Factors associated with COVID-19-related death in people with rheumatic diseases : results from the COVID-19 Global Rheumatology Alliance physician-reported registry

1 Strangfeld A, etal. Ann Rheum Dis 2021;0:1–13. doi:10.1136/annrheumdis-2020-219498 Epidemiology EPIDEMIOLOGICAL SCIENCE Factors associated with COVID-19related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physicianreportedregistry Anja Strangfeld ,1 Martin Schäfer,1 Milena A Gianfrancesco,2 Saskia LawsonTovey,3,4 Jean W Liew,5 Lotta Ljung ,6,7 Elsa F Mateus,8,9 Christophe Richez ,10 Maria J Santos ,11,12 Gabriela Schmajuk,2 Carlo A Scirè ,13 Emily Sirotich,14,15 Jeffrey A Sparks,16 Paul Sufka,17 Thierry Thomas,18,19,20 Laura Trupin,2 Zachary S Wallace,21 Sarah AlAdely,4,22 Javier BachillerCorral ,23,24 Suleman Bhana,25 Patrice Cacoub,26,27,28 Loreto Carmona ,29 Ruth Costello ,22 Wendy Costello,30 Laure Gossec ,31,32 Rebecca Grainger,33 Eric Hachulla ,34 Rebecca Hasseli ,35 Jonathan S Hausmann ,36,37 Kimme L Hyrich ,4,22 Zara Izadi,2 Lindsay Jacobsohn,2 Patricia Katz,2 Lianne KearsleyFleet ,22 Philip C Robinson ,38,39 Jinoos Yazdany,2 Pedro M Machado ,40,41,42 COVID-19 Global Rheumatology Alliance To cite: StrangfeldA, SchäferM, GianfrancescoMA, etal. Ann Rheum Dis Epub ahead of print: [please include Day Month Year]. doi:10.1136/ annrheumdis-2020-219498 Handling editor Josef S Smolen ►Additional material is published online only. To view, please visit the journal online (http:// dx. doi. org/ 10. 1136/ annrheumdis2020219498). For numbered affiliations see end of article. Correspondence to Dr Pedro M Machado, Centre for Rheumatology, UCL Division of Medicine, University College London, London WC1E 6JF, UK; p. machado@ ucl. ac. uk AS and MS contributed equally. PCR, JY and PMM contributed equally. Received 11 November 2020 Revised 17 December 2020 Accepted 2 January 2021 ard. bmj. com © Author(s) (or their employer(s)) 2021. Reuse permitted under CC BYNC. No commercial reuse. See rights and permissions. Published by BMJ. ABSTRACT Objectives To determine factors associated with COVID-19related death in people with rheumatic diseases. Methods Physicianreported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Results Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19related death were age (66–75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisoloneequivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any diseasemodifying antirheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19related death. Conclusion Among people with rheumatic disease, COVID-19related death was associated with known general factors (older age, male sex and specific comorbidities) and diseasespecific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance Key messages What is already known about this subject? ►To date, most available data on outcomes for people with rheumatic diseases infected with SARSCoV-2 come from single centre or single country case series or from one large international registry; the COVID-19 Global Rheumatology Alliance (GRA) physician registry. ►The first GRA publication identified factors associated with higher odds of COVID-19 hospitalisation, including older age, presence of comorbidities and higher dosages of glucocorticoids (≥10 mg/day of prednisolone equivalent). ►Clinical outcome information on patients with COVID-19 who have rheumatic disease therefore remains limited, particularly with regard to factors associated with COVID-19related death. What does this study add? ►In this analysis of 3729 patients with rheumatic diseases, older age, male sex, and cardiovascular and chronic lung disease were associated with COVID-19related death. ►Diseasespecific factors, namely, moderate/ high disease activity and certain medications (rituximab, sulfasalazine and immunosuppressants (as opposed to immunomodulators like diseasemodifying antirheumatic drugs (DMARDs)) were also associated with COVID-19related death. copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from copyright. on March 3, 2021 at Universidade de Lisboa. 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Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from 2Strangfeld A, etal. Ann Rheum Dis 2021;0:1–13. doi:10.1136/annrheumdis-2020-219498 Epidemiology of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants. INTRODUCTION There is a lack of robust data to inform our understanding of outcomes following SARSCoV-2 infection in patients with inflammatory rheumatic diseases, leading to uncertainties regarding chronic disease management, especially for those taking immunosuppressant or immunomodulatory drugs.1–3 Whether people with rheumatic diseases belong to a vulnerable, higher risk population for SARSCoV-2 infection and have poorer outcomes is unclear.1–8 In general, this population seems to have similar or only slightly poorer outcomes compared with those without rheumatic disease.7–9 However, important confounding diseaserelated factors, such as disease activity or treatments, have previously not been addressed. Medications commonly used to treat rheumatic diseases have been used or are being tested for the prevention and/or treatment of COVID-19 and its complications,10 raising questions about the impact of these treatments on the outcomes of SARSCoV-2 infection. Continuation of immunomodulatory or immunosuppressive therapy is essential for controlling rheumatic disease activity, avoiding disease progression and preventing joint or organdamage related to sustained inflammation. Withdrawal of effective treatments should be based on sound evidence, even during a pandemic. To generate more granular data relevant to rheumatic diseases, a global network of rheumatologists, data scientists and patients developed a COVID-19 physicianreported case registry in March 2020.11 12 Analysis of the first 600 patients revealed that older age and comorbidities were associated with hospitalisation,13 similar to results in the general population.8 14 More robust data on the risk of poor outcomes, in particular risk of death, are required. The aim of this study was to investigate factors associated with COVID-19related death in patients with rheumatic diseases and to analyse these associations by disease group. METHODS Data source The COVID-19 Global Rheumatology Alliance (C19GRA) physicianreported registry is an observational registry launched on 24 March 2020. Data are entered voluntarily by rheumatologists or under supervision of rheumatologists; patients are eligible for inclusion if they have a preexisting rheumatic disease and a COVID-19 diagnosis. Data are entered either directly into the global or European data entry systems or transferred from national registries (France, Germany, Italy, Portugal and Sweden). We used data collected on or before 1 July 2020. Further details of this registry have been described elsewhere.11–13 Countries were assigned to the six WHO regions ( www. who. int); the ‘Americas’ was further divided into north and south. Given the registry collects anonymous data, the UK Health Research Authority and the University of California San Francisco Institutional Review Board considered it exempt from patient consent. Patient stratification into diagnostic groups Rheumatic diseases differ regarding the diseasemodifying antirheumatic drugs (DMARDs) approved for their treatment. To minimise the impact of this heterogeneity on the associations of interest, in addition to the main analysis with all patients, diagnostic categories were defined (figure 1) and stratified analyses were undertaken for patients with (1) inflammatory joint diseases (IJD), (2) rheumatoid arthritis (a subset of the IJD subgroup) and (3) connective tissue diseases (CTD)/vasculitis. COVID-19 reporting and outcome Both confirmed and presumptive cases of COVID-19 were reported. The method of COVID-19 diagnosis was specified: PCR, CT scan, metagenomic testing, laboratory assays or based on symptoms only. For analysis, patients were subsequently categorised into (1) confirmed or high likelihood of COVID-19 (chest imaging (CT or chest Xray) showing bilateral infiltrates and/or symptoms after close contact with a known laboratoryconfirmed COVID-19 positive patient) or (2) presumptive cases based on symptoms alone. The primary outcome was COVID-19related death. Treatment prior to COVID-19 Antirheumatic medications used prior to COVID-19 diagnosis were categorised into groups shown in figure 1. Immunomodulatory drugs (conventional synthetic (cs)/biological (b)/targeted synthetic (ts) DMARDs) were distinguished from immunosuppressive drugs (azathioprine, cyclophosphamide, ciclosporin, mycophenolate mofetil/mycophenolic acid, tacrolimus) as recommended by Isaacs and Burmester15; glucocorticoids are also immunosuppressive but they were examined separately and categorised by prednisoloneequivalent dosage (1–10 mg/day and >10 mg/day). Methotrexate monotherapy was adopted as the medication reference group; methotrexate is the anchor drug in multiple rheumatic diseases16 and it represents the largest medication category in the registry. Statistical analyses Descriptive tables were produced for the whole cohort and then by diagnostic group, country (for the six countries with the highest number of cases: France, Germany, Italy, Spain, UK and USA) and medication. Independent associations between demographic and disease features and COVID-19related death were estimated using multivariable logistic regression and reported as OR and 95% CI. Covariates included in the model were age, sex, key comorbidities (hypertension alone or cardiovascular disease (CVD) alone, hypertension combined with CVD, chronic lung disease, chronic kidney disease (CKD) and diabetes), smoking status (ever vs never), rheumatic disease diagnostic group, disease activity as per the physician’s global assessment (severe/ high or moderate disease activity vs minimal/low disease activity or remission), rheumatic disease treatment prior to COVID-19 diagnosis and prednisoloneequivalent glucocorticoid use. Key messages How might this impact on clinical practice or future developments? ►There is differential risk of COVID-19related death according to disease activity and treatments in patients with rheumatic disease, highlighting the need for adequate disease control with DMARDs, preferably without increasing the glucocorticoid dosage. copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from 3 Strangfeld A, etal. Ann Rheum Dis 2021;0:1–13. doi:10.1136/annrheumdis-2020-219498 Epidemiology All patients with confirmed or presumptive COVID-19 were included in the main analyses. Patients with missing primary outcome (N=82) or missing values for age, sex and DMARD (N=19) were excluded from analysis. Missing values for comorbidities, smoking status, glucocorticoid therapy and disease activity were derived by multiple imputation using full conditional specification.17 Results of the logistic regression analyses for 10 imputed datasets were pooled by Rubin’s rules. As disease activity was missing for all French patients, countrylevel life expectancy was used in the imputation model to explain potential structural differences in disease activity between countries not accounted for in the patientlevel data (data from 2018, source: http:// hdr. undp. org/). To account for pronounced heterogeneity between participating countries regarding both healthcare systems and infection dynamics, countries were implicitly considered as data clusters in the regression analysis by assuming that the data arose from a cluster sample design; this was done by applying a Taylor series linearisation in the variance estimation.18 For patients listed as having more than one rheumatic disease or being treated with more than one of the medications of interest, we created a hierarchy based on clinical expertise to categorise patients. This process creates disjoint categories, allowing a clear reference group for interpretation of the regression models and avoiding collinearities. Patients with more than one of the following diseases were grouped according to the following hierarchy: systemic lupus erythematosus (SLE)>vasculitis>other CTD>RA>psoriatic arthritis (PsA)>(other) spondyloarthritis (SpA)>other IJD>other nonIJD/nonCTD rheumatic disease. Patients receiving multiple csDMARDs or immunosuppressants (except glucocorticoids) were grouped according to the following hierarchy: immunosuppressants>- sulfasalazine>antimalarials>leflunomide>methotrexate. Patients receiving a b/tsDMARD were considered solely in the b/tsDMARD group. Patients treated with more than one b/ tsDMARD (N=4), patients receiving IL-1 inhibitors (N=20) and patients receiving DMARDs atypical for their disease subgroup (N=48) were excluded from analysis due to very low numbers (figure 2). Patients were excluded from a particular analysis if the medication they received provided ≤20 patients for that analysis or if there were no deaths reported for that specific medication. The following sensitivity analyses were performed to examine the robustness of our findings to procedures for handling missing data: (1) excluding patients from France (no disease activity data available); (2) complete case analysis. Further sensitivity analyses were conducted to assess the stability of the results: (1) limited to patients with confirmed or highly likely COVID-19; (2) using the alternative outcome ‘death or invasive ventilation’; (3) using a reduced number of covariates to assess the risk of overfitting; (4) analysis explicitly controlling for country, using data from the top six reporting countries; (5) analysis stratified for several binary key variables (age >65 or not, sex, ever smoked vs not, high/moderate/severe disease activity vs remission/low disease activity, CVD, chronic lung disease, glucocorticoid use) to assess the possibility of interactions. Data were considered statistically significant for p values <0.05. All analyses were conducted in SAS (V.9.4) and R (V.3.6.3). RESULTS As of 1 July 2020, 3830 patients were in the registry, of whom 3729 had no missing values for death, age, sex and DMARD therapy (table 1, results for all patients; online supplemental table 1, results stratified by diagnostic subgroup; online supplemental table 2, results stratified by country; online supplemental table 3, results stratified by medication of interest). Patient characteristics and outcomes of COVID-19 Mean age was 57 (15.7) years and most patients were ≤65 years (2586/3729, 69.3%) and female (2534/3729, 68%). The most common disease was RA (1394/3729, 37.4%), followed by CTDs other than SLE (533/3729, 14.3%), SLE (391/3729, 10.5%), PsA (440/3729, 11.8%) and other SpA (431/3729, 11.6%). Patients were primarily from Europe (2315/3729, 62.1%) or North America (1105/3729, 29.6%). Nearly half (1309/2758, 47.5%) had minimal or low disease activity and onethird (893/2758, 32.4%) were in remission before COVID-19. Onequarter of all patients (776/3164, 24.5%) were ever smokers. Most patients had a laboratoryconfirmed diagnosis of COVID-19 (2897/3729, 77.7%); 2.4% (91/3729) had a high likelihood of infection based on imaging or confirmed COVID-19 contacts. Death occurred in 10.5% (390/3729) of patients; 68.7% (268/390) of those who died were >65 years. Nearly half of all patients (1739/3546; 49.0%) were hospitalised. Invasive ventilation was reported in 6.2% (187/2995) of patients, but in 40.8% (120/294) of those who died. Figure 1 Disease and medication groups. ANCA, antineutrophil cytoplasm antibodies; DMARD, diseasemodifying antirheumatic drugs; IgG, immunoglobulin; IL, interleukin; JAK, Janus kinase; TNF, tumour necrosis factor. copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from 4Strangfeld A, etal. Ann Rheum Dis 2021;0:1–13. doi:10.1136/annrheumdis-2020-219498 Epidemiology Comorbidities Most patients (2582/3700, 69.8%) had at least one comorbidity, and 20.5% (760/3700) had more than three. The most frequent were hypertension (1307/3700, 35.3%), chronic lung disease (719/3700, 19.4%), obesity (BMI ≥30; 597/3700, 16.1%), diabetes (505/3700, 13.6%), other CVD (442/3700, 11.9%) and CKD (258/3700, 7.0%). Among deceased patients, the proportion of those with comorbidities was higher, with 42.7% (165/386) having ≥3 comorbidities, namely, 54.9% (212/386) with hypertension, 35.8% (138/386) with chronic lung disease, 24.6% (95/386) with diabetes, 32.1% (124/386) with other CVD and 19.9% (77/386) with CKD. Treatments At the time of COVID-19 diagnosis, 40.6% (1514/3729) of patients were treated only with csDMARDs, immunosuppressants or combinations of these; 35.7% (1331/3729) received Figure 2 Patient flowchart. Some patients had diagnoses in multiple groups; as a result, the sum of patients in each group is greater than the total number of patients. (*) Patients belonging to more than one diagnosic group: IJD and CTD: N=78 (10 deaths); IJD and other: N=70 (12 deaths); CTD and other: N=50 (13 deaths); IJD and CTD and other: N=5 (2 deaths). (§) Patients belonging to more than one diagnosic group: IJD and CTD: N=77 (10 deaths); IJD and other: N=70 (12 deaths); CTD and other: N=49 (12 deaths); IJD and CTD and other: N=5 (2 deaths). (#) Patients belonging to more than one diagnosic group: IJD and CTD: N=59 (7 deaths). (**) Nontypical DMARDs for IJD and RA: immunosuppressants and belimumab; nontypical DMARDs for RA: IL-17/IL-23/IL-12+23 inhibitors. (***) Nontypical DMARDs for CTD: abatacept, IL-17/IL-23/IL-12+23 inhibitors, sulfasalazine, leflunomide and tsDMARDs. b/tsDMARDs, biological/targeted synthetic diseasemodifying antirheumatic drugs; CTD, connective tissue disease/ vasculitis; DMARDs, diseasemodifying antirheumatic drugs; IJD, inflammatory joint disease; IL, interleukin; RA, rheumatoid arthritis. copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from 5 Strangfeld A, etal. Ann Rheum Dis 2021;0:1–13. doi:10.1136/annrheumdis-2020-219498 Epidemiology Table 1 Patient demographic and clinical characteristics Parameter Not deceased Deceased Total N 3339 390 3729 General Age (years) 55.5 (15.2) 69.7 (14.6) 57.0 (15.7) ≤30 197 (5.9) 9 (2.3) 206 (5.5) 31–50 1012 (30.3) 31 (7.9) 1043 (28) 51–65 1255 (37.6) 82 (21) 1337 (35.9) 66–75 536 (16.1) 109 (27.9) 645 (17.3) >75 339 (10.2) 159 (40.8) 498 (13.4) Male sex 1031 (30.9) 164 (42.1) 1195 (32) Ever smoker 664 (23.3) (N=2854) (Missing=485) 112 (36.1) (N=310) (Missing=80) 776 (24.5) (N=3164) (Missing=565) Regions African region 14 (0.4) 2 (0.5) 16 (0.4) Eastern Mediterranean region 83 (2.5) 11 (2.8) 94 (2.5) European region 2040 (61.1) 275 (70.5) 2315 (62.1) North American region 1024 (30.7) 81 (20.8) 1105 (29.6) South American region 112 (3.4) 10 (2.6) 122 (3.3) SouthEast Asian region 11 (0.3) 0 11 (0.3) Western Pacific region 55 (1.6) 11 (2.8) 66 (1.8) Inflammatory joint diseases Rheumatoid arthritis 1224 (36.7) 170 (43.6) 1394 (37.4) Spondyloarthritis 416 (12.5) 15 (3.8) 431 (11.6) Psoriatic arthritis 420 (12.6) 20 (5.1) 440 (11.8) Juvenile idiopathic arthritis (poly, oligo, not systemic) 21 (0.6) 4 (1) 25 (0.7) Other inflammatory arthritis 90 (2.7) 8 (2.1) 98 (2.6) Total Inflammatory joint diseases 2158 (64.6) 215 (55.1) 2373 (63.6) Connective tissue diseases/Vasculitis Systemic lupus erythematosus 355 (10.6) 36 (9.2) 391 (10.5) Connective tissue diseases (other than SLE) 473 (14.2) 60 (15.4) 533 (14.3) Vasculitis 258 (7.7) 68 (17.4) 326 (8.7) Total CTD 1035 (31) 158 (40.5) 1193 (32.0) Other RMDs Total 306 (9.2) 50 (12.8) 356 (9.5) Disease activity N=2464 (Missing=875) N=294 (Missing=96) N=2758 (Missing=971) Remission 799 (32.4) 94 (32) 893 (32.4) Minimal/low disease activity 1202 (48.8) 107 (36.4) 1309 (47.5) Moderate disease activity 388 (15.7) 60 (20.4) 448 (16.2) Severe/high disease activity 75 (3) 33 (11.2) 108 (3.9) Other outcomes Hospitalised 1368 (43.3) (N=3162) (Missing=177) 371 (96.6) (N=384) (Missing=6) 1739 (49) (N=3546) (Missing=183) Invasive ventilation 67 (2.5) (N=2701) (Missing=638) 120 (40.8) (N=294) (Missing=96) 187 (6.2) (N=2995) (Missing=734) Comorbidities N=3314 (Missing=25) N=386 (Missing=4) N=3700 (Missing=29) Hypertension 1095 (33) 212 (54.9) 1307 (35.3) Cardiovascular disease 318 (9.6) 124 (32.1) 442 (11.9) Cerebrovascular disease 89 (2.7) 20 (5.2) 109 (2.9) Chronic lung disease 581 (17.5) 138 (35.8) 719 (19.4) Chronic kidney disease 181 (5.5) 77 (19.9) 258 (7) Obesity (BMI ≥30) 539 (16.3) 58 (15) 597 (16.1) Morbid obesity (BMI ≥40) 106 (3.2) 16 (4.1) 122 (3.3) Diabetes 410 (12.4) 95 (24.6) 505 (13.6) Cancer 165 (5) 49 (12.7) 214 (5.8) Continued Parameter Not deceased Deceased Total Other comorbidities 771 (23.3) 126 (32.6) 897 (24.2) Number of comorbities 1.3 (1.3) 2.5 (1.6) 1.4 (1.3) No comorbidity 1090 (32.9) 28 (7.3) 1118 (30.2) One comorbidity 1032 (31.1) 83 (21.5) 1115 (30.1) Two comorbidities 597 (18) 110 (28.5) 707 (19.1) ≥3 comorbidites 595 (18) 165 (42.7) 760 (20.5) DMARD therapies csDMARDs monotherapy 592 (17.7) 59 (15.1) 651 (17.5) csDMARDs combination therapy 692 (20.7) 61 (15.6) 753 (20.2) Methotrexate monotherapy 531 (15.9) 47 (12.1) 578 (15.5) Methotrexate combination therapy 607 (18.2) 52 (13.3) 659 (17.7) Leflunomide monotherapy 61 (1.8) 12 (3.1) 73 (2) Leflunomide combination therapy 120 (3.6) 10 (2.6) 130 (3.5) Sulfasalazine monotherapy 51 (1.5) 16 (4.1) 67 (1.8) Sulfasalazine combination therapy 129 (3.9) 26 (6.7) 155 (4.2) Antimalarial monotherapy 287 (8.6) 17 (4.4) 304 (8.2) Antimalarial combination therapy 322 (9.6) 39 (10) 361 (9.7) Immunosuppressants monotherapy 149 (4.5) 26 (6.7) 175 (4.7) Immunosuppressants combination therapy 147 (4.4) 21 (5.4) 168 (4.5) Mycophenolate mofetil monotherapy 68 (2) 14 (3.6) 82 (2.2) Mycophenolate mofetil combination therapy 81 (2.4) 15 (3.8) 96 (2.6) Azathioprine monotherapy 63 (1.9) 7 (1.8) 70 (1.9) Azathioprine combination therapy 51 (1.5) 3 (0.8) 54 (1.4) Cyclophosphamide monotherapy 10 (0.3) 3 (0.8) 13 (0.3) Cyclophosphamide combination therapy 5 (0.1) 5 (1.3) 10 (0.3) Tacrolimus monotherapy 5 (0.1) 2 (0.5) 7 (0.2) Tacrolimus combination therapy 11 (0.3) 0 11 (0.3) Ciclosporin monotherapy 3 (0.1) 0 3 (0.1) Ciclosporin combination therapy 11 (0.3) 1 (0.3) 12 (0.3) bDMARDs monotherapy 675 (20.2) 48 (12.3) 723 (19.4) bDMARDs combination therapy 562 (16.8) 46 (11.8) 608 (16.3) TNF inhibitors monotherapy 434 (13) 13 (3.3) 447 (12) TNF inhibitors combination therapy 340 (10.2) 17 (4.4) 357 (9.6) Abatacept monotherapy 28 (0.8) 4 (1) 32 (0.9) Abatacept combination therapy 46 (1.4) 5 (1.3) 51 (1.4) Bcelltargeted bDMARDs monotherapy 71 (2.1) 25 (6.4) 96 (2.6) Bcelltargeted bDMARDs combination therapy 106 (3.2) 18 (4.6) 124 (3.3) Rituximab monotherapy 66 (2) 25 (6.4) 91 (2.4) Rituximab combination therapy 85 (2.5) 17 (4.4) 102 (2.7) Belimumab monotherapy 5 (0.1) 0 5 (0.1) Belimumab combination therapy 22 (0.7) 1 (0.3) 23 (0.6) IL-6 inhibitors monotherapy 51 (1.5) 3 (0.8) 54 (1.4) IL-6 inhibitors combination therapy 34 (1) 2 (0.5) 36 (1) Table 1 Continued Continued copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from 6Strangfeld A, etal. Ann Rheum Dis 2021;0:1–13. doi:10.1136/annrheumdis-2020-219498 Epidemiology bDMARDs and 3.9% (147/3729) received tsDMARDs. Onefifth (739/3729, 19.8%) were not receiving any DMARD/ immunosuppressive treatment (except glucocorticoids), and this proportion was higher among deceased patients (124/390, 31.8%). Among the patients not receiving any DMARD/immunosuppressive treatment, 39.8% (290/729) received glucocorticoids, 9.8% (70/712) with a prednisoloneequivalent dosage of >10 mg/day; the most frequent diagnostic categories being other nonspecified rheumatic diseases (173/739, 23.4%), vasculitis (161/739, 21.8%), CTD other than SLE (156/739, 21.1%) and RA (110/739, 14.9%). Country-specific differences The majority of cases (2993/3729, 80.3%) were reported from six countries with considerable differences in reported percentages of death (online supplemental table 2). Overall, 10.5% (390/3729) of patients died, with highest proportions in the UK (91/435, 20.9%) and Italy (53/315, 16.8%). Death was reported in lower proportions in the USA (70/1005, 7.0%), Germany (15/198, 7.6%), France (62/793, 7.8%) and Spain (21/247, 8.5%). Other major differences between the countries were the distribution of rheumatic diseases and the distribution and frequency of comorbidities. Factors associated with death In multivariable analyses (table 2, figure 3), patients between 66 and 75 years of age were more likely to have died (OR 3.00, 95% CI 2.13 to 4.22) than those ≤65 years. The association was even more pronounced in patients over 75 years (6.18, 4.47 to 8.53; vs ≤65 years). Male sex was also associated with higher odds of death (1.46, 1.11 to 1.91). Current or former smoking was only associated with death in the RA subgroup (1.45, 1.02 to 2.04). Other factors associated with death included chronic lung disease (1.68, 1.26 to 2.25) and CVD combined with hypertension (1.89, 1.31 to 2.73), whereas hypertension or CVD alone did not show a significant association. CKD was significantly associated with death in patients with CTD or vasculitis (2.30, 1.37 to 3.88) but not in other disease subgroups. Across all diagnostic groups, treatments with leflunomide, antimalarials, TNF inhibitors, abatacept, belimumab, IL-6 inhibitors, IL-17/IL-23/IL-12+23 inhibitors and tsDMARDs were not associated with death, as compared with methotrexate monotherapy. In the overall model, not receiving DMARD treatment was associated with death (2.11, 1.48 to 3.01) compared with methotrexate monotherapy. This was also seen in the IJD, RA and CTD subgroups. Compared