 SLE patients included, 1047 (89.6%) were female, with a mean age of 44.5 (SD: 14.1) years. Patient outcomes included 815 (78.8%) not hospitalized/hospitalized without supplementary oxygen;116 (11.2) hospitalized with non-invasive ventilation, 25 (2.4%) hospitalized with mechanical ventilation/ extracorporeal membrane oxygenation and 78 (7.5%) died. In a multivariate model (n=804), increased age [OR=1.03 (1.01, 1.04)], male sex [OR =1.93 (1.21, 3.08)], COVID-19 diagnosis between June 2020 and January 2021 (OR =1.87 (1.17, 3.00)), no IS drug use [OR =2.29 (1.34, 3.91)], chronic renal disease [OR =2.34 (1.48, 3.70)], cardiovascular disease [OR =1.93 (1.34, 3.91)] and moderate/ high disease activity [OR =2.24 (1.46, 3.43)] were associated with more severe COVID-19 outcomes. Compared with no use of GC, patients using GC had a higher odds of poor outcome: 0-5 mg/d, OR =1.98 (1.33, 2.96);5-10 mg/d, OR =2.88 (1.27, 6.56);>10 mg/d, OR =2.01 (1.26, 3.21) (Table 1). Conclusion: Increased age, male sex, glucocorticoid use, chronic renal disease, cardiovascular disease and moderate/high disease activity at time of COVID-19 diagnosis were associated with more severe COVID-19 outcomes in SLE. Potential limitations include possible selection bias (physician reporting), the cross-sectional nature of the data, and the assumptions underlying the outcomes modelling.

Associations of baseline use of biologic or targeted synthetic dmards with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 global rheumatology alliance

Background: Targeted DMARDs may dampen the inflammatory response in COVID-19, perhaps leading to a less severe clinical course. However, some DMARD targets may impair viral immune defenses. Due to sample size limitations, previous studies of DMARD use and COVID-19 outcomes have combined several heterogeneous rheumatic diseases and medications, investigating a single outcome (e.g., hospitalization). Objectives: To investigate the associations of baseline use of biologic or targeted synthetic (b/ts) DMARDs with a range of poor COVID-19 outcomes in rheumatoid arthritis (RA). Methods: We analyzed voluntarily reported cases of COVID-19 in patients with rheumatic diseases in the COVID-19 Global Rheumatology Alliance physician registry (March 12, 2020 -January 6, 2021). We investigated RA treated with b/ tsDMARD at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAK), interleukin-6 inhibitors (IL6i), or tumor necrosis factor inhibitors (TNFi). The outcome was an ordinal scale (1-4) for COVID-19 severity: 1) no hospitalization, 2) hospitalization without oxygen need, 3) hospitalization with any oxygen need or ventilation, or 4) death. Baseline covariates including age, sex, smoking, obesity, comorbidities (e.g., cardiovascular disease, cancer, interstitial lung disease [ILD]), concomitant non-biologic DMARD use, glucocorticoid use/ dose, RA disease activity, country, and calendar time were used to estimate propensity scores (PS) for b/tsDMARD. The primary analysis used PS matching to compare each drug class to TNFi. Ordinal logistic regression estimated ORs for the COVID-19 severity outcome. In a sensitivity analysis, we used traditional multivariable ordinal logistic regression adjusting for covariates without matching. Results: Of the 1,673 patients with RA on b/tsDMARDs at the onset of COVID-19, (mean age 56.7 years, 79.6% female) there were n=154 on ABA, n=224 on RTX, n=306 on JAK, n=180 on IL6i, and n=809 on TNFi. Overall, 498 (34.3%) were hospitalized and 112 (6.7%) died. Among all patients, 353 (25.3%) were ever smokers, 197 (11.8%) were obese, 462 (27.6%) were on glucocorticoids, 1,002 (59.8%) were on concomitant DMARDs, and 299 (21.7%) had moderate/ high RA disease activity. RTX users were more likely than TNFi users to have ILD (11.6% vs. 1.7%) and history of cancer (7.1% vs. 2.0%);JAK users were more likely than TNFi users to be obese (17.3% vs. 9.0%). After propensity score matching, RTX was strongly associated with greater odds of having a worse outcome compared to TNFi (OR 3.80, 95% CI 2.47, 5.85;Figure). Among RTX users, 42 (18.8%) died compared to 27 (3.3%) of TNFi users (Table). JAK use was also associated with greater odds of having a worse COVID-19 severity (OR 1.52, 95%CI 1.02, 2.28). ABA or IL6i use were not associated with COVID-19 severity compared to TNFi. Results were similar in the sensitivity analysis and after excluding cancer or ILD. Conclusion: In this large global registry of patients with RA and COVID-19, baseline use of RTX or JAK was associated with worse severity of COVID-19 compared to TNFi use. The very elevated odds for poor COVID-19 outcomes in RTX users highlights the urgent need for risk-mitigation strategies, such as the optimal timing of vaccination. The novel association of JAK with poor COVID-19 outcomes requires replication.

