Rheumatology International https://doi.org/10.1007/s00296-022-05229-7 Rheumatology INTERNATIONAL OBSERVATIONAL RESEARCH COVID‑19 severity and vaccine breakthrough infections in idiopathic inflammatory myopathies, other systemic autoimmune and inflammatory diseases, and healthy controls: a multicenter cross‑sectional study from the COVID‑19 Vaccination in Autoimmune Diseases (COVAD) survey Leonardo Santos Hoff1 · Naveen Ravichandran2 · Samuel Katsuyuki Shinjo3 · Jessica Day4,5,6 · Parikshit Sen7 · Jucier Gonçalves Junior3 · James B. Lilleker8,9 · Mrudula Joshi10 · Vishwesh Agarwal11 · Sinan Kardes12 · Minchul Kim13 · Marcin Milchert14 · Ashima Makol15 · Tamer Gheita16 · Babur Salim17 · Tsvetelina Velikova18 · Abraham Edgar Gracia‑Ramos19 · Ioannis Parodis20,21 · Albert Selva O’Callaghan22 · Elena Nikiphorou23,24 · Ai Lyn Tan25,26 · Tulika Chatterjee13 · Lorenzo Cavagna27,28 · Miguel A. Saavedra29 · Nelly Ziade30,31 · Johannes Knitza32 · Masataka Kuwana33 · Arvind Nune34 · Oliver Distler35 · Döndü Üsküdar Cansu36 · Lisa Traboco37 · Suryo Angorro Kusumo Wibowo38 · Erick Adrian Zamora Tehozol39 · Jorge Rojas Serrano40 · Ignacio García‑De La Torre41 · Chris Wincup42,43 · John D. Pauling44,45 · Hector Chinoy8,46,47 · Vikas Agarwal2 · Rohit Aggarwal48 · Latika Gupta2,8,49,50 · COVAD Study Group Received: 14 August 2022 / Accepted: 5 October 2022 © The Author(s) 2022 Abstract Objectives We aimed to compare the spectrum and severity of COVID-19 and vaccine breakthrough infections (BIs) among patients with IIMs, other systemic autoimmune and inflammatory diseases (SAIDs), and healthy controls (HCs). Methods This is a cross-sectional study with data from the COVAD study, a self-reported online global survey that col- lected demographics, COVID-19 history, and vaccination details from April to September 2021. Adult patients with at least one COVID-19 vaccine dose were included. BIs were defined as infections occurring > 2 weeks after any dose of vaccine. Characteristics associated with BI were analyzed with a multivariate regression analysis. Results Among 10,900 respondents [42 (30–55) years, 74%-females, 45%-Caucasians] HCs were (47%), SAIDs (42%) and IIMs (11%). Patients with IIMs reported fewer COVID-19 cases before vaccination (6.2%-IIM vs 10.5%-SAIDs vs 14.6%- HC; OR = 0.6, 95% CI 0.4–0.8, and OR = 0.3, 95% CI 0.2–0.5, respectively). BIs were uncommon (1.4%-IIM; 1.9%-SAIDs; 3.2%-HC) and occurred in 17 IIM patients, 13 of whom were on immunosuppressants, and 3(18%) required hospitaliza- tion. All-cause hospitalization was higher in patients with IIM compared to HCs [23 (30%) vs 59 (8%), OR = 2.5, 95% CI 1.2–5.1 before vaccination, and 3 (18%) vs 9 (5%), OR = 2.6, 95% CI 1.3–5.3 in BI]. In a multivariate regression analysis, age 30–60 years was associated with a lower odds of BI (OR = 0.7, 95% CI 0.5–1.0), while the use of immunosuppressants had a higher odds of BI (OR = 1.6, 95% CI 1.1–2.7). Conclusions Patients with IIMs reported fewer COVID-19 cases than HCs and other SAIDs, but had higher odds of all-cause hospitalization from COVID-19 than HCs. BIs were associated with the use of immunosuppressants and were uncommon in IIMs. Rohit Aggarwal and Latika Gupta contributed equally to this work. Disclaimer: This study was already published as a scientific abstract in two medical congresses (https://doi.org/10.1136/annrheumdis- 2022-eular.2160 and https://doi.org/10.47660/CBR.2022.1905). Extended author information available on the last page of the article 13 Vol.:(0123456789) Rheumatology International Keywords Autoimmune diseases · Breakthrough infection · COVID-19 · Idiopathic inflammatory myopathies · SARS- CoV-2 vaccination Introduction vulnerable to breakthrough COVID-19 infections [16]. Little is currently known about the incidence and the severity of The coronavirus disease 2019 (COVID-19) pandemic and breakthrough infections (BI) in patients with IIMs and other the attendant risk of infection have been a serious cause for SAIDs vaccinated against COVID-19, mainly because these concern among patients with idiopathic inflammatory myo- patients were excluded from most trials of COVID-19 vac- pathies (IIMs) and other systemic autoimmune and inflam- cines [16]. Vaccine safety and efficacy data are especially matory diseases (SAIDs) [1]. Patients with IIMs represent limited in patients with IIMs, and scarce data on the specific a unique vulnerable subgroup, as they typically require risks of COVID-19 vaccination in this patient group are cur- long-term treatment with multiple immunosuppressive and rently available [22]. immunomodulatory (IS/IM) therapy [2, 3], which is associ- This study aimed to compare the frequency, profile, and ated with impaired host response to infections [3, 4]. Patients severity of COVID-19 infection both prior to and post-vac- with IIMs may also have multiple sequelae of their disease cination in patients with IIMs, other SAIDs, and healthy (e.g., impaired strength, lung fibrosis) and frequent comor- controls (HCs). bidities (e.g., cardiovascular disease, obesity, and diabetes) [5]. Thus, this patient subgroup may be more susceptible to COVID-19 infection and at greater risk of severe COVID-19 Materials and methods complications than healthy controls and most other SAIDs [6]. Study design and ethics statement Large cohort studies have indeed indicated higher COVID-19 associated mortality and poorer clinical out- This is a cross-sectional study with secondary data from the comes in patients with autoimmune rheumatic diseases com- COVID-19 Vaccination in Autoimmune Diseases (COVAD) pared to the general population [7–9], with a hospitalization study. COVAD study is an ongoing online questionnaire- rate of 58% and fatality of 7% in these patients according to based study that evaluates COVID-19 characteristics and a meta-analysis [10], as opposed to a hospitalization rate in vaccine safety in adult participants (older than 18 years old) intensive care unit of 11% [11] and a fatality rate of only 1% diagnosed with SAIDs and healthy controls [23]. Before in the general population [12]. Furthermore, despite some answering the questionnaire, participants are asked to pro- contradictory data regarding the incidence of COVID-19 vide their informed consent and no financial support is infection among patients with autoimmune rheumatic dis- offered for survey completion. COVAD study was approved eases versus the general population, a recent systematic by the local ethics committee of Sanjay Gandhi Postgraduate review and meta-analysis of 100 studies has demonstrated Institute, Lucknow (IEC Code: 2021-143-IP-EXP-39). The that patients with rheumatic and musculoskeletal diseases current manuscript is reported according to the Checklist for have a higher rate of SARS-CoV-2 infection and increased Reporting Results of the Internet E-Surveys [24, 25]. odds of mortality [13]. COVID-19 characteristics and out- comes are usually studied in patients with SAIDs as a large Case definition group [1, 5–10, 13], but specific data about COVID-19 in the subset of IIMs patients are scarce [14]. Participants answered the question “Did you ever test posi- While there is a paucity of long-term safety and efficacy tive for COVID-19?” and specified the number of events and data regarding COVID-19 vaccination in patients with the dates of occurrence; they also stated the dates of vaccina- SAIDs, current evidence suggests that the benefits of vacci- tion. BI was defined as an infection occurring more than 2 nation far outweigh the potential risks of adverse effects and weeks after receipt of a first or second dose of a COVID-19 vaccination-induced disease flares in this vulnerable patient vaccine. Though CDC currently defines BI as an infection group [15–17]. Thus, prominent medical organizations have occurring after receipt of the second dose of a COVID-19 recommended COVID-19 vaccination in patients with auto- vaccine, we included infections occurring after the first pri- immune rheumatic diseases [18–21]. Of major concern is the mary dose because most people globally had only received possibility of attenuated immunogenicity and, consequently, a single vaccine dose at the time of survey dissemination, reduced efficacy of vaccines induced by the concomitant use and the definition of BI was still evolving [26]. Regarding of IS/IM therapies in these patients, which could leave them diagnostic tests, we did not confirm COVID-19 serology or 13 Rheumatology International vaccine immunogenicity, and this is included as a limitation was stratified by country of origin and adjusted for age, gen- of the study in the Discussion section. der, and covariates with a P < 0.1 in the univariate analysis. A P value < 0.05 was considered statistically significant. Data collection and participants Scale variables were compared with Mann–Whitney U test and regression analysis. Statistical analysis was performed Participants answered an electronic survey consisting of 36 using the SPSS version 26 and Software R 3.5.3 (R Core COVID-19 and SAIDs-related questions, which included Team 2020). demographics, diagnosis confirmed by a physician, current disease activity status, and treatment, COVID-19 infection history (symptoms and complications like all-cause hospi- Results talization and requirement of oxygen), COVID-19 vaccina- tion status and adverse effects, and outcome measures as per Population characteristics the Patient-Reported Outcomes Measurement Information System (PROMIS) tool [27]. The survey was developed by Out of 16,328 respondents, 2866 did not receive any international rheumatology experts and was disseminated on COVID-19 vaccine at the time of questionnaire fulfillment an online platform (surveymonkey.com) after pilot testing and 2562 did not entirely complete the surveyl therefore, and translation into 18 languages. Over 110 physicians from they were excluded from the final analysis. The flow dia- 94 countries participated in the COVAD study group and gram with the 10,900 vaccinated respondents with com- supported the dissemination of the survey on social media plete responses included in the analysis is shown in Fig. 1. and online patient advocacy organizations. The questions Patients with IIMs were 1227 (11.2%), while patients with analyzed in the current study were closed-ended. Detailed other SAIDs were 4640 (42.6%), and 5033 (46.2%) were methods of the COVAD study protocol have been published HCs. The respondents resided in 96 countries as follows: elsewhere [23]. 