{'fraction_non_alphanumeric': 0.04558579053285502, 'fraction_numerical': 0.021611689561641438, 'mean_word_length': 5.1617250673854445, 'pattern_counts': {'":': 0, '<': 2, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
COVID‐19 Vaccination in Autoimmune Diseases (COVAD) study: Vaccine safety in idiopathic inflammatory myopathies

Abstract Introduction/Aims In this study we investigated COVID‐19 vaccination–related adverse events (ADEs) 7 days postvaccination in patients with idiopathic inflammatory myopathies (IIMs) and other systemic autoimmune and inflammatory disorders (SAIDs). Methods Seven‐day vaccine ADEs were collected in an international patient self‐reported e‐survey. Descriptive statistics were obtained and multivariable regression was performed. Results Ten thousand nine hundred respondents were analyzed (1227 IIM cases, 4640 SAID cases, and 5033 healthy controls [HCs]; median age, 42 [interquartile range, 30‐455] years; 74% female; 45% Caucasian; 69% completely vaccinated). Major ADEs were reported by 76.3% of the IIM patients and 4.6% reported major ADEs. Patients with active IIMs reported more frequent major (odds ratio [OR], 2.7; interquartile range [IQR], 1.04‐7.3) and minor (OR, 1.5; IQR, 1.1‐2.2) ADEs than patients with inactive IIMs. Rashes were more frequent in IIMs (OR, 2.3; IQR, 1.2‐4.2) than HCs. ADEs were not impacted by steroid dose, although hydroxychloroquine and intravenous/subcutaneous immunoglobulins were associated with a higher risk of minor ADEs (OR, 1.9; IQR, 1.1‐3.3; and OR, 2.2; IQR, 1.1‐4.3, respectively). Overall, ADEs were less frequent in inclusion‐body myositis (IBM) and BNT162b2 (Pfizer) vaccine recipients. Discussion Seven‐day postvaccination ADEs were comparable in patients with IIMs, SAIDs, and HCs, except for a higher risk of rash in IIMs. Patients with dermatomyositis with active disease may be at higher risk, and IBM patients may be at lower risk of specific ADEs. Overall, the benefit of preventing severe COVID‐19 through vaccination likely outweighs the risk of vaccine‐related ADEs. Our results may inform future guidelines regarding COVID‐19 vaccination in patients with SAIDs, specifically in those with IIMs. Studies to evaluate long‐term outcomes and disease flares are needed to shed more light on developing future COVID‐19 vaccination guidelines.

and minor (OR,1.5;IQR, ADEs than patients with inactive IIMs. Rashes were more frequent in IIMs (OR,2.3;IQR, than HCs. ADEs were not impacted by steroid dose, although hydroxychloroquine and intravenous/ subcutaneous immunoglobulins were associated with a higher risk of minor ADEs (OR, 1.9;IQR,and OR,2.2;IQR,respectively). Overall, ADEs were less frequent in inclusion-body myositis (IBM) and BNT162b2 (Pfizer) vaccine recipients.
Discussion: Seven-day postvaccination ADEs were comparable in patients with IIMs, SAIDs, and HCs, except for a higher risk of rash in IIMs. Patients with dermatomyositis with active disease may be at higher risk, and IBM patients may be at lower risk of specific ADEs. Overall, the benefit of preventing severe COVID-19 through vaccination likely outweighs the risk of vaccine-related ADEs. Our results may inform future guidelines regarding COVID-19 vaccination in patients with SAIDs, specifically in those with IIMs. Studies to evaluate long-term outcomes and disease flares are needed to shed more light on developing future COVID-19 vaccination guidelines. Several reports have demonstrated the safety and efficacy of  vaccines in the general population, but there are significant gaps in vaccine safety and efficacy data in vulnerable populations, including patients with systemic autoimmune and inflammatory disorders (SAIDs), those on immunosuppressive medications, and in pregnant women. [1][2][3] The exclusion of patients with SAIDs and those on immunosuppressive medication from the initial vaccine safety trials has inevitably resulted in a paucity of safety and efficacy data of COVID-19 vaccination in this vulnerable patient group. Although recent studies have included rheumatic disorders, significant gaps exist in understanding the safety of COVID-19 vaccination in patients with rare diseases, such as idiopathic inflammatory myopathies (IIMs). [4][5][6] The study on vaccination-related adverse events (ADEs) in dermatomyositis (DM) from the TrinetX (Cambridge, MA) database has looked at the overall 1-, 30-, and 60-day ADEs after three vaccines (BNT162b2, mRNA-1273, and Ad26.COV.2.S) used in USA. 7 The study included a total of 6104 vaccinated dermatomyositis (DM) patients from the USA. DM patients demonstrated a higher rate of ADEs compared with age-matched healthy controls (HCs). The studies so far available on vaccine ADEs in SAIDs or IIMs are largely regional and small. 8 Studies claiming to be global have had an underrepresentation of various ethnic groups (blacks and Asians). 4 An interplay between underlying autoimmunity and dysregulated immune pathways compounded by the effect of immunosuppressive medications and potentially impacted by comorbid illness may predispose IIM patients to an increased risk of postvaccination ADEs, including allergic reactions, anaphylaxis, and disease flares. 9,10 Concerns have recently emerged that adjuvants and immune activators in vaccines induce autoimmune disease flares and de-novo immune thrombotic and demyelinating events. 11,12 Poor characterization of postvaccination ADEs in IIM patients due to a lack of vaccine safety and efficacy study in this group may have contributed to vaccine hesitancy. 13,14 Therefore, there is a need for evidence-based vaccine safety data with proper characterization of post-vaccination ADEs to potentially improve vaccination rates in patients with IIM, a vulnerable patient group.
In this study, we evaluated the short-term safety of COVID-19 vaccination using a patient self-reported global multicenter electronic survey.