with methotrexate monotherapy, treatments associated with a higher odds of death were rituximab (4.04, 2.32 to 7.03, in the overall model; 5.42, 2.77 to 10.61, in the IJD subgroup; 4.99, 2.43 to 10.26, in the RA subgroup; 3.72, 1.21 to 11.48, in the CTD/vasculitis subgroup), sulfasalazine (3.60, 1.66 to 7.78, in the overall model and consistent across all subgroups) and immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46, in the overall model; 2.44, 1.06 to 5.65, in the CTD/ vasculitis subgroup; not applicable to other subgroups). An additional analysis indicated that the association of sulfasalazine with an increased odds for death was mainly driven by the larger group of sulfasalazine monotherapy and persisted even when sulfasalazine combination treatment (plus either antimalarials, leflunomide or methotrexate) was considered separately (data not shown). Treatment with higher dosages of glucocorticoids (>10 mg/ day prednisoloneequivalent dose vs no use) was also found to be associated with death (1.69, 1.18 to 2.41), particularly in the CTD/vasculitis subgroup (1.93, 1.11 to 3.36). Higher disease activity at COVID-19 diagnosis was consistently associated with death across all disease groups. Patients with high/moderate/severe disease activity had higher odds of death (1.87, 1.27 to 2.77) than patients with low disease activity or in remission (overall model and consistent across all subgroups). Sensitivity analyses Results were largely consistent in our sensitivity analyses (online supplemental tables 4–9). In the complete case analysis (online supplemental table 5), the association between sulfasalazine and death was no longer statistically significant. In stratified analyses (online supplemental tables 10–16), sulfasalazine use was not associated with death among patients that never smoked, with the OR among ever smokers being almost threefold than among nonsmokers (online supplemental table 12). DISCUSSION With global cooperation, the C19GRA physicianreported registry is the largest collection to date of patients with rheumatic Parameter Not deceased Deceased Total IL-1 inhibitors monotherapy 10 (0.3) 2 (0.5) 12 (0.3) IL-1 inhibitors combination therapy 4 (0.1) 4 (1) 8 (0.2) IL-17, IL-23, IL-12/23 inhibitors monotherapy 79 (2.4) 1 (0.3) 80 (2.1) IL-17, IL-23, IL-12/23 inhibitors combination therapy 36 (1.1) 0 36 (1) tsDMARDs monotherapy 61 (1.8) 5 (1.3) 66 (1.8) tsDMARDs (*) combination therapy 71 (2.1) 10 (2.6) 81 (2.2) JAK inhibitors monotherapy 54 (1.6) 4 (1) 58 (1.6) JAK inhibitors combination therapy 67 (2) 9 (2.3) 76 (2) Apremilast monotherapy 7 (0.2) 1 (0.3) 8 (0.2) Apremilast combination therapy 3 (0.1) 1 (0.3) 4 (0.1) No DMARD therapies 615 (18.4) 124 (31.8) 739 (19.8) Further therapies Glucocorticoids (#) 1056 (32) (N=3302) (Missing=37) 217 (57.1) (N=380) (Missing=10) 1273 (34.6) (N=3682) (Missing=47) Glucocorticoids 1–10 mg/day 833 (25.6) (N=3254) (Missing=85) 150 (41.3) (N=363) (Missing=27) 983 (27.2) (N=3617) (Missing=112) Glucocorticoids>10 mg/day 171 (5.3) (N=3254) (Missing=85) 49 (13.5) (N=363) (Missing=27) 220 (6.1) (N=3617) (Missing=112) NSAIDs 600 (19.3) (N=3103) (Missing=236) 38 (11.0) (N=345) (Missing=45) 638 (18.5) (N=3448) (Missing=281) Data are N (column %) for categorical variables or mean (SD) for continuous variables. The table includes all patients with a nonmissing outcome and nonmissing values for age, sex and diseasemodifying antirheumatic drugs (DMARDs) (101 patients excluded). Data refer to patients with nonmissing values for the respective variable; total N for patients with nonmissing values is given in parentheses for variables with missing values; the total number of missing values is also given in parenthesis, for the applicable variables. (*) Includes one patient on a study medication (Lenabasum). (#) Includes patients with a missing glucocorticoid dosage. bDMARD, biological diseasemodifying antirheumatic drug; BMI, body mass index; csDMARD, conventional synthetic diseasemodifying antirheumatic drug; CTD, connective tissue diseases; DMARD, diseasemodifying antirheumatic drug; IL, interleukin; JAK, Janus kinase; JIA, juvenile idiopathic arthritis; N, number; NSAID, nonsteroidal antiinflammatory drugs; SLE, systemic lupus erythematosus; TNF, tumour necrosis factor; tsDMARD, targeted synthetic diseasemodifying antirheumatic drug. Table 1 Continued copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from 7 Strangfeld A, etal. Ann Rheum Dis 2021;0:1–13. doi:10.1136/annrheumdis-2020-219498 Epidemiology Table 2 Multivariable logistic regression analysis of factors associated with COVID-19related death in patients with rheumatic diseases (all patients) N deaths/patients (%) All Patients with inflammatory joint diseases (IJDs) Only patients with rheumatoid arthritis Patients with connective tissue diseases (CTDs) or vasculitis 384/3705 (10.4%) 211/2348 (9.0%) 166/1371 (12.1%) 147/1157 (12.7%) N deaths/patients OR 95% CI N deaths/patients OR 95% CI N deaths/ patients OR 95% CI N deaths/ patients OR 95% CI Age, years Age≤65 118/2565 1 Reference 55/1657 1 Reference 40/840 1 Reference 56/779 1 Reference 65 years<Age≤75 109/644 3 2.13 to 4.22 71/426 3.63 2.55 to 5.15 55/314 3.10 1.68 to 5.72 33/187 2.29 1.34 to 3.93 Age>75 157/496 6.18 4.47 to 8.53 85/265 8.21 5.54 to 12.18 71/217 7.30 4.42 to 12.06 58/191 4.08 2.27 to 7.36 Male sex (vs female) 161/1188 1.46 1.11 to 1.91 82/788 1.31 0.95 to 1.8 55/345 1.17 0.78 to 1.76 63/296 1.66 0.96 to 2.86 Ever smoked (vs never) 140/922 1.21 0.94 to 1.57 84/607 1.26 0.93 to 1.72 71/385 1.45 1.02 to 2.04 42/248 1.11 0.67 to 1.86 Comorbidities Hypertension alone or CVD alone 155/1150 1.19 0.89 to 1.59 79/690 1.04 0.74 to 1.46 66/454 1.11 0.74 to 1.67 69/406 1.56 1.06 to 2.29 Hypertension and CVD 89/301 1.89 1.31 to 2.73 53/168 2.29 1.25 to 4.23 38/118 2.03 1.03 to 3.97 28/106 1.57 0.78 to 3.16 Chronic lung disease 136/721 1.68 1.26 to 2.25 76/406 1.52 1.04 to 2.21 63/293 1.44 0.99 to 2.09 54/285 2.05 1.47 to 2.85 Chronic kidney disease 76/259 1.67 0.99 to 2.8 27/111 1.09 0.54 to 2.21 21/83 1.01 0.46 to 2.24 41/124 2.30 1.37 to 3.88 Diabetes mellitus 96/508 1.38 0.88 to 2.17 55/313 1.31 0.95 to 1.79 39/213 1.08 0.72 to 1.61 32/154 1.39 0.64 to 3 Rheumatic disease Rheumatoid arthritis 160/1326 1 Reference 166/1373 1 Reference n.a. n.a. Systemic lupus erythematosus 36/391 1.2 0.70 to 2.04 n.a. n.a. 32/378 1 Reference Vasculitis 67/325 0.8 0.60 to 1.08 n.a. n.a. 64/318 0.81 0.49 to 1.33 Other connective tissue diseases 53/473 0.75 0.58 to 0.97 n.a. n.a. 51/461 0.78 0.39 to 1.54 Psoriasis arthritis 19/429 0.75 0.53 to 1.07 19/437 0.82 0.55 to 1.22 n.a. n.a. Spondyloarthritis 15/423 0.72 0.34 to 1.54 15/424 0.82 0.4 to 1.69 n.a. n.a. Other inflammatory arthritis or nonsystemic JIA 10/109 0.79 0.46 to 1.34 11/114 0.76 0.43 to 1.36 n.a. n.a. Other rheumatic diseases (not IJDs/CTDs/ vasculitis) 24/229 0.51 0.35 to 0.73 n.a. n.a. n.a. High/moderate/severe disease activity (DA) vs remission/low DA 109/722 1.87 1.27 to 2.77 54/453 1.6 1.13 to 2.26 44/274 1.60 1.03 to 2.47 51/230 2.45 1.49 to 4.02 Medication Methotrexate 47/595 1 Reference 41/487 1 Reference 34/354 1 Reference 6/94 1 Reference No DMARD therapy 124/739 2.11 1.48 to 3.01 38/239 2.08 1.38 to 3.14 25/110 2.12 1.34 to 3.37 67/353 3.18 1.61 to 6.27 Leflunomide 12/90 1.56 0.9 to 2.7 10/83 1.37 0.69 to 2.73 9/68 1.43 0.71 to 2.86 n.a. Antimalarials 27/426 0.99 0.66 to 1.48 17/167 1.14 0.65 to 2 17/141 1.24 0.7 to 2.19 11/271 1.38 0.48 to 4.02 Sulfasalazine 33/144 3.6 1.66 to 7.78 31/137 3.40 1.46 to 7.93 21/85 2.62 1.21 to 5.68 n.a. Immunosuppressants 38/276 2.22 1.43 to 3.46 n.a. n.a. 32/247 2.44 1.06 to 5.65 TNF inhibitors 30/803 0.85 0.52 to 1.36 26/764 0.77 0.42 to 1.41 16/292 0.82 0.39 to 1.76 4/39 2.00 0.36 to 11.2 Abatacept 9/81 1.20 0.61 to 2.34 9/75 1.3 0.62 to 2.71 9/68 1.4 0.65 to 2.99 n.a. Rituximab 42/192 4.04 2.32 to 7.03 22/90 5.42 2.77 to 10.61 21/86 4.99 2.43 to 10.26 22/104 3.72 1.21 to 11.48 Belimumab 1/27 0.71 0.19 to 2.68 n.a. n.a. 1/27 1.07 0.21 to 5.37 IL-6 inhibitors 5/90 0.83 0.38 to 1.84 1/68 0.25 0.03 to 2.43 1/63 0.25 0.03 to 2.33 4/23 2.69 0.88 to 8.19 IL-17/IL-23/IL-12+23 inhibitors 1/115 0.25 0.03 to 2.04 1/112 0.26 0.03 to 2.06 n.a. n.a. tsDMARDs 15/145 1.60 0.91 to 2.8 15/142 1.75 0.99 to 3.12 13/118 1.57 0.75 to 3.27 n.a. Glucocorticoids (GCs) No GCs 165/2417 1 Reference 109/1721 1 Reference 78/863 1 Reference 38/551 1 Reference GCs 1–10 mg/day 170/1062 1.43 0.98 to 2.09 89/567 1.36 0.76 to 2.45 78/464 1.34 0.66 to 2.74 75/469 1.69 1.11 to 2.57 Continued copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from 8Strangfeld A, etal. Ann Rheum Dis 2021;0:1–13. doi:10.1136/annrheumdis-2020-219498 Epidemiology diseases and COVID-19. We found that moderate/high disease activity was significantly associated with COVID-19related death, confirming recent recommendations regarding the importance of disease control in rheumatic diseases in the COVID-19 era.1 Other factors associated with death were older age, male sex and the presence of comorbidities, which is consistent with reports from the general population.8 Overall, compared with methotrexate monotherapy, most DMARDs were not associated with higher odds of death, although rituximab and sulfasalazine were notable exceptions. Prednisoloneequivalent dosages >10 mg/day and other immunosuppressive drugs (as opposed to immunomodulatory DMARDs) were also associated with COVID-19related death. In this cohort of patients with underlying rheumatic diseases, the COVID-19related death rate was 10.5%, clearly higher than that reported in the general population in most countries. However, this study was not designed to calculate a precise point estimate for mortality. Reporting biases and populationrelated factors, including COVID-19 testing rates, could explain this figure and, importantly, it should not be taken as an estimate of the overall death rate among patients with rheumatic diseases and COVID-19. The association of rituximab with poorer COVID-19related outcomes is a previously unreported finding outside of case reports. Rituximab binds to CD20 on the surface of Bcells, effectively depleting this cell type, and interferes with antibody development. Therefore, Bcell depletion could potentially compromise antiviral immunity, including the development of SARSCoV-2 antibodies.19 With our data, it was not possible to determine the exact timing of infection following rituximab infusion, although all patients were clinically judged by their rheumatologist to have been exposed to the immunological effects of the drug at the time of COVID-19 diagnosis. The association between rituximab and COVID-19related death could have also been influenced by the typical coadministration of methylprednisolone with rituximab. A finding that merits further research is the higher odds of death found with sulfasalazine treatment. This association has also been reported in results from an international registry of patients with inflammatory bowel disease and COVID-19, where sulfasalazine or 5aminosalicylate (5ASA) use was associated with severe COVID-19 (adjusted OR of 3.1 (1.3 to 7.7)).20 This finding is surprising as sulfasalazine is usually considered to have a low immunosuppressive effect. Prior research supports an immune regulatory effect driven by sulfasalazine or its metabolite 5ASA against other RNA viruses.21–24 However, causal interpretation of the association between sulfasalazine and COVID-19related death should not be made. The perceived low immunosuppressive effect of sulfasalazine may have led rheumatologists to prescribe preferentially sulfasalazine over methotrexate in patients who were perceived to be at higher risk, for example, patients with pulmonary disease, smoking or recurrent chest infections. In an observational study like ours, this could lead to unmeasured confounding. A salient difference in sulfasalazine users in our study was a higher proportion of current or former smokers, compared with nonusers. In the stratified analyses for chronic lung disease, the association between death and sulfasalazine was significant in both subgroups with and without chronic lung disease, while in the stratified analyses for smoking, the association between death and sulfasalazine was limited to ever smokers, so the factor ‘smoking’ could potentially be an effect modifier. Another potential explanation for this finding could be the N deaths/patients (%) All Patients with inflammatory joint diseases (IJDs) Only patients with rheumatoid arthritis Patients with connective tissue diseases (CTDs) or vasculitis 384/3705 (10.4%) 211/2348 (9.0%) 166/1371 (12.1%) 147/1157 (12.7%) N deaths/patients OR 95% CI N deaths/patients OR 95% CI N deaths/ patients OR 95% CI N deaths/ patients OR 95% CI GCs>10 mg/day 49/226 