14.9% in Turkey, 12.5% in Mexico, 13.1% in India, 11.6% in Data were retrieved from April 1st 2021 to 30th Sep- the United Kingdom, 9.9% in the United States of America, tember 2021. We have chosen to analyze data from this 5.5% in Italy, and 32.5% in other countries (Supplementary time interval because it is considered the “first wave” of the Table 1). COVAD study, comprising the period that we began to dis- The most common SAID was rheumatoid arthritis (13%, seminate the survey and the moment we had enough answers n = 1459), followed by IIMs (11%, n = 1227), and Graves’ to analyze multiple scenarios and outcomes. or Hashimoto’s disease (9%, n = 1051). Patients with IIMs included those with dermatomyositis, polymyositis, inclu- Inclusion and exclusion criteria sion body myositis, antisynthetase syndrome, necrotizing autoimmune myopathy, juvenile dermatomyositis, and All respondents who received at least a single dose of the overlap myositis. A similar proportion of patients with COVID-19 vaccine and fully completed the survey were IIMs (12%) and other SAIDs (13%) discontinued their IS/ included in the final analysis. Duplicate responses from a IM therapy prior to vaccination (Supplementary Table 2). single respondent were identified using electronic protocols. All respondents included in the final analysis had received Participants who were not vaccinated against COVID-19 at at least a single dose of the vaccine at the time of survey the time of survey completion and those who did not fully completion and 7559 (69%) respondents had received two answer the survey were excluded from the analysis. doses. The largest number of respondents received the BNT162b2 (Pfizer)-BioNTech vaccine (39.8%, n = 4333), Statistical analysis followed by the BBIBP-CorV Sinopharm (16.7%, n = 1821), ChadOx1 nCOV-19 (Oxford/AstraZeneca) (13.4%, Median and interquartile range (IQR) were reported for n = 1456), and ChAdOx1 nCoV-19 (Covishield Serum variables with non-normal distribution. Categorical vari- Institute India) (10.9%, n = 1194) vaccines (Supplementary ables were presented as frequencies and proportions. When Table 2). comparing the frequency of COVID-19 and the severity of The majority of COVID-19 cases occurred prior to vac- COVID-19 among IIM, other SAIDs, and HC, odds ratio cination, as seen in Table 1as follows: 1297 cases (78%) (OR) adjusted for age, gender, ethnicity, and stratified by occurred prior to vaccination, 92 (6%) occurred within 2 country of origin was presented. We performed a univariate weeks of receiving COVID-19 vaccination, and 267 (16%) regression analysis to explore if age, gender, ethnicity, vac- occurred after the first- or second-dose of vaccination and cination status, diagnosis, corticosteroid use, and immuno- were, therefore, considered BI. Interestingly, patients with suppressive or immunomodulatory therapies (IS/IM) were IIMs reported fewer COVID-19 cases before vaccination associated with BI. The multivariable regression analysis (76 cases, 6.2%) than patients with other SAIDs (488 cases, 13 Rheumatology International Fig. 1  Flow diagram of study participants Table 1  COVID-19 cases reported before and after vaccination COVID-19 cases: all Total (n = 10900) IIMs (n = 1227) Other HCs (n = 5033) IIMs versus Other IIMs versus HCs subjects SAIDs SAIDs (n = 4640) OR (95% CI) P value OR (95% CI) P value Before vaccination 1297 (11.9) 76 (6.2) 488 (10.5) 733 (14.6) 0.6 (0.4–0.8) 0.002 0.3 (0.2–0.5) < 0.001 ≤ Two weeks after first or 92 (0.8) 10 (0.8) 40 (0.9) 42 (0.8) 0.7 (0.1–2.6) 0.613 0.6 (0.2–2.2) 0.497 second primary vaccine dose > Two weeks after first or 267 (2.5) 17 (1.4) 89 (1.9) 161 (3.2) 0.7 (0.4–1.5) 0.480 0.5 (0.2–1.1) 0.070 second primary vaccine dose (breakthrough infection) Total 1656 (15.2) 103 (8.4) 617 (13.3) 936 (18.6) 0.6 (0.4–0.8) 0.001 0.4 (0.3–0.5) < 0.001 CI confidence interval, HCs healthy controls, IIMs idiopathic inflammatory myopathies, OR odds ratio, NS not significant, SAIDs systemic auto- immune and inflammatory diseases *Odds ratio adjusted for age, gender, ethnicity, and stratified by country of origin 10.5%) and HCs (733 cases, 14.6%) (OR = 0.6, 95% CI and cough were the most common symptoms seen in them. 0.4–0.8, p = 0.002, and OR = 0.3, 95% CI 0.2–0.5, p < 0.001, Three (18%) were asymptomatic. The median disease dura- respectively). tion was 7 (3–10) days. Three patients (18%) were hospital- ized with or without O2 requirement following BI. Among Breakthrough infections (BIs) the 89 patients with BI in SAIDs, thyroid disease (n = 18) and type one diabetes mellitus (n = 10) were the most com- BIs were seen in 17 (1.4%) of IIM patients, 89 (1.9%) of mon. Six patients (7%) were asymptomatic among them. other SAID patients, and 161 (3.2%) of HC. Among the IIM ChAdOx1 nCoV-19 (Covishield Serum Institute India) patients with BI, nine were dermatomyositis (DM), three (n = 24) and BNT162b2 (Pfizer)-BioNTech (n = 22) were the were anti-synthetase syndrome (ASSD), two polymyositis most frequent vaccine received prior to BI in them. Median (PM), one overlap myositis (OM), one necrotizing autoim- disease duration was 11 (5–20) days. Ten patients (11%) mune myositis (NAM), and one juvenile dermatomyositis had required hospitalization following BI. Among the 161 (JDM) (Table 2). ChAdOx1 nCoV-19 (Covishield Serum HC with BI, asymptomatic infection was seen in 20 (12%). Institute India) (n = 5) followed by BNT162b2 (Pfizer)- BBIBP-CorV (Sinopharm) (n = 60) and ChAdOx1 nCoV-19 BioNTech vaccine (n = 4) takers were most frequent vac- (Covishield Serum Institute India) (n = 45) were the most cine received by them prior to BI. Fever, fatigue, myalgia, common vaccine received by them prior to BI. The median 13 Table 2  Detailed characteristics of IIMs patients with COVID-19 breakthrough infections N Vaccine received Age Gender Country IIMs type Symptoms COVID-19 symptoms Hospitaliza- IS received prior infec- Whether IS was Days between duration tion or ­O2 tion discontinued during BI and vaccina- (days) support infection tion 1 ChAdOx1 nCoV-19 45 F India DM 3 Fever, fatigue, myalgia, No None – 19 (Covishield Serum cough, diarrhea Institute India) Rheumatology International 2 BNT162b2 (Pfizer)- 26 F Mexico DM 6 Headache, anosmia No Mtx, Aza, Prednisolone Yes (Mtx for 7 days) 19 BioNTech (< 10 mg/day) 3 