Risk of flare or relapse in patients with immune-mediated diseases following SARS-CoV-2 vaccination: a systematic review and meta-analysis

Background Patients with autoimmune and immune-mediated diseases (AI-IMD) are at greater risk of COVID-19 infection; therefore, they should be prioritized in vaccination programs. However, there are concerns regarding the safety of COVID-19 vaccines in terms of disease relapse, flare, or exacerbation. In this study, we aimed to provide a more precise and reliable vision using systematic review and meta-analysis. Methods PubMed-MEDLINE, Embase, and Web of Science were searched for original articles reporting the relapse/flare in adult patients with AI-IMD between June 1, 2020 and September 25, 2022. Subgroup analysis and sensitivity analysis were conducted to investigate the sources of heterogeneity. Statistical analysis was performed using R software. Results A total of 134 observations of various AI-IMDs across 74 studies assessed the rate of relapse, flare, or exacerbation in AI-IMD patients. Accordingly, the crude overall prevalence of relapse, flare, or exacerbation was 6.28% (95% CI [4.78%; 7.95%], I2 = 97.6%), changing from 6.28% (I2 = 97.6%) to 6.24% (I2 = 65.1%) after removing the outliers. AI-IMD patients administering mRNA, vector-based, and inactive vaccines showed 8.13% ([5.6%; 11.03%], I2 = 98.1%), 0.32% ([0.0%; 4.03%], I2 = 93.5%), and 3.07% ([1.09%; 5.9%], I2 = 96.2%) relapse, flare, or exacerbation, respectively (p-value = 0.0086). In terms of disease category, nephrologic (26.66%) and hematologic (14.12%) disorders had the highest and dermatologic (4.81%) and neurologic (2.62%) disorders exhibited to have the lowest crude prevalence of relapse, flare, or exacerbation (p-value < 0.0001). Conclusion The risk of flare/relapse/exacerbation in AI-IMD patients is found to be minimal, especially with vector-based vaccines. Vaccination against COVID-19 is recommended in this population. Supplementary Information The online version contains supplementary material available at 10.1186/s40001-024-01639-4.


Introduction
Among the general population, patients with autoimmune and immune-mediated diseases (AI-IMD) are at greater risk of COVID-19 infection due to their underlying disease-related immune dysfunction along with the immunosuppressive treatments [1].Increased morbidity, mortality, and costs are attributed to AI-IMD flares [2] highlighting the significance of disease activity control during this pandemic.There is also evidence supporting disease relapse after COVID-19 in MS patients [3].
Vaccination is considered the best strategy to effectively reduce COVID-19-related morbidity and mortality [4].Approved vaccines against SARS-CoV-2 are categorized into different main types including mRNA, vector-based, and inactive [5].Concern regarding the vaccine's suboptimal efficacy and safety, especially vaccine-induced flare, is shown to have the strongest association with vaccine hesitancy among AI-IMD patients [6].Although vaccines are generally safe, several studies reported SLE flare following influenza and papilloma vaccines [7][8][9].
There are different technologies for developing SARS-CoV-2 vaccines, including inactivated and nucleic-acid vaccines composed of mRNA or plasmid or viral DNA vectors, which code for a specific antigen.To achieve a robust long-lasting immunogenicity in both humoral and cellular immune systems, an adjuvant component is added to the antigen activating three pathways [10].Major histocompatibility complex-T cell receptor (MHC-TCR) interaction (specific), costimulatory signal to TCR (non-specific), and pro-inflammatory signals (non-specific) using cytokines to develop Th1, Th2, and Th17 from T lymphocytes [11].Adjuvants also trigger innate immunity through toll-like receptors (TLRs) [12].Although these components are critical for robust immunity, they might also initiate an undesired immune response and trigger autoimmune disease relapse [13].Besides, the abundance of cytokines produced during this process can result in the reactivation of reminiscent self-reacting lymphocyte clones through bystander activation and blunt the mechanisms of tolerance [14].
Data on SARS-CoV-2 vaccine safety in this vulnerable population are limited as they were widely excluded from the original vaccine trials; however, it is increasingly investigated through different clinical trials [15,16].Despite the ample evidence in the literature investigating the immunogenicity of COVID-19 vaccines in AI-IMD patients, their safety profile, particularly disease flare/relapse, has been less studied [5,17].There is inconsistency regarding the safety of COVID-19 vaccines in AI-IMD patients; hence, we aimed to provide a more precise and reliable vision using systematic review and meta-analysis.