1.69 1.18 to 2.41 12/60 1.55 0.67 to 3.57 10/44 1.59 0.6 to 4.18 34/137 1.93 1.11 to 3.36 Missing values were imputed via multiple imputation, patient numbers may thus be rounded. Effects significant at level α=0.05 are marked in bold. Patients were excluded from a particular analysis if the medication they received provided ≤20 patients for that analysis or if there were no deaths reported for that specific medication. TNF; tumour necrosis factor; CTD, connective tissue diseases; CVD, cardiovascular duisease; DMARD, diseasemodifying antirheumatic drugs; GC, glucocorticoids; IL, interleukin; JIA, juvenile idiopathic arthritis; N, number; n.a., not applicable; tsDMARD, targeted synthetic diseasemodifying antirheumatic drugs. Table 2 Continued copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from 9 Strangfeld A, etal. Ann Rheum Dis 2021;0:1–13. doi:10.1136/annrheumdis-2020-219498 Epidemiology merging of sulfasalazine combination therapy (with other csDMARDs) with sulfasalazine monotherapy; however, the increased odds for death persisted in the sulfasalazine monotherapy group and was not driven by the combination treatment (data not shown). Despite the large overall sample size, for some therapies (eg, IL-6 and IL-17/IL-23/IL-12+23 inhibitors) the number of users was low and no firm conclusions could be made. IL-6 inhibitors have been used to counteract the hyperinflammatory state produced by COVID-19, with mostly disappointing randomised trial results.25 26 Their efficacy is still being investigated in ongoing trials, but it is reassuring that they were not associated with COVID-19related death in our analyses. Previous studies had shown an association between TNF inhibitors and a decreased risk of sepsis and mortality in patients with RA after serious infection compared with csDMARDs.27 28 We could not confirm such an association after stratification by disease and adjustment for disease activity. However, the data indicate that some associations may exist among patients diagnosed with IJD other than RA (a subgroup comprising predominantly patients with axial SpA and PsA), in whom male sex and diabetes mellitus were associated with a higher odds of death, and TNF inhibitor use was associated with a lower odds of death (univariable analysis, data not shown). Due to a small number of deceased patients in this subgroup with nonRA subtypes of IJD (n=37 deaths), these effects could not be assessed in a multivariable model and this should be investigated in the future when higher case numbers allow a more stable assessment. This study has limitations. As a crosssectional, casereporting registry, it may be subject to selection bias if more Figure 3 Results of the main logistic regression analysis. Shown are multivariableadjusted ORs for the outcome COVID-19related death with 95% CIs, assessing the association with (A) general patient characteristics, (B) comorbidities, (C) rheumatic disease diagnoses (RMD) and (D) rheumatic disease medications. ORs are shown for four groups: all patients (black), patients with inflammatory joint disease (red), patients with rheumatoid arthritis (orange), and patients with a connective tissue disease or vasculitis (blue). For (C), only ORs for all patients are shown. The reference categories are as follows: (A) ≤65 years, females, never smoked, remission or low disease activity; (B) the nonpresence of the specific comorbidities (for all effects); (C) rheumatoid arthritis (for all effects); (D) methotrexate monotherapy (for all effects except for glucocorticoids), no glucocorticoids (for glucocorticoid dosage groups). Patients receiving multiple csDMARDs or immunosuppressants (except glucocorticoids) were grouped according to the following hierarchy: immunosuppressants>sulfasalazine>antimalarials>leflunomide>methotrexate; patients receiving a b/tsDMARD were considered solely in the b/tsDMARD group; glucocorticoids were examined separately and categorised by prednisoloneequivalent dosage (1–10 mg/ day and >10 mg/day). bDMARD, biological diseasemodifying antirheumatic drug; csDMARD, conventional synthetic diseasemodifying antirheumatic drug; CTD, connective tissue diseases; CVD, cardiovascular disease; JIA, juvenile idiopathic arthritis; tsDMARD, targeted synthetic diseasemodifying antirheumatic drug. copyright. on March 3, 2021 at Universidade de Lisboa. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219498 on 27 January 2021. Downloaded from 3 Cancer 98 (4.6) 23 (10.7) 121 (5.1) 68 (5.6) 18 (10.7) 86 (6.2) 61 (5.9) 20 (12.9) 81 (6.9) Other comorbidities 509 (23.8) 73 (34.1) 582 (24.7) 216 (17.8) 48 (28.4) 264 (19.1) 230 (22.4) 45 (29.0) 275 (23.3) Number of comorbities 1.2 (1.3) 2.5 (1.7) 1.4 (1.4) 1.3 (1.3) 2.3 (1.6) 1.4 (1.4) 1.5 (1.4) 2.5 (1.5) 1.6 (1.4) No comorbidity 770 (35.9) 18 (8.4) 788 (33.4) 397 (32.7) 16 (9.5) 413 (29.8) 267 (26) 10 (6.5) 277 (23.5) One comorbidity 639 (29.8) 50 (23.4) 689 (29.2) 374 (30.8) 39 (23.1) 413 (29.8) 357 (34.8) 31 (20) 388 (32.9) Two comorbidities 390 (18.2) 63 (29.4) 453 (19.2) 238 (19.6) 52 (30.8) 290 (21) 182 (17.7) 43 (27.7) 225 (19.1) ≥ 3 comorbidites 344 (16.1) 83 (38.8) 427 (18.1) 206 (17) 62 (36.7) 268 (19.4) 220 (21.4) 71 (45.8) 291 (24.6) DMARD therapies csDMARDs monotherapy 487 (22.6) 51 (23.7) 538 (22.7) 351 (28.7) 43 (25.3) 394 (28.3) 91 (8.8) 10 (6.3) 101 (8.5) csDMARDs combination therapy 611 (28.3) 53 (24.7) 664 (28) 440 (35.9) 51 (30) 491 (35.2) 92 (8.9) 12 (7.6) 104 (8.7) Methotrexate monotherapy 430 (19.9) 41 (19.1) 471 (19.8) 306 (25) 34 (20) 340 (24.4) 88 (8.5) 6 (3.8) 94 (7.9) Methotrexate combination therapy 531 (24.6) 45 (20.9) 576 (24.3) 372 (30.4) 44 (25.9) 416 (29.8) 87 (8.4) 9 (5.7) 96 (8) Leflunomide monotherapy 57 (2.6) 10 (4.7) 67 (2.8) 45 (3.7) 9 (5.3) 54 (3.9) 3 (0.3) 4 (2.5) 7 (0.6) Leflunomide combination therapy 114 (5.3) 9 (4.2) 123 (5.2) 98 (8) 8 (4.7) 106 (7.6) 7 (0.7) 3 (1.9) 10 (0.8) Sulfasalazine monotherapy 48 (2.2) 16 (7.4) 64 (2.7) 22 (1.8) 8 (4.7) 30 (2.2) 3 (0.3) 1 (0.6) 4 (0.3) Sulfasalazine combination therapy 124 (5.7) 24 (11.2) 148 (6.2) 76 (6.2) 20 (11.8) 96 (6.9) 7 (0.7) 2 (1.3) 9 (0.8) Antimalarial monotherapy 74 (3.4) 8 (3.7) 82 (3.5) 56 (4.6) 8 (4.7) 64 (4.6) 212 (20.5) 9 (5.7) 221 (18.5) Antimalarial combination therapy 175 (8.1) 23 (10.7) 198 (8.3) 156 (12.7) 23 (13.5) 179 (12.8) 169 (16.3) 17 (10.8) 186 (15.6) Immunosuppressants monotherapy 9 (0.4) 3 (1.4) 12 (0.5) 7 (0.6) 3 (1.8) 10 (0.7) 132 (12.8) 21 (13.3) 153 (12.8) Immunosuppressants combination therapy 20 (0.9) 1 (0.5) 21 (0.9) 16 (1.3) 16 (1.1) 127 (12.3) 18 (11.4) 145 (12.2) Mycophenolate mofetil monotherapy 3 (0.1) 1 (0.5) 4 (0.2) 2 (0.2) 1 (0.6) 3 (0.2) 64 (6.2) 13 (8.2) 77 (6.5) Mycophenolate mofetil combination therapy 3 (0.1) 0 3 (0.1) 3 (0.2) 0 3 (0.2) 77 (7.4) 14 (8.9) 91 (7.6) Azathioprine monotherapy 4 (0.2) 1 (0.5) 5 (0.2) 3 (0.2) 1 (0.6) 4 (0.3) 54 (5.2) 4 (2.5) 58 (4.9) Azathioprine combi 12 (0.6) 1 (0.5) 13 (0.5) 9 (0.7) 0 9 (0.6) 39 (3.8) 2 (1.3) 41 (3.4) Cyclophosphamide monotherapy 0 0 0 0 0 0 9 (0.9) 3 (1.9) 12 (1) Cyclophosphamide combination therapy 0 0 0 0 0 0 5 (0.5) 4 (2.5) 9 (0.8) Tacrolimus monotherapy 0 1 (0.5) 1 (0) 0 1 (0.6) 1 (0.1) 4 (0.4) 1 (0.6) 5 (0.4) Tacrolimus combination therapy 2 (0.1) 0 2 (0.1) 1 (0.1) 0 1 (0.1) 8 (0.8) 0 8 (0.7) Cyclosporin monotherapy 2 (0.1) 0 2 (0.1) 2 (0.2) 0 2 (0.1) 1 (0.1) 0 1 (0.1) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 4 Cyclosporin combination therapy 4 (0.2) 0 4 (0.2) 4 (0.3) 0 4 (0.3) 8 (0.8) 1 (0.6) 9 (0.8) bDMARDs monotherapy 581 (26.9) 29 (13.5) 610 (25.7) 163 (13.3) 19 (11.2) 182 (13.1) 81 ( 7.8) 18 (11.4) 99 (8.3) bDMARD combination therapy 478 (22.2) 31 (14.4) 509 (21.5) 308 (25.2) 29 (17.1) 337 (24.2) 91 (8.8) 15 (9.5) 106 (8.9) TNF inhibitors monotherapy 417 (19.3) 12 (5.6) 429 (18.1) 88 (7.2) 4 (2.4) 92 (6.6) 15 (1.4) 1 (0.6) 16 (1.3) TNF inhibitors combination therapy 322 (14.9) 14 (6.5) 336 (14.2) 189 (15.4) 12 (7.1) 201 (14.4) 20 (1.9) 3 (1.9) 23 (1.9) Abatacept monotherapy 25 (1.2) 4 (1.9) 29 (1.2) 20 (1.6) 4 (2.4) 24 (1.7) 2 (0.2) 0 2 (0.2) Abatacept combination therapy 43 (2) 5 (2.3) 48 (2) 41 (3.3) 5 (2.9) 46 (3.3) 6 (0.6) 0 6 (0.5) B-cell-targeted bDMARDs monotherapy 22 (1) 11 (5.1) 33 (1.4) 20 (1.6) 10 (5.9) 30 (2.2) 45 (4.3) 15 (9.5) 60 (5) B-cell-targeted bDMARDs combination therapy 49 (2.3) 11 (5.1) 60 (2.5) 48 (3.9) 11 (6.5) 59 (4.2) 62 (6) 8 (5.1) 70 (5.9) Rituximab monotherapy 22 (1) 11 (5.1) 33 (1.4) 20 (1.6) 10 (5.9) 30 (2.2) 40 (3.9) 15 (9.5) 55 (4.6) Rituximab combi 47 (2.2) 11 (5.1) 58 (2.4) 46 (3.8) 11 (6.5) 57 (4.1) 42 (4.1) 7 (4.4) 49 (4.1) Belimumab monotherapy 0 0 0 0 0 0 5 (0.5) 0 5 (0.4) Belimumab combination therapy 2 (0.1) 0 2 (0.1) 2 (0.2) 0 2 (0.1) 21 (2) 1 (0.6) 22 (1.8) IL-6 inhibitors monotherapy 36 (1.7) 1 (0.5) 37 (1.6) 33 (2.7) 1 (0.6) 34 (2.4) 18 (1.7) 2 (1.3) 20 (1.7) IL-6 inhibitors combination therapy 31 (1.4) 0 31 (1.3) 29 (2.4) 0 29 (2.1) 1 (0.1) 2 (1.3) 3 (0.3) IL-1 inhibitors monotherapy 1 (0) 0 1 (0) 0 0 0 1 (0.1) 0 1 (0.1) IL-1 inhibitors combination therapy 3 (0.1) 1 (0.5) 4 (0.2) 3 (0.2) 1 (0.6) 4 (0.3) 1 (0.1) 2 (1.3) 3 (0.3) IL-17, Il-23, Il-12/23 inhibitors monotherapy 78 (3.6) 1 (0.5) 79 (3.3) 1 (0.1) 0 1 (0.1) 0 0 0 IL-17, Il-23, Il-12/23 inhibitors combination therapy 34 (1.6) 0 34 (1.4) 1 (0.1) 0 1 (0.1) 1 (0.1) 0 1 (0.1) tsDMARDs monotherapy 61 (2.8) 5 (2.3) 66 (2.8) 47 (3.8) 4 (2.4) 51 (3.7) 0 0 0 tsDMARDs (*) combination therapy 68 (3.2) 10 (4.7) 78 (3.3) 59 (4.8) 9 (5.3) 68 (4.9) 6 (0.6) 2 (1.3) 8 (0.7) JAK inhibitors monotherapy 54 (2.5) 4 (1.9) 58 (2.4) 47 (3.8) 4 (2.4) 51 (3.7) 0 0 0 JAK inhibitors combination therapy 65 (3) 9 (4.2) 74 (3.1) 59 (4.8) 9 (5.3) 68 (4.9) 5 (0.5) 2 (1.3) 7 (0.6) Apremilast monotherapy 7 (0.3) 1 (0.5) 8 (0.3) 0 0 0 0 0 0 Apremilast combination therapy 3 (0.1) 1 (0.5) 4 (0.2) 0 0 0 0 0 0 No DMARD therapies 201 (9.3) 38 (17.7) 239 (10.1) 85 (6.9) 25 (14.7) 110 (7.9) 286 (27.6) 67 (42.4) 353 (29.6) Further therapies Glucocorticoids (#) 521 (24.5) (N=2130) 101 (48.6) (N=208) 622 (26.6) (N=2338) 417 (34.6) (N=1205) 90 (54.2) (N=166) 507 (37) (N=1371) 501 (48.8) (N=1027) 115 (74.2) (N=155) 616 (52.1) (N=1182) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 5 0 mg/d < Glucocorticoids <= 10mg/d 448 (21.3) (N=2108) 83 (40.9) (N=203) 531 (23) (N=2311) 366 (30.8) (N=1190) 74 (46) (N=161) 440 (32.6) (N=1351) 373 (37.3) (N=999) 68 (47.6) (N=143) 441 (38.6) (N=1142) Glucocorticoids > 10 mg/d 48 (2.3) (N=2108) 12 (5.9) (N=203) 60 (2.6) (N=2311) 34 (2.9) (N=1190) 10 (6.2) (N=161) 44 (3.3) (N=1351) 100 (10) (N=999) 35 (24.5) (N=143) 135 (11.8) (N=1142) NSAID 484 (24.2) (N=2002) 26 (13.8) (N=188) 510 (23.3) (N=2190) 240 (21.3) (N=1129) 22 (14.8) (N=149) 262 (20.5) (N=1278) 112 (11.6) (N=966) 12 (8.6) (N=140) 124 (11.2) (N=1106) Data are N (column %) for categorical variables or mean (SD) for continuous variables. Table includes all patients with a non-missing outcome and non-missing values for age, sex and disease modifying anti-rheumatic drugs (DMARDs) (101 patients excluded). Data refers to patients with non-missing values for the respective variable, total N for patients with non-missing values is given in parentheses for variables with missing values. (*) Includes one patient on a study medication (Lenabasum). (#) Includes patients with a missing glucocorticoid dose. bDMARD, biologic disease modifying antirheumatic drugs; BMI, body mass index; csDMARD, conventional synthetic disease modifying antirheumatic drugs; CTD, connective tissue diseases; DMARD, disease modifying antirheumatic drugs; IL, interleukin; JAK, Janus kinase; JIA, juvenile idiopathic arthritis; N, number; NSAID, non-steroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 6 Supplementary table 2. Patient demographic and clinical characteristics stratified by country (six countries with the highest number of reported cases) Parameter USA France UK Italy Spain Germany Total N 1005 793 435 315 247 198 2993 General Age [years] 55.2 (15.1) 56.2 (16.3) 61.2 (16.4) 61.9 (13.7) 59.7 (15.7) 58.2 (13.8) 57.6 (15.6) < 30 years 66 (6.6) 39 (4.9) 16 (3.7) 6 (1.9) 10 (4) 6 (3) 143 (4.8) 30 – 49 years 300 (29.9) 268 (33.8) 97 (22.3) 58 (18.4) 56 (22.7) 48 (24.2) 268 (33.8) 50 – 65 years 390 (38.8) 248 (31.3) 131 (30.1) 107 (34) 92 (37.2) 93 (47) 248 (31.3) 66 - 75 years 146 (14.5) 128 (16.1) 92 (21.1) 93 (29.5) 43 (17.4) 26 (13.1) 528 (17.6) > 75 years 103 (10.2) 110 (13.9) 99 (22.8) 51 (16.2) 46 (18.6) 25 (12.6) 434 (14.5) Male sex 241 (24) 272 (34.3) 169 (38.9) 107 (34) 95 (38.5) 74 (37.4) 958 (32) Ever smoker 261 (27.3) (N=956) 80 (10.1) (N=793) 132 (45.2) (N=292) 86 (29.5) (N=292) 60 (27.5) (N=218) 14 (77.8) (N=18) 633 (24.6) (N=2569) Inflammatory joint diseases Rheumatoid arthritis 388 (38.6) 247 (31.2) 187 (43.0) 105 (33.3) 88 (35.6) 99 (50.0) 1114 (37.2) Spondyloarthritis 