BNT162b2 (Pfizer)- 62 M USA NAM 0 Loss of taste No IVIG, prednisolone No 21 BioNTech (> 20 mg/day) 4 ChAdOx1 nCoV-19 62 F India DM 5 Fever, fatigue, cough, No MMF, prednisolone No 22 (Covishield Serum breathlessness (< 10 mg/day) Institute India) 5 mRNA-1273 (Moderna) 58 F USA DM 8 Fever, fatigue, myalgia, No HCQ, Rtx Yes (Rtx for 7 days) 25 cough, skin rashes 6 ChadOx1 nCOV-19 – – – JDM 47 Myalgia, breathlessness Yes None – 30 (Oxford/AstraZeneca) 7 BNT162b2 (Pfizer)- 54 F USA DM 7 Fatigue No MMF, HCQ, IVIG No 30 BioNTech 8 ChAdOx1 nCoV-19 – – – PM 11 Diarrhea, headache Yes Mtx No 34 (Covishield Serum Institute India) 9 Coronovac 29 F Brazil ASSD 10 Fatigue, myalgia, chest No Aza No 35 pain, headache 10 ChadOx1 nCOV-19 52 F UK ASSD 0 Fatigue, anosmia No Cyclo, prednisolone No 47 (Oxford/AstraZeneca) (> 20 mg/day) 11 mRNA-1273 (Moderna) 43 F USA DM 7 Fever, fatigue, cough, Yes MMF, Rtx, predniso- No 48 breathlessness, diar- lone (10 mg/day) rhea 12 BNT162b2 (Pfizer)- 54 F USA OM 0 None No MMF, HCQ No 48 BioNTech 13 ChAdOx1 nCoV-19 – – – DM 9 None No Mtx No 53 (Covishield Serum Institute India) 14 ChAdOx1 nCoV-19 – – – DM 12 Fatigue No None – 56 (Covishield Serum Institute India) 15 BBIBP-CorV (Sinop- – – – PM 0 None No None – 57 harm) 16 BBV152 (Covaxin 21 M India DM 11 Fever, fatigue, myalgia, No Mtx, prednisolone No 94 Bharat Biotech) cough (< 10 mg/day) 13 Rheumatology International disease duration was 7 (3–12) days. All cause hospitalization ASSD antisynthetase syndrome, Aza azathioprine, BI breakthrough infection, DM dermatomyositis, F female, HCQ hydroxychloroquine, IIM idiopathic inflammatory myopathies, IS immuno- suppressor, IVIG intravenous immunoglobulin, JDM juvenile dermatomyositis, M male, MMF mycophenolate mofetil, Mtx methotrexate, NAM necrotizing myositis, OM overlap myositis, PM BI and vaccina- Days between were seen in 9 (5%) of them (Table 3). COVID‑19 severity among IIM, other SAIDs, and HCs tion Yes (MMF for 14 days) 141 Patients with IIMs had higher odds of all-cause hospitaliza- tion in comparison to HCs either in COVID-19 cases that discontinued during occurred prior to vaccination (OR = 2.5, 95% CI 1.2, 5.1, Whether IS was p = 0.011) or in BI (OR = 2.6, 95% CI 1.3–5.3, p = 0.006). Hospitalization with supplemental oxygen requirement infection was also higher in patients with IIMs versus HCs in both situations (prior to vaccination and BI, OR = 3.5, 95% CI 1.3–8.9, p = 0.008, and OR = 3.8, 95% CI 1.5–9.0, p = 0.004, IS received prior infec- MMF, HCQ, predniso- respectively). However, all-cause hospitalization was similar lone (< 10 mg/day) in IIM in comparison to SAIDs. The specific COVID-19 symptoms and disease duration were comparable among the three groups, except for headache and the duration of break- through COVID-19 infections, which were less frequent and tion of shorter duration in IIMs than in patients with other SAIDs (OR = 0.2, 95% CI 0.1–0.9, p = 0.045, and OR = 0.8, 95% CI 0.7–0.9, p = 0.021, respectively) (Table 3). Hospitaliza- tion or ­O2 support Characteristics associated with BIs Fever, fatigue, myalgia, No cough, breathlessness, We assessed whether age, gender, ethnicity, vaccination sta- chest pain, headache, COVID-19 symptoms tus, diagnosis, corticosteroid use, and other IS/IM therapies nausea/vomiting were associated with BI. In a multivariate model adjusted for covariates with a p < 0.1 in the univariate analysis, the following covariates had an association with BI: age 30–60 years (OR = 0.7, 95% CI 0.5–1.0, p = 0.041), two or more COVID-19 vaccine doses (OR = 2.0, 95% CI 1.4–2.8, polymyositis, Rtx rituximab, UK United Kingdom, USA United States of America p < 0.001), and exposure to IS/IM therapies (OR = 1.6, 95% Age Gender Country IIMs type Symptoms CI 1.1–2.7, p = 0.029) (Table 4). duration (days) 5 Discussion ASSD In the present study, we found that patients with IIMs reported fewer COVID-19 infections prior to vaccination than patients with other SAIDs and HCs, yet they had higher UK odds for all-cause hospitalization than HCs. Vaccine BI was uncommon and their characteristics were comparable among the groups of IIMs, SAIDs, and HCs, except for headache F and duration of COVID-19 symptoms, which was shorter in 44 IIMs than in SAIDs. The factors associated with higher odds of BI infections were exposure to IS/IM therapies and more (Oxford/AstraZeneca) than two doses of COVID-19 vaccine, while age 30–60 was 17 ChadOx1 nCOV-19 associated with lower odds of BI. Gender, ethnicity, steroid Vaccine received Table 2  (continued) use, and diagnosis (IIM, SAID, HC) conferred similar odds of BI in the multivariate analysis. Patients with SAIDs, including IIMs, are a vulnerable population at an increased risk of disease severity and poorer clinical outcomes related to COVID-19 infection N 13 Rheumatology International Table 3  COVID-19 severity in patients with idiopathic inflammatory myopathies, other autoimmune diseases, and healthy controls Parameters COVID-19 before vaccination IIMs versus other SAIDs IIMs versus HCs IIMs (n = 76) Other SAIDs HCs (n = 733) ORa (95% CI) P value ORa (95% CI) P value (n = 488) COVID-19 symptoms, n (%) 68 (89) 458 (94) 677 (92) 0.7 (0.3–1.7) 0.470 1.6 (0.5–4.7) 0.372 Different types of ­symptomsb – – – NS NS NS NS Duration of COVID-19 symptoms, 10 (7, 20) 12 (7, 21) 10 (5, 15) 1.01 (0.9–1.02) 0.117 0.9 (0.9–1.1) 0.578 median (IQR), days Asymptomatic infection 8 (11) 30 (6) 56 (8) 1.3 (0.5–3.2) 0.470 0.6 (0.2–1.7) 0.372 All-cause hospitalization and ­O2 12 (16) 36 (7) 21 (3) 0.4 (0.2–1.05) 0.066 3.5 (1.3–8.9) 0.008 therapy, n (%) All-cause hospitalization (with or 23 (30) 84 (17) 59 (8) 0.7 (0.4–1.4) 0.454 2.5 (1.2–5.1) 0.011 without ­O2 therapy), n (%) Parameters COVID-19 breakthrough i­nfectionc IIMs versus Other IIMs versus HCs SAIDs IIMs (n = 17) Other SAIDs (n = 89) HCs (n = 161) ORa (95% CI) P value ORa (95% CI) P value COVID-19 symptoms, n (%) 14 (82) 83 (93) 141 (88) 0.6 (0.1–8.7) 0.767 0.6 (0.2–1.4) 0.276 Headache 4 (24) 44 (49) 54 (34) 0.2 (0.1–0.9) 0.045 0.6 (0.3–1.0) 0.066 Other ­symptomsb – – – NS NS NS NS Duration of COVID-19 symptoms, 7 (3, 10) 11 (5, 20) 7 (3, 12) 0.8 (0.7–0.9) 0.021 1.0 (0.9–1.1) 0.624 median (IQR), days Asymptomatic infection 3 (18) 6 (7) 20 (12) 1.4 (0.1–1.8) 0.767 1.6 (0.6–3.7) 0.276 All-cause hospitalization and ­O2 1 (6) 4 (4) 5 (3) 1.8 (0.1–2.0) 0.609 3.8 (1.5–9.0) 0.004 therapy, n (%) All-cause hospitalization (with or 3 (18) 10 (11) 9 (5) 1.5 (0.1–1.8) 0.714 2.6 (1.3–5.3) 0.006 without ­O2 therapy), n (%) CI confidence interval, HCs healthy control, IIMs idiopathic inflammatory myopathies, IQR interquartile range, OR odds ratio, NS not signifi- cant, SAIDs systemic autoimmune and inflammatory diseases a Odds ratio adjusted for age, gender, ethnicity, and stratified by country of origin b COVID-19 symptoms individually assessed were as follows: fever, fatigue, myalgia, cough, breathlessness, chest pain, diarrhea, headache, oral ulcers, nausea/vomiting, arthralgia, skin rashes, or others c Breakthrough infection was defined as an infection occurring more than two weeks after receipt of a first or second dose of a COVID-19 vac- cine and possibly a higher incidence of COVID-19 infection In our study, all-cause hospitalizations in IIMs patients compared to healthy counterparts [10, 13, 14]. We found a were higher than in patients with other SAIDs (30 versus reported frequency of COVID-19 of 6.2% in IIMs patients 17%, respectively). Considering that IS/IM therapies are and 10.5% in SAIDs before vaccination, which is higher a known risk factor for worst outcomes in COVID-19 [9, than the rate of 0.36% previously reported in a systematic 11, 14], our sample of patients with IIMs was more on IS/ review of patients with inflammatory and autoimmune IM therapy than patients with other SAIDs, which may rheumatic diseases [13]. This may be explained by the explain this finding. It is unclear why IIMs patients with BI design of our study, which is prone to recall and selection had a lower incidence of headache and shorter duration of bias, with patients willing to answer the e-survey more COVID-19 symptoms than patients with other SAIDs; this likely to have had COVID-19 infection and thus more may represent a unique feature of COVID-19 in this subset likely to remember the symptoms. Surprisingly, the self- of patients, which needs to be confirmed in future studies, reported pre-vaccination incidence of COVID-19 infection or more probably a spurious finding owing to few BI cases was lower in patients with IIMs than in patients with other in the IIMs group. SAIDs and HCs, and the diagnosis of IIMs was associated Exposure to IS/IM therapies was associated with with a smaller odds of COVID-19 than other SAIDs and higher odds of BI. Evidence suggests that IS/IM medica- HCs, possibly due to protective behaviors taken by this tions, particularly B-cell depleting agents, may impair the extremely vulnerable population like physical distancing host response to COVID-19 vaccines, thus reducing their and shielding [1]. immunogenicity [15, 16]. In our study, few patients with 13 Rheumatology International Table 4  Univariate and multivariable regression analysis of characteristics associated with COVID-19 breakthrough infection Variable Category Univariate Multivariatea OR (95% CI) P value OR (95% CI) P value Age < 30 years Reference Reference Reference Reference 30–60 years 1.1 (0.9–1.2) 0.098 0.7 (0.5–1.0) 0.041 > 60 years 1.4 (0.8–2.4) 0.155 1.3 (0.7–2.2) 0.312 Gender Male Reference Reference Reference Reference Female 0.8 (0.6–1.1) 0.225 0.8 (0.6–1.1) 0.379 Ethnicity Caucasian Reference Reference Reference Reference Not caucasian 1.1 (0.8–1.4) 0.546 1.0 (0.7–1.4) 0.735 COVID-19 vaccination None – – – – One dose Reference Reference Reference Reference ≥ Two doses 1.5 (1.2–1.9) < 0.001 2.0 (1.4–2.8) < 0.001 Diagnosis IIM Reference Reference Reference Reference Other SAIDs 0.8 (0.4–1.5) 0.581 0.9 (0.4–1.9) 0.957 HC 1.0 (0.6–1.8) 0.898 0.9 (0.6–1.3) 0.882 Corticosteroid use None Reference Reference Reference Reference ≤ 10 mg of prednisone equivalent 0.6 (0.3–1.2) 0.149 0.6 (0.3–1.2) 0.202 > 10 mg of prednisone equivalent 0.6 (0.2–1.7) 0.422 0.7 (0.2–2.2) 0.627 Other IS/IM therapies None Reference Reference Reference Reference Yes 1.5 (1.1–2.3) 0.023 1.6 (1.1–2.7) 0.029 Breakthrough infection was defined as an infection occurring more than 2 weeks after receipt of a first or second dose of a COVID-19 vaccine CI confidence interval, HCs healthy control, IIMs idiopathic inflammatory myopathies, IS/IM immunosuppressive and immunomodulatory ther- apy, OD odds ratio, NS not significant, SAIDs systemic autoimmune and inflammatory diseases a Multivariate regression analysis was stratified by country of origin and adjusted for age, gender, and covariates with a p < 0.1 in the univariate analysis BI discontinued their IS/IM treatment before vaccination, not explore possible risk factors for BIs in this study, nor which may explain this finding. However, suspension of IS/ could associate these cases with a specific type of vaccine IM therapy prior to COVID-19 vaccination may not always [29]. The efficacy of different vaccines in preventing BI in be clinically appropriate, and