Protocol and literature search
This systematic review and meta-analysis study was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Two reviewers independently conducted the literature search, and any disagreement was resolved by discussion or consultation with a third expert.The authors were not blinded to the data of the articles, including the author, institution, or journal, while screening studies or extracting data.EndNote version × 20 was used for literature management.
(3) Study design: all cross-sectional, observational, retrospective, and prospective studies were included.(4) Outcomes: the primary outcome of this study was disease relapse/flare/exacerbation following COVID-19 vaccination in AI-IMD patients after COVID-19 vaccination.The exclusion criteria were as follows: (1) case reports or case series patients; (2) non-original studies including reviews and editorials; (3) partially overlapping patient cohorts; (4) not reporting the relapse/flare percentage after COVID-19 vaccination; (5) articles not written in English; and (6) non-human studies.Two reviewers independently screened the literature in consensus.

Data extraction
Two groups of reviewers independently evaluated eligible studies and recorded the following data: the first author, publication year, country of origin, study design, studied disease, inclusion and exclusion criteria, study sample size, the number of AI-IMD patients, female percentage, mean (SD)/median [IQR] of age, flare or relapse or exacerbation and its percentage, and the type of vaccine.Any disagreement in data extraction was resolved by consensus or consultation with a third expert.

Quality assessment
The National Institutes of Health (NIH) quality assessment tool [18] was employed to assess the quality of the included studies.The scores of 11-14, 6-10, and 0-5 were considered good, fair, and poor quality, respectively.Furthermore, two independent expert reviewers assessed the included studies in terms of methodology; any conflict was resolved by consensus.

Statistical analysis
We used the 'metaprop' function and the Der Simonian and Laird random-effect model to assess the pooled effect of the prevalence of relapse, flare, or exacerbation in AI-IMD patients.A forest plot was created to depict the summary of meta-analysis findings and heterogeneity.The funnel plot and Egger's regression tests were used to screen for publication bias, with a p-value of < 0.05 regarded to suggest probable publication bias.Cochrane's Q statistic was used to assess between-study heterogeneity.I 2 was used to assess between-study heterogeneity, with values of 0 representing no heterogeneity, and 25, 50, and 75% representing low, medium, and increasing heterogeneity, respectively.All computations and visualizations were carried out using R version 4.2.1 (R Core Team [2020].R: A language and environment for statistical computing.R Foundation for Statistical Computing, Vienna, Austria).We used the following packages: "meta" (version 4.17-0), "metafor" (version 2.4-0), "dmetar" (version 0.0-9), and "tidyverse" (version 1.3.0).All forest and funnel plots were designed using R. A p-value of < 0.05 was considered statistically significant.
Regarding the publication bias, Egger's test did not corroborate funnel plot asymmetry as well as the illustrated funnel plot (p-value = 0.27, Fig. 3).

Subgroup analysis By vaccine category
Considering the administered vaccine category as mRNA, vector-based, and inactive vaccines, we carried out a subgroup analysis consisting of 47, 10, and 15 observations, respectively.AI-IMD patients administering mRNA, vector-based, and inactive vaccines showed 8.13% (95% CI 5.6%; 11.03%, test of heterogeneity: I 2 = 98.1%), 0.32% (95% CI 0.0%; 4.03%, test of heterogeneity: I 2 = 93.5%),and 3.07% (95% CI 1.09%; 5.9%, test of heterogeneity: I 2 = 96.2%)relapse, flare, or exacerbation, respectively (Fig. 4a; Table 2).Overall, a p-value of 0.0086 demonstrated a significant statistical difference in the prevalence of relapse, flare, or exacerbation between these three vaccine categories.Of note, some studies utilized a mixture of vaccine platforms, and accordingly, they were not eligible to enter as an observation in the proposed subgroup meta-analysis.Additionally, the results of the pair-wised analysis of the vaccine category are stated in Table 2, showing that only mRNA vs. inactivated vaccine platforms have a statistically significant difference in the prevalence of relapse, flare, or exacerbation.

By disease category
The sample sizes of the included studies in the present systematic review and meta-analysis were heterogenous as they were as follows: rheumatic and musculoskeletal, gastroenterologic, dermatologic, neurologic, nephrologic, and hematologic disorders.To deal with the existing heterogeneity due to the disease category of the participants, we aimed to perform a subgroup metaanalysis based on their disease types.Fig. 2c and Table 2 show the proportion of relapse, flare, or exacerbation in each disease category, along with the number of observations.As illustrated, nephrologic disorders had the highest relapse, flare, or exacerbation prevalence.Thereafter, hematologic, gastroenterologic, and rheumatic disorders showed 14.12%, 7.86%, and 7.25% relapse, flare, or exacerbation, respectively.Moreover, dermatologic and neurologic disorders exhibited to have the lowest crude prevalence of relapse, flare, or exacerbation at 4.81% and 2.62%, respectively.The prevalence of relapse, flare, or exacerbation was statistically significantly different across the six disease categories overall, as shown by a p-value of < 0.0001.Table 2 shows complete statistical indices for this meta-analysis.

