Characteristics of emerging new autoimmune diseases after COVID‐19 vaccination: A sub‐study by the COVAD group

Despite the overall safety and efficacy of COVID‐19 vaccinations, rare cases of systemic autoimmune diseases (SAIDs) have been reported post‐vaccination. This study used a global survey to analyze SAIDs in susceptible individuals' post‐vaccination.


| INTRODUC TI ON
The introduction of COVID-19 vaccines has resulted in a significant reduction in both morbidity and mortality associated with COVID-19 infection among individuals affected by rheumatic and musculoskeletal diseases, a population at higher risk for severe outcomes than the general population.Although these vaccines have demonstrated a favorable safety profile, 1 there have been documented instances of new-onset systemic autoimmune diseases (SAIDs) following vaccination, which has given rise to apprehension and the potential to contribute to vaccine hesitancy. 2range of postvaccination new-onset SAIDs have been reported, including autoimmune rheumatic diseases, immunemediated nephropathies, and autoimmune hematological diseases.3 While the underlying pathogenic mechanism is not well established, hypotheses include molecular mimicry and immune cross-reactivity, bystander activation, and the role of vaccine adjuvants.4 These emerging reports warrant careful consideration to better understand the potential association between COVID-19 vaccination and the development of autoimmune conditions.A comprehensive analysis of such cases has the potential to advance our knowledge of vaccine-related adverse events and aid in the formulation of appropriate management strategies.

Conclusion:
This study reports a low occurrence of new-onset SAIDs following COVID-19 vaccination, primarily IIMs, PMR, and inflammatory arthritis.Identified risk factors included pre-existing AID multimorbidity, mental health diseases, and mixed race.Revaccination was well tolerated by most patients; therefore, we recommend continuing COVID-19 vaccination in the general population.However, long-term studies are needed to understand the autoimmune phenomena arising post-vaccination.

K E Y W O R D S
autoimmune diseases, COVID-19, idiopathic inflammatory myopathies, SAIDs, vaccination respondents who reported new-onset SAID could be healthy previously or with pre-existing different SAID.
A follow-up questionnaire was distributed to eligible participants who provided consent for further contact.The survey link included a cover letter outlining the purpose, content, data handling, and study investigators.No incentives were offered to the participants to complete the survey.(Figure 1) provides a detailed flowchart illustrating the participant selection process for the study.
Autoimmune disease (AID) multimorbidity was defined as the presence of two or more coexisting SAIDs in a patient prior to vaccination.Hybrid vaccination refers to respondents who received different vaccines as part of their primary or booster vaccination.

| Survey regulatory approvals
An exemption from review was obtained from the local institutional ethics review committee as per local guidelines. 6We adhered to the Checklist for Reporting Results of Internet E-surveys (CHERRIES) to report the data. 7,8

| Statistical analysis
Descriptive statistics were used, and data were expressed as median (range: 25th-75th), or numbers (%).A 1:4 propensity score (PS) matched analysis between new-onset SAIDs and vaccinated HCs without new-onset SAIDs was performed with age and sex variables and a tolerance of 0.2, with an emphasis on exact matches.
Chi-Square/Fisher's Exact and Mann-Whitney U were used to compare categorical and continuous variables, respectively.Predictors of new-onset SAIDs were assessed using binary logistic regression adjusted for age, sex, ethnicity, and country using the Human Development Index (HDI). 9Statistical analyses were performed using SPSS version 28.  1).
Among the seven cases of vasculitis, four cases of giant cell arteritis (GCA) (n = 4, 57.1%) and a further three cases of ANCA-associated vasculitis, including microscopic polyangiitis, and granulomatosis with polyangiitis were reported.These were in relation to Oxford/ Astra Zeneca (n = 4, 57.1%), followed by Pfizer (n = 3, 42.9%).None of the seven individuals with vasculitis chose to revaccinate (Table S5).

| Comparison of new-onset SAIDs and vaccinated HCs (PS-matched analysis)
Comparisons of the reported SAIDs with HCs suggest potential variations in the risk of developing new-onset SAIDs based on ethnicity and the type of COVID-19 vaccine administered (Table 2).

| Associations of new-onset SAIDs
The in the pre-COVID era. 13The difference in percentages can be attributed to a much larger sample size and duration when compared to our study.This implies that the incidence of SAIDs following COVID-19 vaccination may be regarded as a co-incidence rather than a consequence of the vaccination.Abbreviations: CI, confidence interval; OR, odd's ratio.