this is a decision that must be patients with IIMs and other SAIDs needs to be evaluated made on an individual basis [17–21]. in future studies with an appropriate design and long-term Two or more COVID-19 vaccine doses were also associ- follow-up. The most recent recommendation from the Amer- ated with a higher odds of BI than one vaccine dose. The ican College of Rheumatology emphasizes the response to most reasonable explanation for this finding is this may rep- COVID-19 vaccination in patients with SAIDs receiving IS/ resent a follow-up bias, as patients with two or more vaccine IM drugs is likely to be blunted in comparison to the general doses have a longer follow-up and, therefore, are more prone population; therefore, it may explain a higher number of BIs to BI than patients with a shorter follow-up. A recent sys- in fully vaccinated patients with SAIDs [19]. tematic review has shown that COVID-19 vaccines are effec- COVAD is one of the largest studies about COVID-19 tive against infection, but this protection wanes over time, vaccination in patients with SAIDs, with a representative especially in mild to moderate cases [28]. Considering that sample from 94 countries. This is a strength of the current most of COVID-19 cases described in our study were mild study, contributing to the external validity of our findings. or even asymptomatic, this also may explain why so many However, this study has limitations. Using the proper sta- patients with two or more vaccine doses presented with BI. tistical analysis for a cross-sectional study (a multivariate The type of vaccine received may also influence the risk regression analysis), we found that BIs were associated of breakthrough COVID-19 infection, owing to their vari- with exposure to IS/IM drugs. We acknowledge that we able efficacy, mechanism of action, immunogenicity, adju- cannot assume a cause-and-effect relationship between vants, and host interaction [16]. A large cohort of patients IS/IM drugs and BI; therefore, this association should be with rheumatic disease followed in almost the same period in further confirmed in cohort or randomized controlled trial 2021 has shown a BI rate of 0.9%, and half of these patients studies. We did not disseminate our survey in a systematic had received two or more vaccine doses; the authors did way, so our population represents a convenience sample. 13 Rheumatology International We targeted our survey to patients with SAIDs in general, Gil-Vila, Raquel Aranega Gonzalez, Akira Yoshida, Ran Nakashima, and there were no steps taken to make any subgroup of Shinji Sato, Naoki Kimura, Yuko Kaneko, Stylianos Tomaras, Marga- rita Aleksandrovna Gromova, Or Aharonov, Ihsane Hmamouchi, Mar- SAIDs representative. Considering the inherent profile of gherita Giannini, François Maurier, Julien Campagne, Alain Meyer, patients who can respond to an online survey, we may infer Melinda Nagy-Vincze, Daman Langguth, Vidya Limaye, Merrilee that low-income patients without internet access, severely Needham, Nilesh Srivastav, Marie Hudson, Océane Landon-Cardi- disabled, and deceased are not represented in our study. nal, Syahrul Sazliyana Shaharir, Wilmer Gerardo Rojas Zuleta, José António Pereira Silva, João Eurico Fonseca, Olena Zimba. Additionally, our conclusions are based on self-reported data that could not be checked on medical records. Fur- Author contributions Conceptualization: LSH, SKS, NR, JGJ, LG, thermore, we did not explore several confounding vari- RA. Data curation: All authors. Formal analysis: LSH, SKS, NR, JGJ, ables that could impact the outcomes assessed, including JD, LG, RA Funding acquisition: N/A. Investigation: Methodology: LG, RA, JBL, LSH, SKS, VA. Software: LG. Validation: All Authors. protective behaviors against COVID-19 infection, edu- Visualization: All authors, Writing-original draft: LSH, SKS, JD, NR, cation level, income, access to health services, multiple PS. Writing-review & editing: All authors. vaccine combinations, and comorbidities. Considering the small number of BI in our samples, we could not assess Funding No specific funding was obtained for this manuscript. whether different types of vaccines influenced the risk of Declarations BI. Finally, we neither confirmed COVID-19 serology nor vaccine immunogenicity. Though we have used a broader Conflict of interest ALT has received honoraria for advisory boards definition for BI, this study provides unique insights into and speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, the protection offered by a single dose of vaccine against UCB. CW has received travel support from Abbvie, unrelated to this manuscript. EN has received speaker honoraria/participated in advi- COVID-19. sory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, In conclusion, unvaccinated patients with IIMs reported Lilly and holds research grants from Pfizer and Lilly. HC has received fewer COVID-19 cases in comparison to patients with grant support from Eli Lilly and UCB; consulting fees from Novartis, other SAIDs and HCs, but were more vulnerable to all- Eli Lilly, Orphazyme, Astra Zeneca; speaker for UCB, Biogen. HC is supported by the National Institution for Health Research Manchester cause hospitalization in comparison to HCs. Overall, Biomedical Research Centre Funding Scheme. The views expressed in COVID-19 BI was uncommon and was comparable among this publication are those of the authors and not necessarily those of IIMs, other SAIDs, and HCs. Despite the aforementioned the NHS, the National Institute for Health Research or the Department limitations, this study adds to the