| Study design
This is an international, online, cross-sectional, multicenter survey, part of the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. 15

| Active and inactive disease
Active and inactive disease 4 weeks before vaccination were assessed by patients' response to questions about their symptoms before vaccination (eg rash, muscle weakness, joint pain, and swelling, etc) and need to step-up immunosuppression (Supplementary Methods).

| ADEs postvaccination
Seven-day ADEs were categorized as injection-site pain and reaction, minor ADEs, major ADEs, and hospitalizations. Minor ADEs included myalgia, body aches, fever, chills, nausea and vomiting, headache, rashes, fatigue, diarrhea, abdominal pain, high pulse rate or palpitations, rise in blood pressure, fainting, difficulty in breathing, dizziness, and chest pain. Major ADEs consisted of serious reactions to vaccination requiring urgent medical attention, including anaphylaxis, a marked difficulty in breathing, throat closure (choking), and severe rashes. 19 Other ADEs that were not listed were reported as "others" via an open-ended question.

| Statistical analysis
Chi-square and Mann-Whitney U tests were used for categorical and continuous variables, respectively. The variables expected to be independently significant between IIMs, SAIDs, and HCs, and between different IIM subtypes, after univariable analysis, underwent binary logistic regression analysis with adjustment for factors considered relevant based on evidence from current literature and clinical judgment, including the factors of age, gender, ethnicity, immunosuppressant use, and vaccine received, and stratified by country of origin. The results for continuous variables are expressed as median (interquartile range [IQR]). P < .05 was F I G U R E 1 Data extraction. considered significant. The Bonferroni-corrected P value for univariate analysis was taken as significant (P < 0.0125 for 2 Â 2 chi-square analysis).
Nonparametric tests were used because the data were not normally distributed (by Kolmogorov-Smirnov test and Shapiro-Wilk test). Statistical analysis was performed using SPSS version 20 (IBM Corporation, Armonk, NY) and R software version 3.5.3 (R Core Team, Vienna, Austria). were primarily from Turkey, Mexico, India, UK, and the USA, and consisted of 11.2% with IIMs, 42.6% with other SAIDs, and 46.2% HCs. The most common SAIDs reported in the cohort were rheumatoid arthritis, followed by IIM and hyper/hypothyroidism. Of the respondents, 69% had received both primary doses of the COVID-19 vaccine. The largest number of respondents received the BNT162b2 (Pfizer) vaccine (39.8%), followed by theChadOx1 nCOV-19 vaccine (Oxford/AstraZeneca). Of the IIM patients, 34% had dermatomyositis, 17% had polymyositis, and 23% had inclusion-body myositis (IBM). Other population characteristics of the study cohort are provided in Tables S1 and S5, and Tables S1,S2, and S6.

| Post-COVID-19 vaccination-associated ADEs in patients with IIM
Any ADE was seen in 76.5%, with minor ADEs in 76.3% and major ADEs in 4.6%. All-cause hospitalization was seen in 0.6%. Minor ADEs most commonly seen were fatigue, myalgia, and fever. Severe rashes were statistically more frequent in IIM patients when compared with HCs (Table 5).

| Post-COVID-19 vaccination-associated ADEs in patients with IIM based on immunosuppression received
Although the wide variety of treatments used for IIMs results in a low frequency for each, an adjusted analysis shows that IIM patients who were on rituximab (n = 40, 3%) more frequently had chills (odds ratio IQR, 1.1-4.3; P = .019) was more frequent and muscle pain (OR, 0.28; IQR, 0.1-0.7; P =.01) was less frequent.

| Post-COVID-19 vaccination-associated ADEs in patients with IIM compared with HCs
The incidence of injection site pain was similar in IIM patients (63%) and HCs (62%), with a very small absolute risk difference. Among minor ADEs, patients with IIM were at a higher risk of rashes compared with HCs, although the absolute risk of rash in both IIMs and HCs was very low (1%-2%) ( Table 5 and Table S3). The absolute risk of major ADEs and hospitalizations was low (0%-4%), and was similar between IIM patients and HCs (Table 5).
Thus, limited events in each subgroup, such as major ADEs and hospitalization, would make it difficult to find any statistically significant correlations. Finally, the survey used in our study focused on short-term ADEs, and long-term outcomes and disease flares were not assessed.

| CONCLUSION
In this study we have shown that COVID-19 vaccination has a favorable short-term safety profile in IIM patients as in healthy individuals and those with other SAIDs. Marginally higher ADRs, such as rashes, may have been related to disease phenotype and did not lead to an increased hospitalization rate. Those with active disease before vaccination reported higher ADEs. Among IIM patients, the DM patients may have been predisposed to specific ADEs, whereas those with IBM subgroup had fewer reported ADEs. Studies on long-term outcomes and disease flares are needed to shed more light on developing future COVID-19 vaccination guidelines.

ROLE OF THE FUNDING SOURCE
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

DECLARATIONS
The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health.

ETHICAL APPROVAL STATEMENT
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.