COVID-19, caused by SARS-CoV-2, was declared a pandemic by the World Health Organization on 11 March 2020.1 Thereafter, the pandemic led to a dramatic loss of human life and unprecedented challenges to public health and healthcare systems worldwide.2 As a goal of reducing the COVID-19 impact, two vaccines using mRNA technology (Pfizer/BioNTech and Moderna) and one vaccine using a nonreplicating adenoviral vector expressing the spike protein (AstraZeneca/Oxford) were authorized for use during December 2020.3 Later, numerous candidate vaccines emerged worldwide. The development of vaccines against COVID-19 was efficacious in reducing infectivity and decreasing morbidity and mortality.

Although vaccination is essential for patients with rheumatic and musculoskeletal disease (RMD) as well as those receiving specific medications that may influence the functional competence of their immune system due to an increased risk for poor outcomes from COVID-19,4 patients with RMD were excluded from the initial COVID-19 vaccine clinical development trials.5,6 There are a few studies that support the safety and effectiveness of COVID-19 vaccines in patients with RMD.7–10 However, there is limited data on the vaccine-associated adverse effects and risk factors among these patients, many of whom take immunosuppressants.11 This study explored rates and risk factors for COVID-19 vaccination-reported side effects in patients with rheumatic disease compared to healthy controls. Additionally, we aimed to determine if there were any significant differences in these parameters between patients with inflammatory RMDs (I-RMDs) and non-inflammatory RMDs (NI-RMDs).

Methods

This cross-sectional study was carried out by the Egyptian College of Rheumatology-COVID-19 study group, which invited physicians (rheumatologists and internists) across Egypt via social network communications to participate in the ECR-VaXurvey3. Physicians reported data from December 2021 to June 2022. All patients presenting for an appointment who had pre-existing RMD and had received one or more doses of any vaccine against COVID-19 with or without adverse events were eligible for inclusion. Healthy individuals who received at least one dose of the COVID-19 vaccine were collected randomly from the community and included as a control group.

The study protocol was approved by the Institutional Research Board of the Faculty of Medicine at Mansoura University (approval registration number: R.24.05.2629), and the research was conducted in compliance with the Helsinki Declaration.12 The objectives of the study and participant rights were disclosed to all potential participants. Those who provided informed written consent were included.

The RMD cases in the study were divided into I-RMD and NI-RMD types and included primary diseases as chosen by Machado et al,7 COVID-19 vaccine clinical study on autoimmune rheumatic diseases.

Under I-RMDs, we included these primary diseases: (1) inflammatory arthritis: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, axial spondylarthritis, inflammatory bowel disease, reactive arthritis, and palindromic rheumatism; (2) connective tissue diseases (CTDs): systemic lupus erythematosus (SLE), systemic sclerosis, antiphospholipid syndrome, Sjögren's syndrome, inflammatory myositis (dermatomyositis, polymyositis), overlap syndrome, mixed CTDs, and undifferentiated CTDs; (3) vasculitis (small and medium vasculitis); and (4) others: Behcet Disease, autoinflammatory diseases such as familial Mediterranean fever and sarcoidosis. Under NI-RMD were included: (1) osteoarthritis, (2) osteoporosis, (3) crystal arthropathy, and (4) fibromyalgia syndrome and complex regional pain syndrome.7

The following information was collected and entered into an Excel spreadsheet: (1) participant’s characteristics including age, sex, educational level, comorbidities including diabetes, obesity, hypertension, respiratory diseases, or cardiovascular disease; (2) details of primary RMD diagnoses and disease activity, as assessed by Physician Global Assessment, as well as immunomodulatory/immunosuppressive treatments at the time of vaccination and I-RMD flare-up following vaccination that required a change in rheumatic medication; and (3) COVID-19 vaccination history including willingness to receive the COVID-19 vaccine, type of vaccine received, number of doses, diagnosis of COVID-19 before or after vaccination (breakthrough infection), and vaccine-related adverse events.