47 (4.7) 193 (24.3) 29 (6.7) 24 (7.6) 32 (13) 19 (9.6) 344 (11.5) Psoriatic arthritis 101 (10) 74 (9.3) 61 (14) 64 (20.3) 31 (12.6) 32 (16.2) 363 (12.1) JIA (poly, oligo, not systemic) 7 (0.7) 2 (0.3) 2 (0.5) 2 (0.6) 3 (1.2) 0 16 (0.5) Other inflammatory arthritis 41 (4.1) 15 (1.9) 28 (6.4) 3 (1) 3 (1.2) 0 90 (3) Total IJD 577 (57.4) 531 (67) 305 (70.1) 198 (62.9) 157 (63.6) 150 (75.8) 1918 (64.1) Connective tissue diseases / Vasculitis Systemic lupus erythematosus 167 (16.6) 50 (6.3) 28 (6.4) 18 (5.7) 27 (10.9) 9 (4.5) 299 (10) CTDs (other than SLE) 186 (18.5) 90 (11.3) 38 (8.7) 53 (16.8) 44 (17.8) 19 (9.6) 430 (14.4) Vasculitis 67 (6.7) 71 (9) 51 (11.7) 44 (14) 22 (8.9) 18 (9.1) 273 (9.1) Total CTD 394 (39.2) 211 (26.6) 111 (25.5) 114 (36.2) 85 (34.4) 43 (21.7) 958 (32) Other rheumatic diseases Total 132 (13.1) 52 (6.6) 53 (12.2) 8 (2.5) 20 (8.1) 13 (6.6) 278 (9.3) Disease activity (DA) N=950 N=364 N=315 242 N=181 N=2052 Remission 211 (22.2) N/A 109 (29.9) 93 (29.5) 113 (46.7) 102 (56.4) 628 (30.6) Minimal/low DA 521 (54.8) N/A 172 (47.3) 160 (50.8) 108 (44.6) 53 (29.3) 1014 (49.4) Moderate DA 185 (19.5) N/A 69 (19) 53 (16.8) 17 (7) 19 (10.5) 343 (16.7) Severe/high DA 33 (3.5) N/A 14 (3.8) 9 (2.9) 4 (1.7) 7 (3.9) 67 (3.3) Other outcomes Death 70 (7.0) 62 (7.8) 91 (20.9) 53 (16.8) 21 (8.5) 15 (7.6) 312 (10.4) Hospitalised 357 (39.1) (N=914) 334 (42.1) (N=793) 275 (65.8) (N=418) 201 (64.2) (N=313) 133 (55.6) (N=239) 60 (30.6) (N=196) 1360 (47.3) (N=2873) Invasive ventilation 64 (7.9) (N=807) N/A 28 (7.5) (N=371) 23 (7.5) (N=308) 7 (3) (N=231) 15 (7.7) (N=196) 137 (5.8) (N=1913) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 7 Comorbidities N=1000 N=791 N=434 N=300 N=247 N=192 N=2964 Hypertension 399 (39.9) 220 (27.8) 140 (32.3) 147 (49) 103 (41.7) 72 (36.4) 1081 (36.4) Cardiovascular disease 112 (11.2) 76 (9.6) 72 (16.6) 72 (24) 18 (7.3) 27 (13.6) 377 (12.7) Cerebrovascular disease 27 (2.7) 28 (3.5) 17 (3.9) 14 (4.7) 6 (2.4) 0 92 (3.1) Chronic lung disease 231 (23.1) 113 (14.3) 108 (24.9) 75 (25) 54 (21.9) 32 (16.2) 613 (20.6) Chronic kidney disease 85 (8.5) 46 (5.8) 28 (6.5) 27 (9) 11 (4.5) 15 (7.6) 212 (7.1) Obesity (BMI ≥ 30) 244 (24.4) 138 (17.4) 39 (9) 47 (15.7) 31 (12.6) 30 (15.2) 529 (17.8) Morbid obesity (BMI ≥ 40) 87 (8.7) 0 11 (2.5) 7 (2.3) 2 (0.8) 7 (3.5) 114 (3.8) Diabetes 171 (17.1) 74 (9.4) 73 (16.8) 42 (14) 31 (12.6) 17 (8.6) 408 (13.7) Cancer 68 (6.8) 36 (4.6) 19 (4.4) 34 (11.3) 23 (9.3) 7 (3.5) 187 (6.3) Other comorbidities 213 (21.3) 159 (20.1) 151 (34.8) 145 (48.3) 67 (27.1) 53 (27.6) 788 (36.2) Number of comorbities 1.7 (1.5) 1.1 (1.1) 1.6 (1.4) 2.3 (1.8) 1.5 (1.4) 1.3 (1.3) 1.5 (1.5) No comorbidity 250 (25) 277 (35) 105 (24.2) 44 (14.7) 70 (28.3) 67 (33.8) 813 (27.4) One comorbidity 275 (27.5) 276 (34.9) 136 (31.3) 79 (26.3) 77 (31.2) 58 (29.3) 901 (30.3) Two comorbidities 211 (21.1) 143 (18.1) 98 (22.6) 57 (19) 51 (20.6) 39 (19.7) 599 (20.2) ≥ 3 comorbidites 264 (26.4) 95 (12) 95 (21.9) 120 (40) 49 (19.8) 34 (17.2) 657 (22.1) DMARD therapies csDMARDs mono 106 (10.5) 159 (20.1) 91 (20.9) 66 (21) 51 (20.6) 52 (26.3) 525 (17.5) csDMARDs combi 208 (20.7) 164 (20.7) 84 (19.3) 58 (18.4) 40 (16.2) 33 (16.7) 587 (19.6) Methotrexate mono 88 (8.8) 151 (19) 83 (19.1) 55 (17.5) 45 (18.2) 47 (23.7) 469 (15.7) Methotrexate combi 174 (17.3) 142 (17.9) 78 (17.9) 52 (16.5) 36 (14.6) 33 (16.7) 515 (17.2) Leflunomide mono 18 (1.8) 8 (1) 8 (1.8) 11 (3.5) 6 (2.4) 5 (2.5) 56 (1.9) Leflunomide combi 40 (4) 22 (2.8) 11 (2.5) 6 (1.9) 7 (2.8) 3 (1.5) 89 (3) Sulfasalazine mono 7 (0.7) 3 (0.4) 21 (4.8) 4 (1.3) 6 (2.4) 7 (3.5) 48 (1.6) Sulfasalazine combi 33 (3.3) 6 (0.8) 47 (10.8) 10 (3.2) 10 (4) 2 (1) 108 (3.6) Antimalarial mono 120 (11.9) 32 (4) 20 (4.6) 28 (8.9) 15 (6.1) 8 (4) 223 (7.5) Antimalarial combi 132 (13.1) 34 (4.3) 48 (11) 31 (9.8) 18 (7.3) 10 (5.1) 273 (9.1) Immunosuppressants mono 66 (6.6) 14 (1.8) 23 (5.3) 17 (5.4) 9 (3.6) 10 (5.1) 139 (4.6) Immunosuppressants combi 75 (7.5) 14 (1.8) 17 (3.9) 13 (4.1) 6 (2.4) 2 (1) 127 (4.2) Mycophenolate mofetil mono 42 (4.2) 8 (1) 11 (2.5) 6 (1.9) 3 (1.2) 2 (1) 72 (2.4) Mycophenolate mofetil combi 44 (4.4) 9 (1.1) 13 (3) 6 (1.9) 3 (1.2) 2 (1) 77 (2.6) Azathioprine mono 17 (1.7) 6 (0.8) 9 (2.1) 8 (2.5) 5 (2) 7 (3.5) 52 (1.7) Azathioprine combi 24 (2.4) 5 (0.6) 3 (0.7) 4 (1.3) 3 (1.2) 0 39 (1.3) Cyclophosph. mono 2 (0.2) 0 3 (0.7) 2 (0.6) 1 (0.4) 1 (0.5) 9 (0.3) Cyclophosph. combi 6 (0.6) 0 1 (0.2) 1 (0.3) 0 0 8 (0.3) Tacrolimus mono 5 (0.5) 0 0 0 0 0 5 (0.2) Tacrolimus combi 9 (0.9) 0 0 0 1 (0.4) 0 10 (0.3) Cyclosporin mono 0 0 0 1 (0.3) 0 0 1 (0) Cyclosporin combi 1 (0.1) 0 1 (0.2) 4 (1.3) 0 0 6 (0.2) bDMARDs monotherapy 174 (17.3) 228 (28.8) 53 (12.2) 63 (20) 44 ( 17.8) 43 ( 21.7) 605 ( 20.2) bDMARDs combination therapy 178 (17.7) 144 (18.2) 67 (15.4) 48 (15.2) 34 (13.8) 29 (14.7) 500 (16.7) TNF inhibitors mono 100 (10) 145 (18.3) 29 (6.7) 45 (14.3) 27 (10.9) 26 (13.1) 372 (12.4) TNF inhibitors combi 106 (10.5) 84 (10.6) 39 (9) 28 (8.9) 19 (7.7) 13 (6.6) 289 (9.7) Abatacept mono 14 (1.4) 6 (0.8) 1 (0.2) 5 (1.6) 0 0 26 (0.9) Abatacept combi 20 (2) 13 (1.6) 3 (0.7) 2 (0.6) 3 (1.2) 3 (1.5) 44 (1.5) B-cell affecting bDMARDs mono 29 (2.9) 26 (3.3) 10 (2.3) 1 (0.3) 8 (3.2) 3 (1.5) 77 (2.6) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 8 B-cell affecting bDMARDs combi 37 (3.7) 22 (2.8) 20 (4.6) 9 (2.9) 8 (3.2) 10 (5.1) 106 (3.5) Rituximab mono 26 (2.6) 26 (3.3) 10 (2.3) 1 (0.3) 7 (2.8) 3 (1.5) 73 (2.4) Rituximab combi 24 (2.4) 20 (2.5) 19 (4.4) 7 (2.2) 8 (3.2) 8 (4) 86 (2.9) Belimumab mono 3 (0.3) 0 0 0 1 (0.4) 0 4 (0.1) Belimumab combi 13 (1.3) 2 (0.3) 1 (0.2) 2 (0.6) 1 (0.4) 2 (1) 21 (0.7) IL-6 inhibitors mono 11 (1.1) 18 (2.3) 3 (0.7) 4 (1.3) 3 (1.2) 6 (3) 45 (1.5) IL-6 inhibitors combi 12 (1.2) 11 (1.4) 2 (0.5) 3 (1) 3 (1.2) 0 31 (1) IL-1 inhibitors mono 0 9 (1.1) 1 (0.2) 0 1 (0.4) 0 11 (0.4) IL-1 inhibitors combi 2 (0.2) 0 1 (0.2) 2 (0.6) 0 0 5 (0.2) Other IL inhibitors ( IL-17, Il-23, Il-12/23 inh.) mono 19 (1.9) 24 (3) 9 (2.1) 7 (2.2) 5 (2) 8 (4) 72 (2.4) Other IL inhibitors ( IL-17, Il-23, Il-12/23 inh.) combi 3 (0.3) 14 (1.8) 2 (0.5) 6 (1.9) 1 (0.4) 3 (1.5) 29 (1) tsDMARDs mono 32 (3.2) 10 (1.3) 7 (1.6) 4 (1.3) 3 (1.2) 4 (2) 60 (2) tsDMARDs (*) combi 43 (4.3) 15 (1.9) 4 (0.9) 9 (2.9) 3 (1.2) 3 (1.5) 77 (2.6) JAK inhibitors mono 26 (2.6) 10 (1.3) 7 (1.6) 4 (1.3) 2 (0.8) 4 (2) 53 (1.8) JAK inhibitors combi 40 (4) 15 (1.9) 3 (0.7) 8 (2.5) 3 (1.2) 3 (1.5) 72 (2.4) Apremilast mono 6 (0.6) 0 0 0 1 (0.4) 0 7 (0.2) Apremilast combi 2 (0.2) 0 1 (0.2) 1 (0.3) 0 0 4 (0.1) No DMARD therapies 192 (19.1) 161 (20.3) 98 (22.5) 52 (16.5) 64 (25.9) 35 (17.7) 602 (20.1) Further therapies Glucocorticoids (#) 283 (28.6) (N=990) 253 (31.9) (N=793) 128 (30) (N=427) 165 (52.4) (N=315) 98 (40.3) (N=243) 82 (41.6) (N=197) 1009 (34) (N=2965) 0 mg/d < GC <= 10mg/d 226 (22.9) (N=985) 205 (25.9) (N=791) 87 (20.5) (N=425) 135 (43.7) (N=309) 64 (30.2) (N=212) 74 (37.8) (N=196) 791 (27.1) (N=2918) GC > 10 mg/d 52 (5.3) (N=985) 45 (5.7) (N=791) 37 (8.7) (N=425) 24 (7.8) (N=309) 3 (1.4) (N=212) 6 (3.1) (N=196) 167 (5.7) (N=2918) NSAID 209 (22.9) (N=914) 85 (10.7) (N=793) 51 (13.3) (N=385) 53 (18.6) (N=285) 52 (21.9) (N=21.9) 36 (19.7) (N=19.7) 486 (17.4) (N=2798) Data are N (column %) for categorical variables or mean (SD) for continuous variables. Table includes all patients with a non-missing outcome and nonmissing values for age, sex and disease modifying anti-rheumatic drugs (DMARDs) (101 patients excluded). Data refers to patients with non-missing values for the respective variable, total N for patients with non-missing values is given in parentheses for variables with missing values. (*) Includes one patient on a study medication (Lenabasum). (#) Includes patients with a missing glucocorticoid dose. bDMARD, biologic disease modifying antirheumatic drugs; BMI, body mass index; csDMARD, conventional synthetic disease modifying antirheumatic drugs; combi, combination therapy; CTD, connective tissue diseases; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, glucocorticoids; IL, interleukin; JAK, Janus kinase; JIA, juvenile idiopathic arthritis; mono, monotherapy; N, number; NSAID, non-steroidal antiinflammatory drugs; SLE, systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 9 Supplementary table 3. Patient demographic and clinical characteristics stratified by main medication of interest Parameter MTX LEF ANTIMALARIALS SSZ IMMUNO SUPPR. TNFi ABA RTX IL-6i IL-17/23/ 12+23i JAKi No DMARDs TOTAL N 1237 203 665 222 338 804 83 193 90 116 134 739 3729 General Age [years] 58.3 (14.5) 59.5 (12.3) 53.3 (15.2) 59.0 (14.8) 50.1 (15.8) 51.1 (13.7) 59.0 (15.0) 56.2 (15.1) 57.7 (16.4) 50.1 (11.3) 58.3 (13.3) 62.8 (16.6) 57.0 (15.7) Male sex 390 (31.5) 44 (21.7) 117 (17.6) 82 (36.9) 93 (27.5) 312 (38.8) 24 (28.9) 60 (31.1) 21 (23.3) 45 (38.8) 18 (13.4) 280 (37.9) 1195 (32) Ever smoker 244 (23.4) (N=1044) 40 (24.7) (N=162) 129 (22.2) (N=582) 66 (37.3) (N=177) 54 (18.6) (N=290) 167 (23.6) (N=709) 20 (27.8) (N=72) 38 (23.3) (N=163) 10 (12.5) (N=80) 21 (20.8) (N=101) 28 (22.6) (N=124) 181 (29.8) (N=607) 776 (24.5) (N=3164) Inflammatory joint diseases Rheumatoid arthritis 756 (61.1) 160 (78.8) 243 (36.5) 126 (56.8) 26 (7.7) 293 (36.4) 70 (84.3) 87 (45.1) 63 (70) 2 (1.7) 119 (88.8) 110 (14.9) 1394 (37.4) Spondyloartrhitis 74 (6) 4 (2) 6 (0.9) 35 (15.8) 6 (1.8) 271 (33.7) 2 (2.4) 0 2 (2.2) 43 (37.1) 4 (3) 59 (8) 431 (11.6) Psoriatic arthritis 177 (14.3) 23 (11.3) 8 (1.2) 38 (17.1) 1 (0.3) 182 (22.6) 4 (4.8) 1 (0.5) 0 70 (60.3) 9 (6.7) 38 (5.1) 440 (11.8) Total IJD 1047 (84.6) 190 (93.6) 280 (42.1) 212 (95.5) 33 (9.8) 765 (95.1) 77 (92.8) 91 (47.2) 68 (75.6) 113 (97.4) 132 (98.5) 239 (32.3) 2373 (63.6) Connective tissue diseases/ Vasculitis SLE 49 (4) 7 (3.4) 257 (38.6) 3 (1.4) 127 (37.6) 6 (0.7) 2 (2.4) 15 (7.8) 1 (1.1) 1 (0.9) 5 (3.7) 48 (6.5) 391 (10.5) CTDs (other than SLE) 104 (8.4) 4 (2) 171 (25.7) 5 (2.3) 134 (39.6) 19 (2.4) 6 (7.2) 52 (26.9) 1 (1.1) 0 3 (2.2) 156 (21.1) 533 (14.3) Vasculitis 44 (3.6) 7 (3.4) 7 (1.1) 5 (2.3) 53 (15.7) 14 (1.7) 0 39 (20.2) 21 (23.3) 0 0 161 (21.8) 326 (8.7) Total CTD 190 (15.4) 17 (8.4) 407 (61.2) 13 (5.9) 294 (87) 39 (4.9) 8 (9.6) 104 (53.9) 23 (25.6) 1 (0.9) 7 (5.2) 353 (47.8) 1193 (32) Other RMDs Total 60 (4.9) 7 (3.4) 33 (5) 17 (7.7) 49 (14.5) 33 (4.1) 3 (3.6) 20 (10.4) 3 (3.3) 3 (2.6) 6 (4.5) 173 (23.4) 356 (9.5) Disease activity N=894 N=162 N=574 N=196 N=300 N=547 N=62 N=142 N=61 N=73 N=105 N=517 N=2758 Remission 307 (34.3) 40 (24.7) 146 (25.4) 50 (25.5) 66 (22) 184 (33.6) 14 (22.6) 36 (25.4) 16 (26.2) 20 (27.4) 19 (18.1) 215 (41.6) 893 (32.4) Minimal/low DA 413 (46.2) 84 (51.9) 310 (54) 100 (51) 138 (46) 265 (48.4) 32 (51.6) 64 (45.1) 25 (41) 33 (45.2) 56 (53.3) 211 (40.8) 1309 (47.5) Moderate DA 157 (17.6) 31 (19.1) 91 (15.9) 38 (19.4) 71 (23.7) 89 (16.3) 10 (16.1) 26 (18.3) 16 (26.2) 19 (26) 26 (24.8) 56 (10.8) 448 (16.2) Severe/high DA 17 (1.9) 7 (4.3) 27 (4.7) 8 (4.1) 25 (8.3) 9 (1.6) 6 (9.7) 16 (11.3) 4 (6.6) 1 (1.4) 4 (3.8) 35 (6.8) 108 (3.9) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 10 Other outcomes Hospitalised 541 (46.2) (N=1170) 103 (52.8) (N=195) 298 (47.1) (N=633) 126 (62.4) (N=202) 197 (60.4) (N=326) 207 (27.3) (N=758) 33 (42.9) (N=77) 127 (71.3) (N=178) 26 (29.9) (N=87) 37 (34.3) (N=108) 55 (43.7) (N=126) 442 (61.7) (N=716) 1739 (49) (N=3546) Death 99 (8) 22 (10.8) 56 (8.4) 42 (18.9) 46 (13.6) 30 (3.7) 9 (10.8) 42 (21.8) 5 (5.6) 1 (0.9) 13 (9.7) 124 (16.8) 390 (10.5) Comorbidities N=1224 N=202 N=661 N=219 N=337 N=800 N=83 N=190 N=90 N=115 N=133 N=733 N=3700 Hypertension 422 (34.5) 71 (35.1) 239 (36.2) 85 (38.8) 127 (37.7) 196 (24.5) 28 (33.7) 58 (30.5) 24 (26.7) 29 (25.2) 55 (41.4) 332 (45.3) 1307 (35.3) Cardiovascular disease 121 (9.9) 23 (11.4) 63 (9.5) 36 (16.4) 38 (11.3) 53 (6.6) 12 (14.5) 25 (13.2) 13 (14.4) 9 (7.8) 12 (9) 146 (19.9) 442 (11.9) Cerebrovascular disease 31 (2.5) 7 (3.5) 19 (2.9) 9 (4.1) 11 (3.3) 13 (1.6) 1 (1.2) 5 (2.6) 3 (3.3) 2 (1.7) 4 (3) 31 (4.2) 109 (2.9) Chronic lung disease 216 (17.6) 48 (23.8) 136 (20.6) 45 (20.5) 113 (33.5) 108 (13.5) 17 (20.5) 64 (33.7) 7 (7.8) 13 (11.3) 34 (25.6) 137 (18.7) 719 (19.4) Chronic kidney disease 42 (3.4) 12 (5.9) 58 (8.8) 11 (5) 54 (16) 24 (3) 6 (7.2) 22 (11.6) 3 (3.3) 3 (2.6) 6 (4.5) 83 (11.3) 258 (7) Obesity (BMI ≥ 30) 187 (15.3) 30 (14.9) 108 (16.3) 38 (17.4) 55 (16.3) 148 (18.5) 15 (18.1) 22 (11.6) 18 (20) 27 (23.5) 36 (27.1) 102 (13.9) 597 (16.1) Morbid obesity (BMI ≥ 40) 33 (2.7) 6 (3) 34 (5.1) 6 (2.7) 26 (7.7) 24 (3) 4 (4.8) 13 (6.8) 2 (2.2) 2 (1.7) 12 (9) 20 (2.7) 122 (3.3) Diabetes 170 (13.9) 39 (19.3) 80 (12.1) 38 (17.4) 46 (13.6) 75 (9.4) 14 (16.9) 26 (13.7) 13 (14.4) 12 (10.4) 19 (14.3) 121 (16.5) 505 (13.6) Cancer 64 (5.2) 7 (3.5) 32 (4.8) 12 (5.5) 13 (3.9) 17 (2.1) 5 (6) 18 (9.5) 3 (3.3) 5 (4.3) 2 (1.5) 76 (10.4) 214 (5.8) Other