valuable understanding of Health. IP has received research funding and/or honoraria from Am- gen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, of COVID-19 severity and characteristics in vaccinated Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis and unvaccinated patients with IIMs and other SAIDs. and F. Hoffmann-La Roche AG. JD has received research funding from CSL Limited. JBL has received speaker honoraria/participated in ad- Supplementary Information The online version contains supplemen- visory boards for Sanofi Genzyme, Roche, and Biogen. None is related tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00296-0​ 22-0​ 5229-7. to this manuscript. JP has received consulting fees, speaking fees, and/ or honoraria from Actelion, Sojournix Pharma, and Boehringer Ingel- Acknowledgements The authors are grateful to all respondents for heim. None is related to this manuscript. NZ has received speaker fees, filling out the questionnaire. The authors also thank The Myositis advisory board fees and research grants from Pfizer, Roche, Abbvie, Association, Myositis India, Myositis UK, Myositis Support and Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, Understanding, the Myositis Global Network, Deutsche Gesellschaft Pierre Fabre; none is related to this manuscript. OD has/had consul- für Muskelkranke e.V. (DGM), Dutch and Swedish Myositis patient tancy relationship with and/or has received research funding from or support groups, Cure JM, Cure IBM, Sjögren’s India Foundation, has served as a speaker for the following companies in the area of Patients Engage, Scleroderma India, Lupus UK, Lupus Sweden, Emir- potential treatments for systemic sclerosis and its complications in ates Arthritis Foundation, EULAR PARE, ArLAR research group, the last three years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, AAAA patient group, APLAR myositis special interest group, Thai Arxx, Baecon, Blade, Bayer, Boehringer Ingelheim, ChemomAb, Cor- Rheumatism association, PANLAR, NRAS, Anti-Synthetase Syn- bus, CSL Behring, Galapagos, Glenmark, GSK, Horizon (Curzion), drome support group, and various other patient support groups and Inventiva, iQvia, Kymera, Lupin, Medac, Medscape, Mitsubishi Ta- organizations for their contribution in the dissemination of this survey. nabe, Novartis, Roche, Roivant, Sanofi, Serodapharm, Topadur and Finally, the authors wish to thank all members of the COVAD study UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” group for their invaluable role in data collection. COVAD Study Group (US8247389, EP2331143). RA has/had a consultancy relationship Authors: Bhupen Barman, Yogesh Preet Singh, Rajiv Ranjan, Avinash with and/or has received research funding from the following com- Jain, Sapan C Pandya, Rakesh Kumar Pilania, Aman Sharma, Manesh panies-Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Manoj M, Vikas Gupta, Chengappa G Kavadichanda, Pradeepta Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, and Abbvie, Sekhar Patro, Sajal Ajmani, Sanat Phatak, Rudra Prosad Goswami, Janssen, Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, Abhra Chandra Chowdhury, Ashish Jacob Mathew, Padnamabha Roivant. Rest of the authors have no conflict of interest relevant to this Shenoy, Ajay Asranna, Keerthi Talari Bommakanti, Anuj Shukla, manuscript. Arunkumar R Pande, Kunal Chandwar, Nicoletta Del Papa, Gianluca Sambataro, Atzeni Fabiola, Marcello Govoni, Simone Parisi, Elena Ethical approval Ethical approval was obtained from the Institutional Bartoloni Bocci, Gian Domenico Sebastiani, Enrico Fusaro, Marco Ethics Committee of Sanjay Gandhi Postgraduate Institute of Medical Sebastiani, Luca Quartuccio, Franco Franceschini, Pier Paolo Sainaghi, Sciences, Raebareli Road, Lucknow, 226014 (IEC Code: 2021-143-IP- Giovanni Orsolini, Rossella De Angelis, Maria Giovanna Danielli, Vin- EXP-39). cenzo Venerito, Jesús Loarce-Martos, Sergio Prieto-González, Albert 13 Rheumatology International Open Access This article is licensed under a Creative Commons Attri- 12. 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BMC Infect Publisher's Note Springer Nature remains neutral with regard to Dis 22:439. https://​doi.​org/​10.​1186/​s12879-​022-​07418-y jurisdictional claims in published maps and institutional affiliations. 29. Machado PM, Lawson-Tovey S, Strangfeld A et al (2022) Safety of vaccination against SARS-CoV-2 in people with rheumatic and musculoskeletal diseases: results from the EULAR Coronavirus Vaccine (COVAX) physician-reported registry. Ann Rheum Dis 81:695–709. https://​doi.​org/​10.​1136/​annrh​eumdis-​2021-​221490 Authors and Affiliations Leonardo Santos Hoff1 · Naveen Ravichandran2 · Samuel Katsuyuki Shinjo3 · Jessica Day4,5,6 · Parikshit Sen7 · Jucier Gonçalves Junior3 · James B. Lilleker8,9 · Mrudula Joshi10 · Vishwesh Agarwal11 · Sinan Kardes12 · Minchul Kim13 · Marcin Milchert14 · Ashima Makol15 · Tamer Gheita16 · Babur Salim17 · Tsvetelina Velikova18 · Abraham Edgar Gracia‑Ramos19 · Ioannis Parodis20,21 · Albert Selva O’Callaghan22 · Elena Nikiphorou23,24 · Ai Lyn Tan25,26 · Tulika Chatterjee13 · Lorenzo Cavagna27,28 · Miguel A. Saavedra29 · Nelly Ziade30,31 · Johannes Knitza32 · Masataka Kuwana33 · Arvind Nune34 · Oliver Distler35 · Döndü Üsküdar Cansu36 · Lisa Traboco37 · Suryo Angorro Kusumo Wibowo38 · Erick Adrian Zamora Tehozol39 · Jorge Rojas Serrano40 · Ignacio García‑De La Torre41 · Chris Wincup42,43 · John D. Pauling44,45 · Hector Chinoy8,46,47 · Vikas Agarwal2 · Rohit Aggarwal48 · Latika Gupta2,8,49,50 · COVAD Study Group 13 * Latika Gupta Center for Outcomes Research, Department