TA B L E 2 Associations of new-onset
SAIDs compared to vaccinated healthy controls by binary logistic regression.
Our study reported IIM to be the most commonly self-reported new-onset SAID following COVID-19 vaccination, which is otherwise a rare disease.This is similar to the disease distribution found in a systematic review, with IIM being the most common connective tissue disease (CTD) disorder after COVID-19 vaccination. 11The fact that IIM is the most reported SAID likely reflects our sampling strategy/bias.Many investigators who disseminated this survey have a particular interest in IIM, which means their patient populations would be enriched for this disease.Additionally, the survey was circulated among IIM patient groups.IIM was followed by arthritis and PMR.Our study did not assess causality, making it difficult to determine whether the distribution of diseases was due to reporting bias, thus warranting the need for further population-based studies to confirm causality.
Vaccination-associated myositis has also been described in the literature following the use of other vaccines, such as BCG 14 and HBV. 15 Seventy percent of vaccine-associated IIM occurred following an mRNA vaccine, according to one systematic review.7][18][19] Although the exact mechanism underlying vaccine-induced IIM is not clear, it is noteworthy that COVID-19 vaccination and infection have been associated with the development of myositis-specific autoantibodies, particularly anti-melanoma differentiation-associated gene 5 (MDA-5) antibodies. 20However, these links remain tenuous and further warrant extensive research.
2][23] We additionally observed that such individuals may experience an exacerbation of symptoms following revaccination, a phenomenon not observed in other COVID-19 vaccine-induced SAIDs.The recurrence of symptoms with subsequent vaccination may strengthen the possibility of causality in these individuals.This underscores the importance for future studies to document the long-term prognosis and evolution of vaccine-induced SAID.No patients with vasculitis chose to be revaccinated, so response to revaccination within this group remains completely unknown.

Immunomodulatory pharmacological treatment for new-onset
SAIDs was required in nine out of every 10 patients, of whom over two-thirds experienced alleviation of symptoms following treatment.
Oral glucocorticoids were the most common treatment modality for, administered more than half of the patients, followed by methotrexate, and NSAIDs/analgesics.Our study did not collect data on the duration of glucocorticoid use, which should be addressed in future studies.
We found an association between new-onset SAIDs and AID multimorbidity, but no such association with non-autoimmune comorbidities.This could potentially be linked to overactivity of the interferon axis or activation of other immune pathways, predisposing individuals with pre-existing SAIDs or a family history of SAIDs to other SAIDs. 24Similarly, mental health disorders were associated with an increased risk of developing SAIDs.This can possibly be attributed to an altered perception of pain and fatigue, which may lead patients to consider these symptoms as SAID.
In addition, dysregulation of immunological pathways has been shown to underlie certain mental health disorders, potentially leading to autoimmune dysfunction that manifests as new-onset SAID. 25,26izer and Moderna, both mRNA vaccines, were the most commonly used vaccines in our sample size compared to the DNA vaccines, Oxford/AstraZeneca, and Johnson & Johnson.This does not necessarily suggest a stronger association between mRNA vaccines and SAIDs.The increased usage of mRNA vaccines may be due to their higher efficacy compared to DNA vaccines (94.1% and 91.6%, respectively) 27,28 or more effective marketing and distribution.
Limited literature is available on the comparison of COVID-19 vaccines with regard to the incidence of SAIDs following administration.
Data on the background incidence of SAIDs in the general population are critical to establishing an association between vaccination and SAIDs.Clinical trials and postmarketing surveillance studies conducted during the COVID-19 vaccination drive have not demonstrated substantially increased rates of SAID diagnoses in the population since the onset of the pandemic.Further, the intra-pandemic incidence of rheumatological SAIDs was shown to be reduced compared to pre-pandemic levels in a case series. 29ey found a reduction in the intra-pandemic levels of the disease compared to its pre-pandemic levels, potentially due to modifications during the pandemic.This illustrates how unmeasured confounders cause difficulty in drawing associations from case series or biased retrospective cohort studies on SAIDs and COVID-19 vaccinations.
Treatment of SAIDs can have implications for the future health outcomes of patients who undergo vaccination, including their risk of severe COVID-19, the very condition the vaccination aims to prevent.A limitation of this study is the lack of long-term follow-up or assessment of the severity, outcome of autoimmune diseases, the efficacy of vaccination, or antibody associations.
Our study was a self-reported survey that was prone to selection, non-responder, and recall biases.The circulation of surveys across social media could lead to an "echo chamber" effect where the survey is more likely to be shared among individuals who have developed certain subtypes of autoimmune disease following vaccination or by clinicians with a particular sub-specialist interest.This may explain the higher frequency of IIM reports, despite being a rare SAID.Social media behavior has also been linked to vaccine hesitancy due to the spread of misinformation and conspiracy theories. 30This is a patient self-reported survey.
Although the patients report that their physician confirmed the diagnosis of new-onset SAID following the COVID vaccination, cross-checking the same individually proves challenging.Also, in such a scenario, temporality alone is not enough to prove causation.
It is critical to remember that within a relatively short timeframe, enormous numbers of individuals have been vaccinated worldwide.According to the WHO, as of June 29, 2023, over 13.2 billion doses of COVID-19 vaccine have been administered globally. 31Simultaneously, many new patients are being diagnosed globally on a daily basis, irrespective of their SAIDs.While COVID-19 vaccination cannot be excluded as a contributory factor, its association with newly reported SAIDs may be coincidental.Causality cannot be proven using temporal association alone.