comorbidities 267 (21.8) 43 (21.3) 138 (20.9) 63 (28.8) 98 (29.1) 209 (26.1) 19 (22.9) 50 (26.3) 22 (24.4) 44 (38.3) 33 (24.8) 178 (24.3) 897 (24.2) DMARD therapies Methotrexate/Leflunomi de 1237 (100) 203 (100) 199 (29.9) 96 (43.2) 10 (3) 306 (38.1) 41 (49.4) 61 (31.6) 32 (35.6) 30 (25.9) 61 (45.5) 0 1404 (37.7) Sulfasalazine 75 (6.1) 24 (11.8) 39 (5.9) 222 (100) 5 (1.5) 48 (6) 1 (1.2) 6 (3.1) 5 (5.6) 3 (2.6) 11 (8.2) 0 222 (6) Antimalarials 177 (14.3) 33 (16.3) 665 (100) 39 (17.6) 108 (32) 41 (5.1) 10 (12) 29 (15) 7 (7.8) 2 (1.7) 14 (10.4) 0 665 (17.8) Immunosuppressants 9 (0.7) 1 (0.5) 108 (16.2) 5 (2.3) 338 (100) 17 (2.1) 2 (2.4) 27 (14) 0 1 (0.9) 2 (1.5) 0 338 (9.1) bDMARDs 424 (34.3) 63 (31) 109 (16.4) 64 (28.8) 59 (17.5) 804 (100) 83 (100) 193 (100) 90 (100) 116 (100) 1 (0.7) 0 1331 (35.7) tsDMARDs 52 (4.2) 12 (5.9) 14 (2.1) 12 (5.4) 3 (0.9) 0 0 1 (0.5) 0 1 (0.9) 134 (100) 0 147 (3.9) Further therapies Glucocorticoids (#) 410 (33.5) (N=1223) 83 (42.3) (N=196) 252 (38.3) (N=658) 66 (30.6) (N=216) 66 (30.6) (N=335) 130 (16.3) (N=796) 34 (41) (N=83) 100 (52.6) (N=190) 35 (38.9) (N=90) 16 (13.8) (N=116) 48 (36.9) (N=130) 290 (39.8) (N=729) 1273 (34.6) (N=3682) 0 mg/d < GC <= 10mg/d 351 (29.2) (N=1203) 75 (38.9) (N=193) 192 (30) (N=640) 52 (24.4) (N=213) 52 (24.4) (N=323) 102 (12.9) (N=789) 30 (36.6) (N=82) 67 (37) (N=181) 30 (33.7) (N=89) 14 (12.1) (N=116) 44 (33.8) (N=130) 202 (28.4) (N=712) 983 (27.2) (N=3617) GC > 10 mg/d 38 (3.2) (N=1203) 5 (2.6) (N=193) 42 (6.6) (N=640) 11 (5.2) (N=213) 11 (5.2) (N=323) 20 (2.5) (N=789) 3 (3.7) (N=82) 22 (12.2) (N=181) 4 (4.5) (N=89) 2 (1.7) (N=116) 4 (3.1) (N=130) 70 (9.8) (N=712) 220 (6.1) (N=3617) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 11 Data are N (column %) for categorical variables or mean (SD) for continuous variables. Table includes all patients with a non-missing outcome and non-missing values for age, sex and disease modifying anti-rheumatic drugs (DMARDs) (101 patients excluded). Data refers to patients with non-missing values for the respective variable, total N for patients with non-missing values is given in parentheses for variables with missing values. (*) Includes one patient on a study medication (Lenabasum). (#) Includes patients with a missing glucocorticoid dose. ABA, Abatacept; bDMARD, biologic disease modifying antirheumatic drugs; BMI, body mass index; csDMARD, conventional synthetic disease modifying antirheumatic drugs; combi, combination therapy; CTD, connective tissue diseases; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, glucocorticoids; IL-6i, interleukin-6 inhibitors; IL-17/23/12+23i, interleukin-17/23/12+23 inhibitors; IMMMUNOSUPPR, immunosuppressants; .JAKi, Janus kinase inhibitors; JIA, juvenile idiopathic arthritis; LEF, leflunomide; MTX, methotrexate; mono, monotherapy; N, number; NSAID, non-steroidal anti-inflammatory drugs; RTX, rituximab; SLE, systemic lupus erythematosus; SSZ, sulfasalazine; TNFi; tumour necrosis factor inhibitors. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 12 Supplementary table 4. Multivariable logistic regression analysis of factors associated with COVID-19-related death in patients with rheumatic diseases (excluding patients reported from France) All Patients with inflammatory joint diseases (IJDs) Only patients with rheumatoid arthritis Patients with connective tissue diseases (CTDs) or vasculitis N deaths/patients (%) 324 / 2921 (11.1%) 186 / 1818 (10.2%) 146 / 1124 (13.0 %) 113 / 932 (12.1%) N deaths/patients OR 95% CI N deaths/patients OR 95% CI N deaths/patients OR 95% CI N deaths/patients OR 95% CI Age, years Age ≤ 65 108 / 2018 1 [Reference] 52 / 1259 1 [Reference] 38 / 692 1 [Reference] 49 / 657 1 [Reference] 65 years < Age ≤ 75 97 / 516 3.18 2.26 4.47 67 / 351 3.58 2.41 5.33 53 / 259 3.33 1.80 6.18 24 / 139 2.43 1.43 4.13 Age > 75 119 / 387 5.77 4.03 8.28 67 / 208 7.22 4.89 10.66 55 / 173 6.31 3.77 10.54 40 / 136 4.34 2.11 8.91 Male sex (vs. female) 131 / 919 1.39 1.00 1.95 74 / 603 1.39 1.01 1.91 50 / 279 1.27 0.85 1.89 44 / 232 1.38 0.91 2.08 Ever smoked (vs. never) 135 / 873 1.12 0.85 1.49 85 / 576 1.15 0.79 1.67 71 / 373 1.27 0.87 1.86 39 / 234 1.13 0.70 1.82 Comorbidities Hypertension alone or CVD alone 125 / 954 1.08 0.85 1.38 67 / 568 1.03 0.69 1.54 54 / 375 1.05 0.70 1.59 53 / 337 1.40 0.95 2.08 Hypertension and CVD 72 / 253 1.77 1.20 2.62 48 / 146 2.45 1.22 4.92 34 / 102 2.09 0.99 4.42 18 / 82 1.15 0.61 2.18 Chronic lung disease 122 / 610 1.74 1.26 2.40 73 / 342 1.67 1.15 2.41 61 / 258 1.62 1.13 2.32 44 / 241 2.17 1.41 3.35 Chronic kidney disease 58 / 214 1.40 0.81 2.43 21 / 97 0.83 0.45 1.56 16 / 75 0.76 0.36 1.59 30 / 97 2.34 1.16 4.73 Diabetes mellitus 79 / 433 1.26 0.76 2.08 47 / 267 1.23 0.86 1.77 32 / 182 1.00 0.63 1.58 21 / 126 1.01 0.52 1.96 Rheumatic disease Rheumatoid arthritis 140 / 1079 1 [Reference] 146 / 1126 1 [Reference] n.a. n.a. Systemic lupus erythematosus 34 / 341 1.28 0.71 2.29 n.a. 30 / 328 1 [Reference] Vasculitis 49 / 254 0.75 0.54 1.05 43 / 233 0.65 0.40 1.08 Other connective tissue diseases 42 / 384 0.73 0.54 0.98 40 / 371 0.77 0.36 1.64 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 19 Vasculitis 63 / 284 0.92 0.67 1.26 60 / 277 0.81 0.49 1.35 Other connective tissue diseases 50 / 407 0.83 0.62 1.12 48 / 396 0.80 0.40 1.61 Psoriasis arthritis 17 / 324 0.76 0.60 0.97 17 / 331 0.85 0.61 1.17 n.a. Spondyloarthritis 14 / 291 0.77 0.38 1.58 14 / 292 0.92 0.46 1.83 Other inflammatory arthritis or nonsystemic JIA 9 / 84 0.86 0.57 1.31 10 / 89 0.90 0.57 1.44 Other rheumatic diseases (not IJDs / CTDs / vasculitis) 20 / 187 0.49 0.35 0.70 n.a. High/moderate/severe disease activity (DA) vs. remission/low DA 97 / 575 1.77 1.15 2.73 47 / 337 1.63 1.06 2.50 37 / 206 1.63 0.98 2.71 47 / 204 2.11 1.28 3.46 Medication Methotrexate 45 / 476 1 [Reference] 39 / 387 1 [Reference] 32 / 279 1 [Reference] 6 / 80 1 [Reference] No DMARD therapy 109 / 620 1.88 1.31 2.68 28 / 187 1.58 1.01 2.46 17 / 88 1.55 0.92 2.61 64 / 309 3.22 1.58 6.56 Leflunomide 10 / 75 1.38 0.79 2.40 8 / 68 1.15 0.60 2.20 7 / 56 1.12 0.56 2.26 n.a. Antimalarials 24 / 360 0.86 0.52 1.43 15 / 138 1.02 0.51 2.03 15 / 116 1.09 0.54 2.18 10 / 231 1.30 0.43 3.88 Sulfasalazine 28 / 119 3.16 1.36 7.37 26 / 113 2.91 1.14 7.43 18 / 75 2.25 0.98 5.17 n.a. Immunosuppressants 36 / 238 1.99 1.27 3.13 n.a. n.a. 31 / 213 2.46 1.11 5.42 TNF inhibitors 29 / 575 0.92 0.57 1.49 25 / 544 0.83 0.45 1.54 15 / 229 0.87 0.37 2.05 4 / 34 2.09 0.33 13.30 Abatacept 8 / 68 1.06 0.57 1.96 8 / 62 1.14 0.57 2.29 8 / 56 1.21 0.57 2.58 n.a. Rituximab 35 / 160 3.28 1.89 5.69 19 / 72 5.32 2.54 11.13 18 / 68 4.80 2.24 10.29 19 / 89 3.29 1.04 10.43 Belimumab 1 / 23 0.66 0.19 2.31 n.a. n.a. 1 / 23 1.09 0.22 5.39 IL-6 inhibitors 5 / 66 0.91 0.43 1.90 1 / 47 0.29 0.03 2.80 1 / 42 0.29 0.03 2.79 4 / 21 2.72 0.91 8.09 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 20 IL-17/IL-23/IL-12+23 inhibitors 1 / 89 0.30 0.04 2.36 1 / 87 0.31 0.04 2.29 n.a. n.a. tsDMARDs 14 / 114 1.66 0.85 3.21 14 / 111 1.80 0.96 3.34 12 / 91 1.54 0.66 3.60 n.a. Glucocorticoids (GCs) No GCs 148 / 1884 1 [Reference] 97 / 1298 1 [Reference] 67 / 681 1 [Reference] 36 / 467 1 [Reference] GCs 1-10mg/d 151 / 883 1.39 0.93 2.06 76 / 454 1.32 0.71 2.46 67 / 371 1.38 0.64 3.00 70 / 406 1.74 1.14 2.67 GCs > 10 mg/d 46 / 200 1.68 1.11 2.56 11 / 51 1.41 0.68 2.90 9 / 38 1.38 0.59 3.22 33 / 126 2.16 1.21 3.88 Missing values imputed via multiple imputation, patient numbers may thus be rounded. Effects significant at level α=0.05 are marked in bold. Patients were excluded from a particular analysis if the medication they received provided ≤ 20 patients for that analysis or if there were no deaths reported for that specific medication. CI, confidence interval; CTD, connective tissue diseases; CVD, cardiovascular disease; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, glucocorticoids; IJD, inflammatory joint diseases; IL, interleukin; JIA, juvenile idiopathic arthritis; N, number; OR, odds ratio; SLE, systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 21 Supplementary table 7. Multivariable logistic regression analysis of factors associated with COVID-19-related death or invasive ventilation in patients with rheumatic diseases All Patients with inflammatory joint diseases (IJDs) Only patients with rheumatoid arthritis Patients with connective tissue diseases (CTDs) or vasculitis N deaths or invasive ventilations (IV) /patients (%) 451 / 3075 (14.7%) 248 / 1970 (12.6%) 188 / 1148 (16.4%) 170 / 925 (18.4%) N deaths or IVs / patients OR 95% CI N deaths or IVs / patients OR 95% CI N deaths or IVs/patients OR 95% CI N deaths or IVs / patients OR 95% CI Age, years Age ≤ 65 168 / 2173 1 [Reference] 81 / 1425 1 [Reference] 51 / 721 1 [Reference] 80 / 638 1 [Reference] 65 years < Age ≤ 75 120 / 507 2.55 2.00 3.26 78 / 339 2.95 2.14 4.06 62 / 253 3.09 1.96 4.88 90 / 287 1.54 1.14 2.09 Age > 75 163 / 395 5.19 3.35 8.03 89 / 206 7.22 3.90 13.35 75 / 174 7.11 3.65 13.85 58 / 146 3.21 2.08 4.96 Male sex (vs. female) 184 / 977 1.50 1.12 2.00 92 / 652 1.29 0.91 1.83 61 / 287 1.20 0.74 1.96 72 / 242 1.76 1.18 2.60 Ever smoked (vs. never) 161 / 821 0.98 0.74 1.30 96 / 541 0.99 0.70 1.39 78 / 344 1.10 0.74 1.63 51 / 222 1.01 0.65 1.58 Comorbidities Hypertension alone or CVD alone 184 / 927 1.33 1.02 1.74 94 / 560 1.22 0.86 1.72 74 / 371 1.15 0.80 1.66 79 / 323 1.53 1.13 2.06 Hypertension and CVD 95 / 252 1.90 1.25 2.88 57 / 144 2.33 1.20 4.53 41 / 101 1.96 0.93 4.15 30 / 82 1.55 0.74 3.22 Chronic lung disease 158 / 590 1.80 1.38 2.35 91 / 328 1.87 1.26 2.78 74 / 234 1.76 1.21 2.56 62 / 233 2.11 1.52 2.93 Chronic kidney disease 86 / 211 2.00 1.24 3.22 30 / 93 1.13 0.61 2.11 23 / 69 1.01 0.48 2.11 46 / 98 3.16 1.69 5.90 Diabetes mellitus 108 / 393 1.44 0.97 2.14 62 / 246 1.30 1.02 1.67 44 / 171 1.17 0.80 1.71 35 / 114 1.42 0.61 3.31 Rheumatic disease Rheumatoid arthritis 180 / 1107 1 [Reference] 188 / 1150 1 [Reference] n.a. n.a. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 22 Systemic lupus erythematosus 46 / 322 1.26 0.83 1.91 n.a. 42 / 310 1 [Reference] Vasculitis 72 / 267 0.77 0.59 1.02 65 / 246 0.74 0.50 1.09 Other connective tissue diseases 66 / 381 0.89 0.62 1.28 63 / 369 0.95 0.54 1.65 Psoriasis arthritis 27 / 362 0.74 0.51 1.07 27 / 369 0.78 0.51 1.18 n.a. Spondyloarthritis 18 / 357 0.67 0.35 1.27 18 / 358 0.72 0.37 1.41 Other inflammatory arthritis or nonsystemic JIA 13 / 88 1.04 0.72 1.49 15 / 93 1.13 0.83 1.54 Other rheumatic diseases (not IJDs / CTDs / vasculitis) 29 / 191 0.55 0.36 0.83 n.a. High/moderate/severe disease activity (DA) vs. remission/low DA 119 / 592 1.57 1.13 2.19 60 / 380 1.35 0.96 1.89 48 / 235 1.32 0.88 1.98 53 / 182 1.98 1.21 3.24 Medication Methotrexate 56 / 468 1 [Reference] 48 / 390 1 [Reference] 39 / 289 1 [Reference] 8 / 70 1 [Reference] No DMARD therapy 139 / 622 1.96 1.26 3.06 41 / 208 1.93 1.15 3.23 25 / 92 2.00 1.18 3.40 75 / 287 2.77 1.48 5.19 Leflunomide 15 / 71 1.83 0.96 3.48 13 / 66 1.72 0.81 3.69 12 / 56 1.86 0.92 3.78 n.a. Antimalarials 35 / 357 1.02 0.67 1.56 20 / 142 1.13 0.61 2.10 19 / 117 1.25 0.67 2.31 17 / 225 1.53 0.67 3.48 Sulfasalazine 37 / 120 3.67 1.85 7.26 35 / 113 3.67 1.75 7.70 24 / 70 3.04 1.43 6.45 n.a. Immunosuppressants 45 / 231 1.80 1.19 2.72 n.a. n.a. 38 / 209 1.70 0.91 3.18 TNF inhibitors 39 / 692 0.86 0.53 1.37 34 / 657 0.83 0.48 1.43 22 / 254 0.98 0.52 1.86 6 / 37 1.73 0.33 9.04 Abatacept 11 / 65 1.28 0.61 2.71 11 / 62 1.40 0.63 3.12 11 / 58 1.55 0.71 3.42 n.a. Rituximab 46 / 144 4.31 2.48 7.49 25 / 72 5.99 3.00 11.96 24 / 69 6.04 3.01 12.09 23 / 75 3.15 1.12 8.90 Belimumab 3 / 22 1.84 0.58 5.87 n.a. n.a. 3 / 22 2.25 0.73 6.98 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 23 IL-6 inhibitors 5 / 77 0.75 0.34 1.63 1 / 60 0.22 0.02 2.09 1 / 55 0.22 0.02 2.14 n.a. IL-17/IL-23/IL-12+23 inhibitors 6 / 92 1.42 0.59 3.43 6 / 89 1.58 0.63 3.96 n.a. tsDMARDs 17 / 125 1.45 0.81 2.59 17 / 122 1.67 0.94 2.97 14 / 99 1.51 0.76 3.02 n.a. Glucocorticoids (GCs) No GCs 202 / 2032 1 [Reference] 136 / 1450 1 [Reference] 90 / 722 1 [Reference] 45 / 452 1 [Reference] GCs 1-10mg/d 191 / 860 1.45 1.03 2.04 99 / 468 1.31 0.72 2.38 87 / 389 1.37 0.68 2.73 86 / 362 2.02 1.44 2.84 GCs > 10 mg/d 58 / 183 2.11 1.44 3.11 13 / 53 1.47 0.58 3.74 11 / 37 1.74 0.56 5.40 39 / 111 2.51 1.47 4.27 Living patients with missing values for invasive ventilation excluded from the model (dependent variable unknown). Missing values in other variables imputed via multiple imputation, patient numbers may thus be rounded. Effects significant at level α=0.05 are marked in bold. Patients were excluded from a particular analysis if the medication they received provided ≤ 20 patients for that analysis or if there were no deaths reported for that specific medication. CI, confidence interval; CTD, connective