of Internal drlatikagupta@gmail.com Medicine, University of Illinois College of Medicine, Peoria, IL, USA 1 School of Medicine, Universidade Potiguar (UnP), Natal, 14 Department of Internal Medicine, Rheumatology, Geriatrics Brazil and Clinical Immunology, Pomeranian Medical University 2 Department of Clinical Immunology and Rheumatology, in Szczecin, ul Unii Lubelskiej 1, 71‑252 Szczecin, Poland Sanjay Gandhi Postgraduate Institute of Medical Sciences, 15 Division of Rheumatology, Mayo Clinic, Rochester, MN, Lucknow, India USA 3 Division of Rheumatology, Faculdade de Medicina FMUSP, 16 Rheumatology Department, Kasr Al Ainy School Universidade de Sao Paulo, Sao Paulo, SP, Brazil of Medicine, Cairo University, Cairo, Egypt 4 Department of Rheumatology, Royal Melbourne Hospital, 17 Rheumatology Department, Fauji Foundation Hospital, Parkville, VIC 3050, Australia Rawalpindi, Pakistan 5 Walter and Eliza Hall Institute of Medical Research, 18 Department of Clinical Immunology, Medical Faculty, Parkville, VIC 3052, Australia University Hospital “Lozenetz”, Sofia University St. Kliment 6 Department of Medical Biology, University of Melbourne, Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria Parkville, VIC 3052, Australia 19 Department of Internal Medicine, General Hospital, National 7 Maulana Azad Medical College, 2‑Bahadurshah Zafar Marg, Medical Center, La Raza”, Instituto Mexicano del Seguro New Delhi, Delhi 110002, India Social, Av. Jacaranda S/N, Col. La Raza, Del. Azcapotzalco, 8 02990 Mexico City, Mexico Centre for Musculoskeletal Research, Division 20 of Musculoskeletal and Dermatological Sciences, School Division of Rheumatology, Department of Medicine Solna, of Biological Sciences, Faculty of Biology, Medicine Karolinska Institutet and Karolinska University Hospital, and Health, Manchester Academic Health Science Centre, Stockholm, Sweden The University of Manchester, Manchester, UK 21 Department of Rheumatology, Faculty of Medicine 9 Neurology, Manchester Centre for Clinical Neurosciences, and Health, Örebro University, Örebro, Sweden Northern Care Alliance NHS Foundation Trust, Salford, UK 22 Internal Medicine Department, Vall D’hebron General 10 Byramjee Jeejeebhoy Government Medical College Hospital, Universitat Autonoma de Barcelona, and Sassoon General Hospitals, Pune, India 08035 Barcelona, Spain 11 23 Mahatma Gandhi Mission Medical College, Navi Mumbai, Centre for Rheumatic Diseases, King’s College London, Maharashtra, India London, UK 12 24 Department of Medical Ecology and Hydroclimatology, Rheumatology Department, King’s College Hospital, Istanbul Faculty of Medicine, Istanbul University, London, UK Capa‑Fatih, 34093 Istanbul, Turkey 25 NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals Trust, Leeds, UK 13 Rheumatology International 26 39 Leeds Institute of Rheumatic and Musculoskeletal Medicine, Rheumatology, Medical Care and Research, Centro Medico University of Leeds, Leeds, UK Pensiones Hospital, Instituto Mexicano del Seguro Social 27 Delegación Yucatán, Yucatán, Mexico Department of Rheumatology, Fondazione 40 I.R.C.C.S. Policlinico San Matteo, Pavia, Italy Rheumatologist and Clinical Investigator, Interstitial Lung 28 Disease and Rheumatology Unit, Instituto Nacional de Rheumatology Unit, Dipartimento di Medicine Interna e Enfermedades Respiratorias, Mexico City, Mexico Terapia Medica, Università degli studi di Pavia, Lombardy, 41 Pavia, Italy Departamento de Inmunología y Reumatología, Hospital 29 General de Occidente and University of Guadalajara, Departamento de Reumatología Hospital de Especialidades Guadalajara, Jalisco, Mexico Dr. Antonio Fraga Mouret, Centro Médico Nacional La Raza, 42 IMSS, Mexico City, Mexico Department of Rheumatology, Division of Medicine, Rayne 30 Institute, University College London, London, UK Rheumatology Department, Saint-Joseph University, Beirut, 43 Lebanon Centre for Adolescent Rheumatology Versus Arthritis 31 at UCL, UCLH, GOSH, London, UK Rheumatology Department, Hotel-Dieu de France Hospital, 44 Beirut, Lebanon Bristol Medical School Translational Health Sciences, 32 University of Bristol, Bristol, UK Medizinische Klinik 3‑Rheumatologie und 45 Immunologie, Universitätsklinikum Erlangen, Department of Rheumatology, North Bristol NHS Trust, Friedrich-Alexander-Universität Erlangen-Nürnberg, Bristol, UK Ulmenweg 18, 91054 Erlangen, Germany 46 National Institute for Health Research Manchester 33 Department of Allergy and Rheumatology, Nippon Medical Biomedical Research Centre, Manchester University NHS School Graduate School of Medicine, 1‑1‑5 Sendagi, Foundation Trust, The University of Manchester, Manchester, Bunkyo‑ku, Tokyo 113‑8602, Japan UK 34 47 Southport and Ormskirk Hospitals NHS Trust, Department of Rheumatology, Salford Royal Hospital, Southport PR8 6PN, UK Northern Care Alliance NHS Foundation Trust, Salford, UK 35 48 Department of Rheumatology, University Hospital Zurich, Division of Rheumatology and Clinical Immunology, University of Zurich, Zurich, Switzerland University of Pittsburgh School of Medicine, Pittsburgh, PA, 36 USA Division of Rheumatology, Department of Internal Medicine, 49 Eskişehir Osmangazi University, 26480 Eskişehir, Turkey Department of Rheumatology, Royal Wolverhampton 37 Hospitals NHS Trust, Wolverhampton WV10 0QP, UK Philippine Rheumatology Association, St Luke’s Medical 50 Center-Global City, Taguig, Philippines City Hospital, Sandwell and West Birmingham Hospitals 38 NHS Trust, Birmingham, UK Rheumatology Division, Department of Internal Medicine, Fakultas Kedokteran, Universitas Indonesia, Jakarta, Indonesia 13