Medications taken by patients at the time of the COVID-19 vaccine were categorized as: (1) conventional synthetic drugs including hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, mycophenolate mofetil, cyclophosphamide, and azathioprine; (2) biologics including tumor necrosis factor inhibitors, abatacept, belimumab, rituximab, interleukin (IL)-6 inhibitors, and IL-17 inhibitors; and (3) targeted synthetic drugs, specifically JAK inhibitors and glucocorticoids. Any history of discontinuation of anti-rheumatic drugs after the COVID-19 vaccination was included.

Adverse events occurring within six months of receiving a COVID-19 vaccine and lasting for at least two days included symptoms such as pain, redness or swelling at the site of injection, headache, fever, fatigue, chills, generalized muscle pain, joint pain or swelling, low back pain, abdominal pain, vomiting and diarrhea, low back pain, allergic reaction, anaphylaxis, rash, cardiovascular manifestations (palpitations, tachycardia), chest diseases (shortness of breath, pleuritic chest pain, persistent cough), or neurological manifestations (transient ischemic attacks, convulsion, cranial or peripheral neuropathy). These adverse events were chosen because they have been reported in vaccine clinical trials and were reported by physicians.

For statistical analysis, we used Stata software (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LP.). Continuous variables were expressed as mean (± SD) and categorical variables as percentages. A two-sided independent t-test and Chi-square (χ2) test were used to compare differences between groups for continuous and categorical variables, respectively. We examined the frequency of COVID-19 vaccine side effects, COVID-19 breakthrough infections, and disease flares requiring a change in treatment following COVID-19 vaccination among groups. Next, multivariate logistic regression analyses were conducted to investigate potential risk factors independently associated with COVID-19 vaccine adverse events (no vs. yes) among the population with RMDs. First, we used univariate logistic analysis to investigate the variables associated with the occurrence of any adverse events. Then, multivariate logistic regression included variables with a p-value < 0.100. Results were reported as odds ratios (OR) and 95% CI. P-values < 0.05 were considered statistically significant.

Results

The study included 890 RMD patients and 172 healthy controls who had received the COVID-19 vaccination. Participant details were received from healthcare practitioners in different specialties, working in 30 different centers located in Egypt. They were mostly affiliated with various medical institutions, except for a few private practitioners.

The demographic features and clinical characteristics of the participating RMD patients and healthy controls are compared in Table 1.

The significant comorbidities among the RMD patients were hypertension in 160 (18.0%) patients, obesity in 120 (13.5%), and respiratory diseases in 48 (5.4%). Apart from the educational level, the demographic characteristics and frequencies of comorbidities were similar in patients and controls. The frequency of prior COVID-19 infection was significantly lower in patients with RMD compared to controls (70.0% vs. 84.8%; p = 0.002); however, the severity of prior infection was similar in both groups. The majority (77.2%) of RMD patients and (81.4%) controls reported at least one adverse event following vaccination. Apart from injection site pain, there was no significant difference in the individual adverse events between RMD patients and controls. The most frequently reported adverse event in patients with RMD was injection site pain or swelling (59.9%), fatigue (44.7%), myalgia (38.0%), headache (29.9%), and arthralgia (27.1%). A minority (30, 3.4%) of patients reported post-vaccine COVID-19 infection, while none of the controls did. Table 2 compares the demographic and clinical characteristics of I-RMD and NI-RMD patients.

Our participants were administered different types of vaccines, which had not significant association with adverse events [Table 2]. The vast majority (91.7%) of patients had I-RMDs, while the remaining 8.3% had NI-RMDs. Most I-RMD patients’ (78.8%) primary diagnosis was inflammatory joint disease, while osteoarthritis (51.4%) and osteoporosis (23.0%) were the most frequent in NI-RMDs. Hydroxychloroquine, methotrexate, and leflunomide were the most commonly used anti-rheumatic drugs in patients with I-RMD [Table 2].

A comparison of prevalence of post-vaccination adverse events reported by the NI-RMD, IRMD, and control groups are listed in Table 3. Details of adverse events reported by I-RMD patients, stratified by the types of rheumatic flare-up, are given in the Appendix [Supplementary Table 1].