2 | ME THODS 2 . 1 |
onset SAID subsequent to COVID-19 vaccination within a large and diverse population encompassing various ethnicities and geographic regions.Additionally, this study endeavors to identify plausible links between specific COVID-19 vaccines and the exacerbation of symptoms post-revaccination and seeks to comprehensively characterize the determinants, duration of symptoms, and treatment requirements among individuals afflicted by new-onset SAID post-vaccination.Through the accomplishment of these objectives, we aimed to enable early intervention in the anticipation of new-onset SAIDs and facilitate informed decision-making regarding vaccination for high-risk patients.Moreover, we also aimed to bolster public health endeavors geared towards the optimization of future vaccination strategies.Study design 2.1.1 | Population selection The COVID-19 Vaccine in Autoimmune Diseases (COVAD)2 esurvey was developed with the primary objective of gathering patient-reported data on the long-term safety and tolerability of COVID-19 vaccines among individuals with existing SAIDs.The survey was collaboratively disseminated by the COVAD study group, which was composed of researchers spanning multiple countries through diverse channels, including medical clinics, patient support organizations, and social media platforms.The data collection phase for the survey spanned months, with a comprehensive protocol delineating the particulars of the COVAD-2 survey published separately. 5To confirm eligibility for participation in the study, individuals were required to provide an affirmative response to specific questions in the e-survey that inquired about the development of symptoms and formal diagnosis confirming a new-onset autoimmune condition or rheumatic disease after receiving any dosage of the COVID-19 vaccine.Participants lacking a physician-or rheumatologist-confirmed diagnosis of SAID were tagged as non-confirmed cases and deemed ineligible for inclusion.These 4%), followed by Moderna (n = 32, 32.3%), and Oxford/AstraZeneca (n = 26, 26.3%) were the most common vaccines among individuals with postvaccination new-onset SAID.Most individuals received two doses before symptom onset, and the median duration from vaccination to symptom onset was 14 (5-30) days.F I G U R E 1 Flowchart showing the process of study participant selection.Fatigue/lethargy was the most commonly reported symptom (n = 38, 50.7%), and was also the most common initial symptom (n = 15, 20.0%).Other common symptoms included joint pain (n = 35, 46.7%), joint stiffness (n = 27, 36.0%),inability to get up from sitting posture or do overhead work (n = 24, 32.0%), early morning stiffness lasting more than 30 min (n = 24, 32.0%), low back pain (n = 16, 21.3%), rash (n = 16, 21.3%), difficulty in eating or drinking (n = 19, 25.3%), and shortness of breath on exertion/ rest (n = 10, 13.3%).Concerningly, nearly half of the respondents (n = 31, 45.6%) rated their quality of life as less than 5 out of 10 after the development of a new SAID, though the other half did better.TA B L E 1 Propensity score-matched analysis (1:4) between emergent SAIDs and vaccinated HCs without new SAIDs.
More than half of the participants (n = 40) chose to receive additional doses of the COVID-19 vaccine despite experiencing symptoms of their new-onset SAID.In this subgroup, 23 participants (56.1%) reported no worsening of symptoms in their autoimmune condition post COVID-19 revaccination, whereas 18 participants (43.9%) experienced worsening of symptoms.