Quality assessment of included studies
Quality assessment of the included studies is presented in Additional file 1: Table S1.The majority of the studies (n = 65) were of good quality and 9 had fair quality.

Discussion
Our findings confirm the minimal risk (6.28%) of relapse/ flare/exacerbation in AI-IMD patients after vaccination against COVID-19.This risk was minimal in patients with neurologic or dermatologic autoimmune diseases or who were vaccinated with vector-based vaccines.
Although there is a risk of relapse/flare/exacerbation after COVID-19 vaccination, several studies have shown higher rates of relapse/flare of underlying AI-IMD after COVID-19 [93,94].The risk of post-COVID-19 flare in patients with IBD and Takayasu arteritis was 9.8% and 28.5%, respectively.Besides, the risk of flares after COVID-19 and vaccination in patients with MS was 12.8% and 7.7%, respectively, confirming the lower risk of flare after vaccination compared to COVID-19.Of note, COVID-19-related morbidity and mortality are significantly higher in unvaccinated AI-IMD patients [95,96].Putting all together, vaccination against SARS-CoV-2 in AI-IMD patients not only minimizes post-COVID-19 morbidity and mortality but also has a lower risk of flare compared to infection.
The impact of COVID-19 on the immune system is significant, highlighting the development of autoantibodies in infected individuals.Notably, patients with COVID-19 have been reported to develop antinuclear antibodies (ANA) with a "nucleolar" immunofluorescence pattern, a recognized marker of scleroderma with interstitial lung disease.This association is particularly observed in individuals with more severe pulmonary conditions [97,98].Additionally, the development of other autoantibodies, such as anti-platelet factor 4 (anti-PF4), is related to COVID-associated immune thrombocytopenia [99].The exploration of these autoantibodies contributes to a better understanding of the immunological dysregulation associated with COVID-19.
All-cause costs at 90 days after severe SLE flare is reported to be $27,468 in the United States in 2021 [100].Besides the complications the patients will experience, the vaccination will decrease the burden on the healthcare system by minimizing both SARS-CoV-2 infection and disease relapse-related hospitalization and diagnostic and therapeutic costs.Hence, international vaccination protocols should recommend booster vaccines for this vulnerable population.
Although all vaccine types showed a low risk of flare/ relapse/exacerbation in AI-IMD patients, patients who received vector-based vaccines less experienced flare/ relapse/exacerbation.The mechanism of immunity induction is different in mRNA and vector-based vaccines, especially in AI-IMD patients [5].Induced IgG and neutralizing antibodies are more pronounced after mRNA priming, whereas cellular immunity (CD4 and CD8 T cell levels) were higher after vector priming [101].This more prominent humoral response after mRNA vaccination might be the main reason for the higher relapse rate following this vaccine type.
Our findings support the continued vaccination in AI-IMD patients and provide safety information for SARS-CoV-2 vaccines.We believe that the benefits of vaccination greatly outweigh the risks and are vital in controlling the pandemic.We recommend physicians strictly follow the patients with AI-IMD after vaccination to ensure timely diagnosis of potential flare/relapse to maximize the patient's outcome.In addition, the scarcity of data in some groups such as nephrology diseases might lead to statistically significant results; though its clinical significance needs more robust evidence.Of note,  the booster dose administration in patients who experienced relapse/flare after any SARS-CoV-2 vaccine dose should be investigated more.Lastly, we excluded articles not written in English and did not search grey literature reducing the analysis efficiency.

Conclusion
In conclusion, the risk of flare/relapse/exacerbation in AI-IMD patients is found to be minimal.Vaccination against COVID-19 is recommended in this population, especially with vector-based vaccines.

Fig. 1
Fig.1Study selection process according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline.After evaluating the total of 595 studies, 74 studies met the eligibility criteria and used in qualitative and quantitative analyses

Fig. 2
Fig. 2 Forest plots representing the prevalence of relapse, flare, or exacerbation in all patients with autoimmune and immune-mediated diseases (AI-IMD) before (A) and after (B) removing the outliers and based on the type of AI-IMD disease (C) following the COVID-19 vaccination.The prevalence of relapse, flare, or exacerbation was statistically significantly different across the six disease categories overall, as shown by a p-value of < 0.0001

Fig. 3 Fig. 4
Fig. 3 Funnel plots before (A) and after (B) removing the outliers representing no publication bias

Table 1
Details of the data presented by the included studies

Table 2
Results of between-group meta-analyses based on type of vaccine and disease categoryStatistically significant values (p < 0.05) are in bold