tissue diseases; CVD, cardiovascular disease; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, glucocorticoids; IJD, inflammatory joint diseases; IL, interleukin; JIA, juvenile idiopathic arthritis; N, number; OR, odds ratio; SLE, systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 24 Supplementary table 8. Multivariable logistic regression analysis of factors associated with COVID-19-related death in all patients with a reduced number of regressor variables All Patients with inflammatory joint diseases (IJDs) Only patients with rheumatoid arthritis Patients with connective tissue diseases (CTDs) or vasculitis N deaths/patients (%) 384/3705 (10.4%) 211/2348 (9.0%) 166/1371 (12.1%) 147/1157 (12.7%) N deaths/patients OR 95% CI N deaths/patients OR 95% CI N deaths/patients OR 95% CI N deaths/patients OR 95% CI Age, years Age ≤ 65 118 / 2565 1 [Reference] 55 / 1657 1 [Reference] 40 / 840 1 [Reference] 56 / 779 1 [Reference] Age > 65 266 / 1140 4.10 3.06 5.49 156 / 691 5.00 3.63 6.88 126 / 531 4.40 2.74 7.08 91 / 378 3.15 1.91 5.18 Male sex (vs. female) 161 / 1188 1.41 1.08 1.86 82 / 788 1.27 0.94 1.72 55 / 345 1.14 0.77 1.70 63 / 296 1.64 0.97 2.77 Ever smoked (vs. never) 140 / 922 1.18 0.89 1.56 84 / 607 1.21 0.88 1.66 71 / 385 1.38 1.00 1.92 42 / 248 1.07 0.63 1.81 Comorbidities Hypertension alone or CVD alone 155 / 1150 1.23 0.91 1.66 79 / 690 1.08 0.77 1.51 66 / 454 1.16 0.78 1.74 69 / 406 1.58 1.06 2.35 Hypertension and CVD 89 / 301 2.13 1.42 3.18 53 / 168 2.66 1.54 4.60 38 / 118 2.48 1.34 4.56 28 / 106 1.65 0.80 3.43 Chronic lung disease 136 / 721 1.63 1.21 2.20 76 / 406 1.51 1.01 2.26 63 / 293 1.45 0.96 2.20 54 / 285 1.92 1.37 2.69 Chronic kidney disease 76 / 259 1.84 1.07 3.19 27 / 111 1.25 0.59 2.64 21 / 83 1.17 0.50 2.75 41 / 124 2.46 1.41 4.30 Diabetes mellitus 96 / 508 1.35 0.87 2.10 55 / 313 1.27 0.93 1.73 39 / 213 1.06 0.71 1.57 32 / 154 1.37 0.65 2.89 Rheumatic disease Rheumatoid arthritis 160 / 1326 1 [Reference] 166 / 1373 1 [Reference] n.a. n.a. Systemic lupus erythematosus 36 / 391 1.10 0.67 1.81 n.a. 32 / 378 1 [Reference] Vasculitis 67 / 325 0.85 0.64 1.11 115 / 479 0.89 0.53 1.49 Other connective tissue diseases 53 / 473 0.75 0.57 0.97 Psoriasis arthritis 19 / 429 0.66 0.49 0.90 19 / 437 0.73 0.52 1.04 n.a. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 25 Spondyloarthritis 15 / 423 0.66 0.32 1.35 15 / 424 0.76 0.39 1.48 Other inflammatory arthritis or nonsystemic JIA 10 / 109 0.73 0.44 1.22 11 / 114 0.70 0.40 1.23 Other rheumatic diseases (not IJDs / CTDs / vasculitis) 24 / 229 0.52 0.36 0.74 n.a. High/moderate/severe disease activity (DA) vs. remission/low DA 109 / 722 1.84 1.31 2.59 54 / 453 1.49 1.09 2.02 44 / 274 1.49 0.99 2.23 51 / 230 2.54 1.63 3.95 Medication Methotrexate 47 / 595 1 [Reference] 41 / 487 1 [Reference] 34 / 354 1 [Reference] 6 / 94 1 [Reference] No DMARD therapy 124 / 739 2.20 1.55 3.12 38 / 239 2.14 1.44 3.17 25 / 110 2.12 1.36 3.29 67 / 353 3.43 1.72 6.85 Leflunomide 12 / 90 1.47 0.81 2.66 10 / 83 1.27 0.62 2.61 9 / 68 1.32 0.63 2.73 n.a. Antimalarials 27 /426 0.96 0.64 1.43 17 / 167 1.07 0.59 1.93 17 / 141 1.15 0.63 2.10 11 / 271 1.46 0.50 4.23 Sulfasalazine 33 / 144 3.49 1.64 7.45 31 / 137 3.22 1.44 7.23 21 / 85 2.43 1.17 5.04 n.a. Immunosuppressants 38 / 276 2.18 1.44 3.32 n.a. n.a. 32 / 247 2.54 1.15 5.63 Rituximab 42 / 192 3.77 2.23 6.36 22 / 90 4.91 2.60 9.25 21 / 86 4.57 2.35 8.92 22 / 104 3.68 1.24 10.92 TNF inhibitors 30 / 803 0.82 0.52 1.29 26 / 764 0.73 0.41 1.29 16 / 292 0.77 0.37 1.60 9 / 89 2.04 0.60 6.92 Belimumab 16 / 313 0.82 0.47 1.42 n.a. n.a. IL-6 inhibitors 11 / 255 0.69 0.35 1.36 10 / 131 0.89 0.40 1.98 Abatacept n.a. IL-17/IL-23/IL-12+23 inhibitors n.a. tsDMARDs 15 / 145 1.38 0.80 2.36 15 / 142 1.45 0.85 2.47 13 / 118 1.28 0.66 2.49 Glucocorticoids (GCs) No GCs 165 / 2417 1 [Reference] 109 / 1721 1 [Reference] 78 / 863 1 [Reference] 38 / 551 1 [Reference] BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 26 Glucorticoids 219 / 1288 1.50 1.07 2.10 102 / 627 1.46 0.86 2.47 88 / 508 1.44 0.74 2.80 109 / 606 1.77 1.28 2.46 Missing values imputed via multiple imputation, patient numbers may thus be rounded. Effects significant at level α=0.05 are marked in bold. Patients were excluded from a particular analysis if the medication they received provided ≤ 20 patients for that analysis or if there were no deaths reported for that specific medication. CI, confidence interval; CTD, connective tissue diseases; CVD, cardiovascular disease; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, glucocorticoids; IJD, inflammatory joint diseases; IL, interleukin; JIA, juvenile idiopathic arthritis; N, number; OR, odds ratio; SLE, systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 27 Supplementary table 9. Multivariable logistic regression analysis of factors associated with COVID-19 death in patients from the six countries providing the largest number of patients, considering country effects, with an otherwise reduced number of regressor variables All Patients with inflammatory joint diseases (IJDs) Only patients with rheumatoid arthritis Patients with connective tissue diseases (CTDs) or vasculitis N deaths/patients (%) 306 / 2974 (10.3%) 170 / 1903 (8.9%) 134 / 1102 (12.2%) 117 / 927 (12.6%) N deaths/patients OR 95% CI N deaths/patients OR 95% CI N deaths/patients OR 95% CI N deaths/patients OR 95% CI Age, years Age ≤ 65 76 / 2015 1 [Reference] 36 / 1321 1 [Reference] 25 / 658 1 [Reference] 36 / 597 1 [Reference] Age > 65 230 / 959 4.57 3.24 6.45 134 / 582 5.83 3.63 9.37 109 / 444 5.15 3.03 8.75 28 / 160 2.76 1.59 4.80 Male sex (vs. female) 141 / 951 1.68 1.26 2.24 71 / 640 1.41 0.95 2.08 47 / 283 1.24 0.77 1.98 56 / 239 2.03 1.28 3.21 Ever smoked (vs. never) 118 / 745 1.15 0.82 1.60 73 / 500 1.10 0.71 1.70 61 / 323 1.22 0.73 2.03 36 / 207 1.09 0.59 2.03 Comorbidities Hypertension alone or CVD alone 130 / 941 1.41 1.01 1.96 68 / 572 1.25 0.79 1.98 56 / 369 1.41 0.85 2.35 56 / 326 1.94 1.13 3.33 Hypertension and CVD 73 / 259 2.16 1.41 3.31 43 / 141 2.58 1.43 4.68 32 / 100 2.60 1.34 5.04 26 / 100 2.09 1.07 4.11 Lung disease 115 / 614 1.58 1.16 2.16 63 / 344 1.46 0.94 2.25 53 / 245 1.43 0.89 2.30 47 / 250 1.83 1.12 2.99 Chronic kidney disease 59 / 212 1.73 1.12 2.67 24 / 97 1.32 0.68 2.57 19 / 72 1.28 0.63 2.62 30 / 96 2.08 1.09 3.96 Diabetes mellitus 78 / 410 1.26 0.89 1.79 46 / 258 1.31 0.84 2.06 35 / 181 1.23 0.74 2.04 25 / 122 1.09 0.57 2.07 Rheumatic disease Rheumatoid arthritis 128 / 1058 1 [Reference] 134 / 1103 1 [Reference] n.a. n.a. Systemic lupus erythematosus 18 / 299 0.78 0.39 1.55 n.a. 15 / 288 1 [Reference] Vasculitis 60 / 272 0.81 0.50 1.30 102 / 639 1.33 0.65 2.73 Other connective tissue diseases 47 / 384 0.93 0.58 1.47 Psoriasis arthritis 17 / 353 0.70 0.38 1.30 17 / 360 0.81 0.43 1.54 n.a. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 28 Spondyloarthritis 10 / 340 0.57 0.27 1.20 10 / 340 0.70 0.33 1.50 Other inflammatory arthritis or nonsystemic JIA 8 / 95 0.68 0.30 1.58 9 / 100 0.66 0.28 1.57 Other rheumatic diseases (not IJDs / CTDs / vasculitis) 18 / 173 0.60 0.30 1.17 n.a. High/moderate/severe disease activity (DA) vs. remission/low DA 87 / 569 1.84 1.26 2.69 48 / 370 1.64 1.04 2.60 39 / 220 1.62 0.98 2.69 36 / 170 2.21 1.18 4.13 Medication Methotrexate 34 / 477 1 [Reference] 28 / 387 1 [Reference] 23 / 278 1 [Reference] 6 / 77 1 [Reference] No DMARD therapy 101 / 602 2.61 1.61 4.26 32 / 198 2.75 1.46 5.16 21 / 94 2.40 1.14 5.06 56 / 302 2.82 1.22 6.49 Leflunomide 10 / 64 2.32 0.98 5.50 8 / 59 1.78 0.71 4.45 8 / 48 2.16 0.81 5.76 n.a. Antimalarials 18 / 312 1.15 0.59 2.22 14 / 125 1.32 0.61 2.85 14 / 105 1.33 0.59 3.02 4 / 197 0.90 0.24 3.37 Sulfasalazine 27 / 93 5.07 2.64 9.74 26 / 88 5.10 2.55 10.20 18 / 51 3.96 1.72 9.12 n.a. Immunosuppressants 28 / 212 2.94 1.53 5.63 n.a. n.a. 23 / 192 2.59 1.02 6.58 Rituximab 35 / 159 4.38 2.37 8.10 16 / 74 4.65 2.02 10.71 15 / 70 4.45 1.84 10.77 21 / 89 4.17 1.56 11.09 TNF inhibitors 24 / 660 1.10 0.61 2.00 21 / 631 0.99 0.52 1.91 13 / 244 1.04 0.49 2.20 7 / 71 2.13 0.65 6.93 Belimumab 14 / 268 1.25 0.62 2.51 n.a. n.a. IL-6 inhibitors 10 / 216 1.05 0.46 2.40 9 / 109 1.38 0.56 3.41 Abatacept n.a. IL-17/IL-23/IL-12+23 inhibitors n.a. tsDMARDs 15 / 136 2.32 1.08 4.99 15 / 133 2.32 1.05 5.12 13 / 110 1.97 0.87 4.51 Glucocorticoids (GCs) 1 No GCs 120 / 1959 1 [Reference] 80 / 1406 1 [Reference] 55 / 701 1 [Reference] 30 / 454 1 [Reference] BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 35 Other rheumatic diseases (not IJDs / CTDs / vasculitis) 12 / 73 0.59 0.26 1.31 12 / 156 0.40 0.25 0.66 High/moderate/severe disease activity (DA) vs. remission/low DA 32 / 171 1.45 0.85 2.45 77 / 551 2.11 1.31 3.40 Medication Methotrexate 15 / 145 1 [Reference] 33 / 450 1 [Reference] No DMARD therapy 43 / 221 2.35 1.15 4.83 82 / 518 2.18 1.43 3.30 Leflunomide 5 / 21 1.41 0.39 5.12 8 / 69 1.52 0.68 3.39 Antimalarials 13 / 93 1.52 0.68 3.38 14 / 334 0.75 0.46 1.21 Sulfasalazine 21 / 56 6.15 2.23 16.94 12 / 89 2.16 0.81 5.73 Immunosuppressants 12 / 55 3.89 1.53 9.85 26 / 221 1.76 0.96 3.23 Rituximab 12 / 46 3.95 1.29 12.10 30 / 146 4.14 2.16 7.93 Other b/tsDMARDs 20 / 289 1.04 0.48 2.26 41 / 971 0.90 0.59 1.35 Glucocorticoids (GCs) No GCs 67 / 604 1 [Reference] 98 / 1813 1 [Reference] GCs 1-10mg/d 57 / 260 1.52 0.91 2.53 114 / 802 1.35 0.88 2.05 GCs > 10 mg/d 16 / 57 2.53 1.33 4.80 33 / 168 1.48 0.93 2.35 Missing values imputed via multiple imputation, patient numbers may thus be rounded. Effects significant at level α=0.05 are marked in bold. Patients were excluded from a particular analysis if the medication they received provided ≤ 20 patients for that analysis or if there were no deaths reported for that specific medication. CI, confidence interval; CTD, connective tissue diseases; CVD, cardiovascular disease; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, glucocorticoids; IJD, inflammatory joint diseases; IL, interleukin; JIA, juvenile idiopathic arthritis; N, number; OR, odds ratio; SLE, systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 36 Supplementary table 13. Multivariable logistic regression analysis of factors associated with COVID-19-related death stratified by heart disease (hypertension and/or cardiovascular disease) Heart disease No heart disease N deaths/patients (%) 242 / 1439 (16.8%) 384 / 3705 (10.4%) N deaths/patients OR 95% CI N deaths/patients OR 95% CI Age, years Age ≤ 65 63 / 711 1 [Reference] 53 / 1833 1 [Reference] 65 years < Age ≤ 75 58 / 367 1.68 1.12 2.52 49 / 270 5.98 3.72 9.63 Age > 75 121 / 361 4.77 3.08 7.40 36 / 134 7.65 5.24 11.16 Male sex (vs. female) 108 / 525 1.59 1.23 2.06 51 / 655 1.25 0.76 2.05 Ever smoked (vs. never) 93 / 458 1.13 0.82 1.56 46 / 457 1.48 0.94 2.34 Comorbidities Chronic lung disease 84 / 352 1.56 1.15 2.12 51 / 362 2.39 1.77 3.24 Chronic kidney disease 58 / 190 1.58 0.94 2.67 18 / 67 2.83 1.04 7.71 Diabetes mellitus 75 / 358 1.33 0.84 2.12 20 / 145 1.85 1.38 2.48 Rheumatic disease Rheumatoid arthritis 105 / 572 1 [Reference] 63 / 805 1 [Reference] Systemic lupus erythematosus 24 / 154 1.16 0.55 2.46 11 / 235 1.04 0.54 2.02 Vasculitis 39 / 168 0.61 0.36 1.01 27 / 155 1.12 0.69 1.81 Other connective tissue diseases 36 / 201 0.79 0.60 1.02 16 / 264 0.59 0.31 1.12 Psoriasis arthritis 13 / 152 0.70 0.45 1.10 6 / 273 0.60 0.30 1.19 Spondyloarthritis 6 / 87 0.51 0.17 1.51 9 / 336 0.87 0.43 1.74 Other inflammatory arthritis or non-systemic JIA 8 / 34 1.30 0.66 2.55 2 / 73 0.48 0.14 1.70 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 37 Other rheumatic diseases (not IJDs / CTDs / vasculitis) 16 / 100 0.45 0.30 0.68 8 / 128 0.54 0.19 1.51 High/moderate/severe disease activity (DA) vs. remission/low DA 66 / 283 1.92 1.01 3.63 42 / 432 1.92 1.31 2.83 Medication Methotrexate 14 / 352 1 [Reference] 33 / 238 1 [Reference] No DMARD therapy 91 / 372 2.14 1.37 3.35 32 / 361 2.09 1.10 3.97 Leflunomide 5 / 40 0.79 0.24 2.61 7 / 49 3.49 1.23 9.89 Antimalarials 20 / 168 1.10 0.62 1.96 6 / 254 0.64 0.25 1.69 Sulfasalazine 18 / 64 2.78 1.08 7.15 14 / 77 4.82 1.92 12.08 Immunosuppressants 21 / 117 1.82 1.02 3.23 17 / 158 2.25 0.79 6.38 Rituximab 19 / 68 2.49 1.25 4.96 22 / 121 5.86 2.34 14.68 Other b/tsDMARDs 35 / 377 0.96 0.59 1.54 26 / 877 1.08 0.53 2.20 Glucocorticoids (GCs) No GCs 96 / 816 1 [Reference] 69 / 1584 1 [Reference] GCs 1-10mg/d 114 / 510 1.62 1.02 2.56 53 / 541 1.16 0.65 2.07 GCs > 10 mg/d 32 / 112 1.84 1.20 2.82 17 / 112 1.62 0.91 2.87 Missing values imputed via multiple imputation, patient numbers may thus be rounded. Effects significant at level α=0.05 are marked in bold. Patients were excluded from a particular analysis if the medication they received provided ≤ 20 patients for that analysis or if there were no deaths reported for that specific medication. CI, confidence interval; CTD, connective