5 | 1
SAIDs after a native COVID-19 infection; hence, it is possible that susceptible individuals who developed postvaccination SAIDs would have developed them following a native COVID-19 infection.Thus, studies comparing unvaccinated and vaccinated groups are needed to ascertain how vaccination affects the risk of developing SAIDs after a native COVID-19 infection.Although the benefits of COVID-19 vaccination in preventing a COVID-19 infection outweigh associated risks that come with its use, further research is needed to identify vulnerable groups in population-based studies.Attention should be paid to the potential risk of triggering SAID post-vaccination in patients with known genetic susceptibility, a family history of autoimmune diseases, or preexisting autoimmune diseases.Further research is needed into mechanisms underlying these autoimmune phenomena to allow the possibility of preventing them by altering the vaccine type, dose, or schedule.CON CLUS ION Overall, new-onset, postvaccination SAIDs were rarely reported despite sampling and recall bias with survey-based research, where an adverse event is more likely to be remembered, with the most common being IIMs, PMR, arthritis, CTDs, and vasculitis.Most of these patients were treated with oral glucocorticoids and tolerated the revaccination well, though postvaccination exacerbation was more widely reported in those with inflammatory arthritis and SLE.Pre-existing AID multimorbidity, mental health diseases, and mixed race were identified as potential risk factors for new-onset SAID.However, long-term studies are needed to fully understand the autoimmune phenomena that arise post-vaccination, including their causality, prevention, and management.Overall, COVID-19 vaccination remains one of the most efficacious ways of preventing severe COVID-19 and death, and should be positively encouraged, even in patients with underlying SAID who remain at a higher risk.Further case-controlled studies and epidemiological studies are required to identify vulnerable groups in populationlevel studies and to establish how risk compares to that of the unvaccinated population.AUTH O R CO NTR I B UTI O N S Conceptualization: RS, JH, NR, and LG.Data curation: all authors.Formal analysis: NR.Funding acquisition: N/A.Investigation: RS, JH, and NR.Methodology: LG, VA, NR, and RA.Software: LG.Validation: VA, RA, and HC.Visualization: RA, VA, and LG.Writing-original draft: RS, JH, NR, and LG.Writing-review and editing: all authors.A FFI LI ATI O N S Department of Rheumatology, Clinic of Rheumatology, University Hospital "St.Ivan Rilski", Medical University-Sofia, Sofia, Bulgaria 2 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Hybrid vaccination-Those who received more than one type of COVID-19 vaccine.NS not significant p-value, p < .05 is significant.Age and gender are matched in PS matched analysis with 1:4 patients and healthy controls.
Abbreviations: CI, confidence interval; OR, odd's ratio.aChi-squaretest/Fisher'sexactfor categorical variables and Mann-Whitney U-test for continuous variables.3.1 | Autoimmune disease subgroupsPMR was ranked as the third most frequently reported disease following COVID-19 vaccination (TableS3).Within this group, both Pfizer (n = 9, 75.0%) and Moderna (n = 8, 66.7%) vaccines were the most commonly used types.In contrast to the inflammatory arthritis group, the majority of the respondents in the PMR group (n = 6/9, 66.7%) did not experience worsening of their symptoms after receiving subsequent COVID-19 vaccine doses.This suggests a relatively favorable response to vaccination in individuals with PMR.SLE was reported in seven patients (10.0%), associated with Pfizer (n = 4, 57.1%) and Oxford/Astra Zeneca (n = 4, 57.1%) vaccines (one patient with hybrid vaccination), with subsequent worsening with revaccination in half of the group (n = 3/7, 42.9%) (Table