Table 3 shows that the control group was significantly more likely to report injection pain compared to the RMD group (72.1% vs. 59.9%; p = 0.003). The control group also reported higher rates of other minor events such as fatigue, headache, and myalgia, albeit without statistical significance. The RMD group reported more arthralgia, arthritis, and neurological events, of which only arthritis showed a significant difference between the two groups (7.8% vs. 0%; <0.001).

I-RMD patients reported more overall adverse events than NI-RMD patients (79.3% vs. 45.1%; p < 0.001). There was a significantly higher prevalence of injection site pain and constitutional symptoms (headache, myalgia) in the I-RMD group. On the other hand, neurological manifestations were higher in the NI-RMD group (8.1% vs. 3.2% p = 0.029). Patients within the I-RMD group had a comparable overall distribution of adverse events when stratified by rheumatic diseases (RDs) [Table 3].

The frequency of post-vaccine fatigue was highest in the CTDs group (59.3%) and vasculitis group (47.8%), and the frequency of palpitation was lowest in subjects with CTDs (2.8%), followed by inflammatory arthritis (3.6%). Disease flares requiring changes in treatment following COVID-19 vaccination were reported by 12.1% of I-RMD patients and by 9.8% of NI-RMD patients. Patients with NI-RMD had a higher frequency of post-COVID-19 breakthrough infections compared to I-RMD (8.1% vs. 2.9%, p = 0.018).

Among all RMD patients, I-RMD (OR = 4.8, 95% CI: 2.2–10.6; p < 0.001), disease flare requiring change dose of treatment (OR = 4.8, 95% CI: 1.8–13.1; p = 0.002), azathioprine use during the time of vaccine (OR = 3.3, 95% CI: 1.5–7.5; p = 0.004), hydroxychloroquine use (OR = 0.4, 95% CI: 0.2– 0.7; p = 0.003), and biologic use (OR = 0.4, 95% CI: 0.2–0.7; p = 0.001) were associated with COVID-19 vaccine adverse events in a multivariate analysis (data not shown).

A multivariate analysis of the risk factors for post-vaccine adverse events among patients with I-RMD was performed. Previous COVID-19 infections requiring hospitalization were associated with more post-vaccine adverse events (OR = 2.4, 95% CI: 1.0–5.8; p = 0.040). Azathioprine use during the time of vaccination was associated with a higher incidence of adverse events (OR = 2.6, 95% CI: 1.1–5.9; p = 0.024), while it was lower with biologics use (OR = 0.5, 95% CI: 0.3–0.8; p = 0.010) [Tables 4 and 5].

Demographics, comorbidities, and gluco-corticoid use were not significantly associated with the prevalence of adverse events. However, Oxford AstraZeneca vaccine administration was associated with higher adverse events (p = 0.009) [Table 4].

Discussion

This large nationally representative study in Egypt investigated the adverse events following COVID-19 vaccination among patients with various types of RMD from different parts of Egypt.

Interestingly, our control subjects were more likely than RMD patients to report minor post-vaccine adverse events, particularly injection pain (p = 0.003). Similar findings were also reported in a major study by Machado et al.7 However, this is counterintuitive, because RMD patients typically have a lower pain threshold than healthy individuals. The explanation is likely psychological, related to how past pain is remembered. People whose daily lives are pain-free may experience less pain but recall those moments more vividly when asked later. Conversely, individuals who deal with chronic pain may have less vivid memories of minor adverse events. If so, future studies that rely on patients’ memories of past adverse events need to consider whether this phenomenon is a potential confounder.

Our patients with I-RMD were significantly more likely to report adverse events compared to those with NI-RMD. We also found that the severity of prior COVID-19 infection and use of azathioprine were associated with higher odds of reporting adverse events, while the use of biologics was associated with lower odds.