Outcomes of COVID-19 infection among children and young people with pre-existing rheumatic and musculoskeletal diseases

Background: It remains unknown whether children and young people with rheumatic and musculoskeletal diseases (RMD) who acquire COVID-19 infection have a more severe COVID-19 course, due to either underlying disease or immunosuppressive treatments. Objectives: To describe outcomes among children and young people with underlying RMD who acquire COVID-19 infection. Methods: All children and young people <18 years of age with COVID-19 (presumptive or confirmed) reported to the EULAR COVID-19 Database, which collects details regarding RMD diagnosis and treatment, COVID infection and outcomes, between 27 March 2020 and 29 January 2021 (cutoff date for this analysis) were included. Patient characteristics and COVID-19 outcomes are presented. Results: A total of 151 children and young people (age range 2-17 years;Table 1) have been reported to the database from 12 countries;mostly Spain (N=30), France (N=29), Israel (N=29), and Czechia (N=25). Most patients had a diagnosis of juvenile idiopathic arthritis (JIA;N=92;61%). Other diagnoses were autoinflammatory syndrome (including TRAPS, CAPS, FMF;12%), and systemic lupus erythematosus (4%). There were 14 (9%) hospitalisations and 1 (0.7%) death reported due to COVID-19. The most commonly reported symptoms were fever (46%), cough (34%), anosmia (19%), and headache (19%). Only 19 (13%) patients reported glucocorticoid use. DMARD therapy was used by 104 (69%) patients;67 (44%) were on csDMARDs (methotrexate [N=54], antimalarials [N=7]), 45 (30%) on anti-TNF, 9 (6%) on IL-6 inhibitors, and 7 (5%) on IL-1 inhibitors. Among the 145 patients with hospitalisation data, patients on any DMARD therapy (cs/b/tsDMARDs) had similar odds for hospitalisation compared with those not on therapy, adjusted for age (odds ratio 0.7;95% CI 0.2, 2.4). Conclusion: These initial data on outcomes of COVID-19 in paediatric RMDs are very reassuring, with less than 1 in 10 patients reporting hospitalisation. Due to the database design and inherent reporting bias, this is likely an overestimate, suggesting that overall outcomes among this population appear to be generally good, with mild infection. Increasing case reports to the database will allow further exploration of drug-and disease-specific outcomes.

Machine learning algorithms to predict COVID-19 acute respiratory distress syndrome in patients with rheumatic diseases: Results from the global rheumatology alliance provider registry

Background: Acute Respiratory Distress Syndrome (ARDS) is a life-threatening complication of COVID-19 and has been reported in approximately one-third of hospitalized patients with COVID-191. Risk factors associated with the development of ARDS include older age and diabetes2. However, little is known about factors associated with ARDS in the setting of COVID-19, in patients with rheumatic disease or those receiving immunosuppressive medications. Prediction algorithms using traditional regression methods perform poorly with rare outcomes, often yielding high specificity but very low sensitivity. Machine learning algorithms optimized for rare events are an alternative approach with potentially improved sensitivity for rare events, such as ARDS in COVID-19 among patients with rheumatic disease. Objectives: We aimed to develop a prediction model for ARDS in people with COVID-19 and pre-existing rheumatic disease using a series of machine learning algorithms and to identify risk factors associated with ARDS in this population. Methods: We used data from the COVID-19 Global Rheumatology Alliance (GRA) Registry from March 24 to Nov 1, 2020. ARDS diagnosis was indicated by the reporting clinician. Five machine learning algorithms optimized for rare events predicted ARDS using 42 variables covering patient demographics, rheumatic disease diagnoses, medications used at the time of COVID-19 diagnosis, and comorbidities. Model performance was assessed using accuracy, area under curve, sensitivity, specificity, positive predictive value, and negative predictive value. Adjusted odds ratios corresponding to the 10 most influential predictors from the best performing model were derived using hierarchical multivariate mixed-effects logistic regression that accounted for within-country correlations. Results: A total of 5,931 COVID-19 cases from 67 countries were included in the analysis. Mean (SD) age was 54.9 (16.0) years, 4,152 (70.0%) were female, and 2,399 (40.5%) were hospitalized. ARDS was reported in 388 (6.5% of total and 15.6% of hospitalized) cases. Statistically significant differences in the risk of ARDS were observed by demographics, diagnoses, medications, and comorbidities using unadjusted univariate comparisons (data not shown). Gradient boosting machine (GBM) had the highest sensitivity (0.81) and was considered the best performing model (Table 1). Hypertension, interstitial lung disease, kidney disease, diabetes, older age, glucocorticoids, and anti-CD20 monoclonal antibodies were associated with the development of ARDS while tumor necrosis factor inhibitors were associated with a protective effect (Figure 1). Conclusion: In this global cohort of patients with rheumatic disease, a machine learning model, GBM, predicted the onset of ARDS with 81% sensitivity using baseline information obtained at the time of COVID-19 diagnosis. These results identify patients who may be at higher risk of severe COVID-19 outcomes. Further studies are necessary to validate the proposed prediction model in external cohorts and to evaluate its clinical utility. Disclaimer: 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 ACR, NIH, (UK) NHS, NIHR, or the department of Health.