tissue diseases; CVD, cardiovascular disease; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, Glucocorticoids; IJD, inflammatory joint diseases; IL, interleukin; JIA, juvenile idiopathic arthritis; N, number; OR, odds ratio; SLE, Systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 38 Supplementary table 14. Multivariable logistic regression analysis of factors associated with COVID-19-related death stratified by chronic lung disease Chronic lung disease No chronic lung disease N deaths/patients (%) 136 / 721 (18.9%) 248 / 2984 (8.3%) N deaths/patients OR 95% CI N deaths/patients OR 95% CI Age, years Age ≤ 65 35 / 401 1 [Reference] 84 / 2164 1 [Reference] 65 years < Age ≤ 75 48 / 189 3.58 2.40 5.33 61 / 456 3.08 2.18 4.36 Age > 75 54 / 131 8.34 6.29 11.05 103 / 365 5.82 3.43 9.90 Male sex (vs. female) 53 / 232 1.02 0.47 2.22 108 / 956 1.60 1.24 2.07 Ever smoked (vs. never) 62 / 271 1.23 0.68 2.24 77 / 651 1.24 0.93 1.66 Comorbidities Hypertension alone or CVD alone 51 / 260 0.92 0.67 1.27 104 / 890 1.43 1.05 1.94 Hypertension and CVD 34 / 97 1.51 0.84 2.73 55 / 204 2.21 1.50 3.27 Chronic kidney disease 21 / 64 0.96 0.32 2.82 55 / 194 2.04 1.22 3.43 Diabetes mellitus 38 / 140 1.40 0.61 3.21 58 / 368 1.44 1.05 1.96 Rheumatic disease Rheumatoid arthritis 65 / 298 1 [Reference] 104 / 1089 1 [Reference] Systemic lupus erythematosus 5 / 58 0.55 0.18 1.66 31 / 333 1.42 0.81 2.50 Vasculitis 18 / 66 0.87 0.44 1.72 49 / 259 0.75 0.57 1.00 Other connective tissue diseases 35 / 169 1.21 0.66 2.19 19 / 304 0.46 0.30 0.71 Psoriasis arthritis 4 / 44 1.19 0.45 3.14 15 / 385 0.54 0.40 0.75 Spondyloarthritis 4 / 49 0.81 0.43 1.55 11 / 374 0.60 0.26 1.35 Other inflammatory arthritis or non-systemic JIA 4 / 16 1.61 0.53 4.85 6 / 94 0.55 0.26 1.19 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 39 Other rheumatic diseases (not IJDs / CTDs / vasculitis) 6 / 40 0.73 0.24 2.21 18 / 189 0.40 0.24 0.69 High/moderate/severe disease activity (DA) vs. remission/low DA 43 / 173 1.70 1.01 2.87 66 / 549 1.97 1.27 3.04 Medication Methotrexate 16 / 110 1 [Reference] 31 / 485 1 [Reference] No DMARD therapy 35 / 138 2.28 1.31 3.95 89 / 601 2.17 1.39 3.39 Leflunomide 5 / 23 2.21 1.21 4.03 7 / 67 1.44 0.68 3.07 Antimalarials 12 / 78 2.03 0.68 6.06 15 / 348 0.73 0.38 1.41 Sulfasalazine 10 / 33 2.97 1.19 7.39 23 / 111 4.20 1.83 9.65 Immunosuppressants 17 / 93 2.74 1.99 3.78 21 / 183 1.68 0.86 3.28 Rituximab 20 / 65 4.95 1.59 15.39 23 / 127 4.08 1.99 8.39 Other b/tsDMARDs 21 / 183 1.22 0.69 2.16 40 / 1077 0.90 0.52 1.54 Glucocorticoids (GCs) No GCs 52 / 406 1 [Reference] 113 / 2012 1 [Reference] GCs 1-10mg/d 68 / 258 1.95 1.30 2.91 103 / 804 1.23 0.77 1.95 GCs > 10 mg/d 17 / 58 1.70 0.96 3.00 32 / 168 1.65 0.93 2.92 Missing values imputed via multiple imputation, patient numbers may thus be rounded. Effects significant at level α=0.05 are marked in bold. Patients were excluded from a particular analysis if the medication they received provided ≤ 20 patients for that analysis or if there were no deaths reported for that specific medication. CI, confidence interval; CTD, connective tissue diseases; CVD, cardiovascular disease; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, glucocorticoids; IJD, inflammatory joint diseases; IL, interleukin; JIA, juvenile idiopathic arthritis; N, number; OR, odds ratio; SLE, systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 40 Supplementary table 15. Multivariable logistic regression analysis of factors associated with COVID-19-related death stratified by disease activity Moderate / severe disease activity Low disease activity / remission N deaths/patients (%) 109 / 722 (15.1%) 275 / 2983 (9.2%) N deaths/patients OR 95% CI N deaths/patients OR 95% CI Age, years Age ≤ 65 50 / 531 1 [Reference] 69 / 2035 1 [Reference] 65 years < Age ≤ 75 30 / 120 2.52 1.22 5.23 80 / 524 3.47 2.40 5.01 Age > 75 30 / 72 3.92 1.99 7.74 127 / 424 7.50 4.65 12.08 Male sex (vs. female) 34 / 204 1.18 0.62 2.22 127 / 984 1.50 1.15 1.97 Ever smoked (vs. never) 32 / 171 1.09 0.64 1.86 108 / 751 1.25 0.92 1.70 Comorbidities Hypertension alone or CVD alone 43 / 227 1.32 0.70 2.49 112 / 923 1.17 0.88 1.55 Hypertension and CVD 24 / 59 3.26 1.33 8.03 65 / 242 1.71 1.08 2.73 Chronic lung disease 43 / 173 1.78 1.20 2.64 93 / 548 1.69 1.16 2.46 Chronic kidney disease 30 / 61 3.62 1.81 7.25 47 / 197 1.18 0.58 2.39 Diabetes mellitus 25 / 115 0.85 0.39 1.84 71 / 393 1.57 1.03 2.39 Rheumatic disease Rheumatoid arthritis 46 / 283 1 [Reference] 123 / 1104 1 [Reference] Systemic lupus erythematosus 17 / 77 1.42 0.59 3.41 19 / 315 0.96 0.57 1.59 Vasculitis 18 / 52 1.32 0.59 2.92 49 / 273 0.68 0.44 1.04 Other connective tissue diseases 21 / 108 1.17 0.59 2.29 32 / 365 0.63 0.45 0.88 Psoriasis arthritis 5 / 79 0.53 0.16 1.77 15 / 350 0.72 0.41 1.27 Spondyloarthritis 3 / 79 0.45 0.15 1.34 12 / 344 0.77 0.30 1.97 Other inflammatory arthritis or non-systemic JIA 1 / 19 0.68 0.10 4.50 9 / 90 0.77 0.40 1.49 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 41 Other rheumatic diseases (not IJDs / CTDs / vasculitis) 1 / 45 0.01 0.00 1834.66 23 / 184 0.64 0.46 0.88 Medication Methotrexate 5 / 92 1 [Reference] 42 / 503 1 [Reference] No DMARD therapy 27 / 134 4.64 1.64 13.15 97 / 605 1.93 1.33 2.78 Leflunomide 6 / 19 6.96 2.64 18.39 6 / 71 0.96 0.41 2.25 Antimalarials 8 / 60 2.28 0.88 5.92 19 / 366 0.96 0.57 1.60 Sulfasalazine 6 / 25 7.44 1.35 40.89 27 / 119 3.27 1.59 6.72 Immunosuppressants 19 / 83 3.95 1.24 12.59 19 / 193 1.98 1.09 3.58 Rituximab 12 / 52 3.50 1.11 11.07 30 / 140 5.16 3.00 8.89 Other b/tsDMARDs 25 / 261 2.76 1.14 6.70 36 / 999 0.76 0.49 1.20 Glucocorticoids (GCs) No GCs 28 / 336 1 [Reference] 136 / 2081 1 [Reference] GCs 1-10mg/d 51 / 266 1.61 0.86 3.02 119 / 797 1.44 0.94 2.19 GCs > 10 mg/d 30 / 120 1.71 0.94 3.10 19 / 105 1.69 0.80 3.59 Missing values imputed via multiple imputation, patient numbers may thus be rounded. Effects significant at level α=0.05 are marked in bold. Patients were excluded from a particular analysis if the medication they received provided ≤ 20 patients for that analysis or if there were no deaths reported for that specific medication. CI, confidence interval; CTD, connective tissue diseases; CVD, cardiovascular disease; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, Glucocorticoids; IJD, inflammatory joint diseases; IL, interleukin; JIA, juvenile idiopathic arthritis; N, number; OR, odds ratio; SLE, Systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 42 Supplementary table 16. Multivariable logistic regression analysis of factors associated with COVID-19-related death stratified by glucocorticoid use Glucocorticoids No glucocorticoids N deaths/patients (%) 219 / 1288 (17.0%) 165 / 2417 (6.8%) N deaths/patients OR 95% CI N deaths/patients OR 95% CI Age, years Age ≤ 65 71 / 754 1 [Reference] 47 / 1811 1 [Reference] 65 years < Age ≤ 75 52 / 265 1.80 1.21 2.68 57 / 379 5.54 3.17 9.70 Age > 75 97 / 269 4.67 3.25 6.71 61 / 227 8.75 4.48 17.10 Male sex (vs. female) 85 / 407 1.16 0.86 1.57 76 / 781 1.71 1.16 2.51 Ever smoked (vs. never) 73 / 318 1.25 0.94 1.65 67 / 604 1.12 0.74 1.69 Comorbidities Hypertension alone or CVD alone 94 / 474 1.43 0.92 2.23 61 / 676 0.95 0.67 1.36 Hypertension and CVD 54 / 154 1.87 1.09 3.22 35 / 147 1.86 1.28 2.71 Chronic lung disease 84 / 316 2.03 1.43 2.89 52 / 406 1.47 0.89 2.44 Chronic kidney disease 51 / 151 1.79 0.99 3.22 25 / 108 1.58 0.71 3.49 Diabetes mellitus 55 / 215 1.32 0.76 2.31 41 / 293 1.51 0.97 2.35 Rheumatic disease Rheumatoid arthritis 91 / 516 1 [Reference] 78 / 871 1 [Reference] Systemic lupus erythematosus 26 / 198 1.20 0.63 2.31 10 /193 1.11 0.40 3.07 Vasculitis 58 / 240 0.95 0.51 1.76 9 / 85 0.57 0.11 3.11 Other connective tissue diseases 31 / 181 0.84 0.56 1.25 22 / 292 0.59 0.37 0.95 Psoriasis arthritis 4 / 53 0.52 0.11 2.50 15 / 376 0.68 0.41 1.15 Spondyloarthritis 3 / 38 0.69 0.27 1.76 12 / 385 0.68 0.28 1.68 Other inflammatory arthritis or non-systemic JIA 5 / 24 1.04 0.27 3.96 5 / 85 0.58 0.26 1.30 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A 43 Other rheumatic diseases (not IJDs / CTDs / vasculitis) 7 / 69 0.48 0.17 1.33 17 / 160 0.51 0.28 0.91 High/moderate/severe disease activity (DA) vs. remission/low DA 80 / 386 1.95 1.30 2.92 28 / 336 1.74 0.98 3.08 Medication Methotrexate 18 / 212 1 [Reference] 29 / 383 1 [Reference] No DMARD therapy 74 / 296 3.11 2.12 4.57 50 / 444 1.72 0.94 3.17 Leflunomide 9 / 43 3.40 1.83 6.34 3 / 47 0.52 0.17 1.63 Antimalarials 18 / 137 1.81 1.19 2.77 9 / 289 0.59 0.26 1.33 Sulfasalazine 11 / 48 3.17 1.22 8.27 22 / 96 4.00 1.72 9.28 Immunosuppressants 24 / 176 2.27 1.61 3.19 14 / 100 3.26 1.45 7.31 Rituximab 30 / 99 5.52 2.13 14.33 12 / 94 3.41 1.57 7.41 Other b/tsDMARDs 35 / 289 1.78 1.13 2.81 26 / 971 0.62 0.35 1.08 Missing values imputed via multiple imputation, patient numbers may thus be rounded. Effects significant at level α=0.05 are marked in bold. Patients were excluded from a particular analysis if the medication they received provided ≤ 20 patients for that analysis or if there were no deaths reported for that specific medication. CI, confidence interval; CTD, connective tissue diseases; CVD, cardiovascular disease; DA, disease activity; DMARD, disease modifying antirheumatic drugs; GC, glucocorticoids; IJD, inflammatory joint diseases; IL, interleukin; JIA, juvenile idiopathic arthritis; N, number; OR, odds ratio; SLE, systemic lupus erythematosus; TNF; tumour necrosis factor; tsDMARD, targeted synthetic disease modifying antirheumatic drugs. BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Ann Rheum Dis doi: 10.1136/annrheumdis-2020-219498–13.:10 2021;Ann Rheum Dis, et al. Strangfeld A EULAR Office | Seestrasse 240 | 8802 Kilchberg | Switzerland T: +41 44 716 30 30 [email protected] | www.eular.org 1 COVID-19-related death in rheumatic diseases This is the lay version of a paper published on behalf of the COVID-19 Global Rheumatology Alliance Consortium. It examines COVID-19-related death in people with rheumatic diseases. The original publication can be downloaded from the EULAR website: www.eular.org. Strangfeld A, et al. Factors Associated with COVID-19-related Death in People with Rheumatic Diseases: Results from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis Published Online First: 27 January 2021. doi: 10.1136/annrheumdis-2020-219498 Introduction EULAR gives advice to doctors, nurses and patients about the best way to treat and manage rheumatic diseases. As part of the current global effort to understand and combat COVID-19, EULAR gave financial support to this registry project. What do we already know? There are more than 200 rheumatic diseases, including rheumatoid arthritis, spondyloarthritis, and systemic lupus erythematosus. Many of these diseases are autoimmune conditions that cause inflammation in the body. Rheumatic diseases typically affect joints, muscle, or connective tissue. They can also affect a person’s internal organs. People with rheumatic diseases are more prone to infection. This can be because of the disease itself and the way it affects the immune system, but also affected by some of the medicines used to treat the rheumatic disease. COVID-19 is the disease caused by a new type of coronavirus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical information for people with COVID-19 who have a rheumatic disease is limited, especially about factors that might make them more likely to die from the infection. What does the paper say? The registry collected information on 3729 people with rheumatic disease who had either a confirmed or highly likely case of COVID-19, or had symptoms of this infection. In total, 390 people died – just over 10%. The authors looked to see if there were any common factors in the people who died compared to those who recovered from the COVID-19 infection. • Older age and male sex are associated with COVID-19-related death. Of those who died, over two-thirds were over the age of 65. The risk of dying was even higher in people in over the age of 75, and for men compared to women. This is similar to what has been found in the general population. • Comorbidities are more common in people who die from COVID-19. Across all 3729 people included, most people had at least one other disease (comorbidity). The most common were hypertension (high blood pressure), chronic lung disease, and obesity. In the whole group, 21% of people had three or more comorbidities. When the authors looked only at the people who had died, 43% had three or more comorbidities. This is similar to what has been found in the general population. • Cardiovascular and chronic lung disease are more common in people dying from COVID-19. Other factors associated with dying from COVID-19 included chronic lung disease, or having