As stated earlier, overall adverse events were reported at slightly higher rates by controls (81.3%) than by RMD patients (77.2%), mainly due to higher reportage of non-serious adverse events by controls. In previous studies, rates of post-COVID-vaccine adverse events in RMD patients were similar to ours, ranging from 70.2% to 81%,10,13 but lower rates were observed in the European Coronavirus Vaccine (COVAX) registry (47%) and in the COVID-19 Global Rheumatology Alliance Vaccine Survey (37%).7,14 In a real-world digital cohort study including fully vaccinated healthy adults from the USA, 8947 of 11 140 (80.3%) reported adverse events.15 A study from the Netherlands reported that 51% of patients and 52% of controls had at least one mild adverse event, while 21% of patients and 19% of controls reported moderate adverse events after the first COVID-19 vaccine dose.8 In our study, systemic symptoms such as localized pain (72.1%), fatigue (41.3%), myalgia (32.6%), headache, and fever (25.0%) were the most common adverse events similar to findings elsewhere.7,10,13

Overall, the current study’s findings support the safety of COVID-19 vaccines in Egyptian patients with RMD, and are reinforced by recommendation by the American College of Rheumatology to vaccinate RMD patients.15

In the current study, the frequency of post-vaccine adverse events varied across RMD types and was higher in I-RMD patients. Regarding adverse events of special interest, neurological symptoms were higher in NI-RMD (8.1%) compared with I-RMD (3.9%) patients. Machado et al,7 reported a similar adverse event profile in patients with I-RMDs and NI-RMDs in the COVAX registry. These variations are likely related to differences in the study populations, type of vaccine exposure, and diversity of adverse events collected. The frequencies of most adverse events in our patients were similar across RMD types; however, a larger proportion of the I-RMD patients reported injection site pain and general constitutional symptoms compared to NI-RMD patients.

Common reasons for vaccination hesitancy center around fears of RD flare-ups, as reported in previous studies.16–18 Because some post-vaccination adverse events such as fatigue and arthralgia resemble symptoms of underlying RMD flare, we included only flares that required a medication change or an increased medication dose to enhance the specificity of the flare detection.

The risk of post-vaccine flare was 12.1% among our I-RMD patients. Flares requiring a change in treatment following COVID-19 vaccination were reported by 11% in a study of 1377 patients with systemic RDs receiving mRNA vaccines,19 and 15% in a study of > 1000 RD patients in New York,20 while another study observed much lower frequencies (4.9%).21 Prior studies in patients with RDs and SLE found that the occurrence of a flare six to 12 months before COVID-19 vaccination made post-vaccination flares more likely.19,22 In the present study, we lacked information about prior flare history. It is also possible that the natural history of the disease is more predictive of flare recurrence than COVID-19 vaccination. Future long-term prospective studies are needed to determine predictors of disease flare after COVID-19 vaccination in patients with RMD.

In the current study, post-vaccine breakthrough infections occurred in 2.9% of the I-RMD group and 8.1% of the NI-RMD group. Such reinfections have been attributed to the greater infectivity of later strains of the SARS-CoV-2, particularly the Omicron and the Delta variants.23 A study in the Netherlands detected Omicron breakthrough infections in 23% of 1882 patients with immune-mediated inflammatory diseases and 30% of controls.23 Most of them had received a COVID-19 vaccine dose less than three months before being reinfected. In another Dutch study, breakthrough Delta variant infections occurred in 5% of 2206 vaccinated patients with autoimmune inflammatory diseases.24 On the other hand, post-vaccine breakthrough infections were significantly lower in the COVAX registry database (0.7% and 1.1% of cases in the I-RMD and NI-RMD groups, respectively).7 In the current study, hospitalization after a breakthrough infection was required for 1.1% of 890 patients with RMD, which is comparable to results from the earlier mentioned Dutch study where 1% of 431 patients with immune-mediated diseases experienced breakthrough infections.24

Observational studies on patients using immunosuppressive regimens have yielded mixed results. Some reports suggest an increased risk of COVID-19 and its complications for patients who take specific anti-rheumatic therapies, while others indicate the same or even a decreased risk compared with those not on such therapies.25–28,29 The American College of Rheumatology recommended patients with controlled RMD to pause using methotrexate, JAK inhibitors, abatacept, mycophenolate mofetil, and rituximab after receiving COVID-19 vaccinations.15 Nearly a quarter (23.1%) of RMD patients in the current study temporarily discontinued their anti-rheumatic medications after vaccination. Similar behavior was reported by 28.9% of RMD patients who participated in the COVID-19 Global Rheumatology Alliance Vaccine Survey.14 In contrast, the European Alliance of Associations for Rheumatology did not advise temporarily stopping any of these medications (with the exception of rituximab) relative to when the vaccine against SARS-CoV-2 is administered.30 Future studies are needed to establish an evidence base for temporarily holding specific anti-rheumatic therapies to balance vaccine efficacy with the risk of disease flare.

Our study has identified several characteristics as potential risk factors for adverse events following COVID-19 vaccination in patients with I-RMD. Biologic use was associated with a lower incidence of post-vaccine adverse events. Most previous studies suggest that patients with immune-mediated inflammatory diseases receiving biologic therapies may not be at additional risk for adverse events after COVID-19 vaccination.31–33 However, azathioprine use was independently associated with a higher incidence of post-vaccination adverse events. Including the type of I-RMD (arthritis, CTD, vasculitis, and others) in the multivariate analysis supports the conclusion that the associations between RMD drugs and COVID-19 adverse events depend on the specific drug and not the underlying I-RMD.

In the present study, the Oxford-AstraZeneca vaccine was the only one that showed a significant risk of adverse events in RMD patients. The choice of type of COVID-19 vaccine should be based on a risk-benefit analysis. In harmony, the Oxford-AstraZeneca vaccine was associated with the risk of adverse events after COVID-19 vaccination8 as well as the risk of thrombotic events.34 There was no independent association between the demographic variables or comorbidities and the frequency of adverse events. Importantly, no causal conclusions regarding vaccination and the development of adverse events can be firmly drawn from this study.

Strengths of this study include the rapid dissemination of nationwide data reported by rheumatologists and internists through the Egyptian College of Rheumatology networks. Furthermore, defining a post-vaccination flare as one that required a change in treatment reduced the potential misclassification of outcomes, making it less likely to be confused with common vaccine side effects, such as fatigue, fever, and joint pain. However, our study has important limitations. Firstly, this data is physician-reported, leading to possible misestimations of adverse events. Secondly, the short time between vaccination and adverse events limits our ability to draw conclusions regarding the long-term safety profile of COVID-19 vaccines. Moreover, the control group was significantly smaller than the RMD group. Finally, the cross-sectional design prevented us from establishing a causal relationship between the COVID-19 vaccine and adverse events.

Conclusion

Our findings showed that the rate and type of adverse events were comparable between RMD and healthy subjects, thus providing overall confidence in the COVID-19 vaccine’s safety in people with RMDs. Interestingly, azathioprine use, prior COVID-19 infection, and hospitalization are the most important risk factors associated with adverse events of I-RMD following COVID-19 vaccination. Future studies should address the importance of continued long-term evaluation of the risks and benefits of specific medications in patients with RMDs during the COVID-19 vaccine.

Disclosure

The authors declare no conflicts of interest. No funding was received for this study.

Data Availability Statement

Additional data supporting the findings of this study are available from the corresponding author upon reasonable request.

Acknowledgments

Hala A Raafat (Cairo), Samah A El-Bakry (Ain Shams), Alaa Mohamed (Assuit), Iman I El-Gazzar (Cairo), Samar M Fawzy (Cairo), Nahla N Eesa (Cairo), Amany El-Bahnasawy (Mansoura), Mohamed N Salem (Beni-Suef), Rasha M Fawzy (Benha), Ahmed Elsaman (Sohag), Nouran M Abaza (Ain Shams), Ahmed M Abdalla (Aswan), Amany R El-Najjar (Zagazig), Soha Senara (Fayoum), Safaa Sayed (Cairo), Emad El-Shebini (Menoufiya), Dina H El-Hammady (Helwan), Shereen Elwan (Tanta), Marwa A Amer (Alexandria), Maha E Ibrahim (Suez-Canal), Gehad Elsehrawy (Suez Canal), Ahmed Y Ismail (Beni-Suef), Wael Abdel Mohsen (South-Valley).

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