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MINI REVIEW article

Front. Immunol., 04 July 2022
Sec. Vaccines and Molecular Therapeutics

The Flare of Rheumatic Disease After SARS-CoV-2 Vaccination: A Review

Yan XieYan Xie1Yang LiuYang Liu2Yi Liu*Yi Liu1*
  • 1Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
  • 2Tsinghua Clinical Research Institute (TCRI), School of Medicine, Tsinghua University, Beijing, China

As the coronavirus disease 2019 (COVID-19) pandemic continues worldwide, vaccination has been considered an effective measure to protect people from the COVID-19 and end the pandemic. However, for patients with rheumatic diseases (RD), concern for the induction of RD flare may combat the enthusiasm for vaccination. In general, current evidence doesn’t support the increased risk of disease flare after COVID-19 vaccination. However, the disease flare of RDs may be triggered by COVID-19 vaccinations, especially for patients with high disease activity. Most of these flares after vaccination are mild and need no treatment escalation. Considering the benefits and risks, RD patients are recommended to receive the COVID-19 vaccination but should be vaccinated when the RDs are in stable states.

The coronavirus disease 2019 (COVID-19), caused by infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has generated more than five million deaths worldwide (1). As there are still more than a million new cases confirmed daily, the COVID-19 pandemic remains a global threat to humanity (1). To end the pandemic, vaccination has been considered an effective measure. For patients with rheumatic diseases (RD), the American College of Rheumatology (ACR) recommended a priority of receiving vaccination based on the possibility of increased infection risk and severe outcomes of COVID-19 (2, 3). However, a recently published high-quality meta-analysis revealed that patients with RD do not face more risk of contracting SARS-CoV-2 or worse prognosis of COVID-19, which may partly combat the enthusiasm for vaccination in these patients (4).

Besides, many patients may also refuse or hesitate to be vaccinated mainly due to safety concerns, especially the risk of RD flare or relapse after vaccination (5). Thus, understanding the association between disease flare of RD and vaccination is essential to overcome vaccine hesitancy and increase the protection rate.

Theoretically, the risk of disease flare or worsening for RD patients does exist after COVID-19 vaccination. Infectious agents are always considered environmental triggers of autoimmunity for autoimmune diseases (6). The SARS-CoV-2 infection also shares similar molecular networks with RDs and triggers cross-reactivity through molecular mimicry, leading to autoimmunity (7). Vaccines, which contain antigens from these infectious agents, may also induce autoimmunity by similar mechanisms such as molecular mimicry, epitope spreading, bystander activation, and polyclonal activation (8). Except for antigens, adjuvants in the vaccine can also induce autoimmunity through various mechanisms (8, 9). To date, three types of vaccines, including messenger RNA (mRNA) vaccine, adenovirus-based vaccine, and inactivated vaccine, are generally available in different countries (10). The mRNA can serve as both immunogen and adjuvants for mRNA vaccines, stimulating innate immunity by activating the endosomal and cytosolic pattern-recognition receptors (PRRs) (11). For an adenovirus-based vaccine, the DNA contained in the virus particle can also stimulate the PRRs (11). The activated PRRs, such as the toll-like and RIG-I-like receptors, can subsequently trigger the intracellular signaling cascades, leading to inflammasome activation and type I interferon production (12). The implication of the type I interferon pathway has been shown in many rheumatic diseases, such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatic arthritis (RA) (13). Therefore, the interactions between the immune responses to vaccination and RDs raise the concern that vaccination may induce disease flares. A study conducted by Ntouros et al. found that the mRNA vaccine against SARS-CoV-2 can lead to a transient increase of DNA damage via oxidative stress. Compared with healthy volunteers, significantly increased DNA damage formation and impaired repairing capacity were observed in SLE patients (14). The augmented DNA damage accumulation can induce autoantibody production and type I interferon-induced immune activation, which may finally facilitate the progression of systemic autoimmune diseases (15).

Flare Rate

Some observational studies have reported the flare rate of RDs after COVID-19 vaccination, ranging from 0.4% to 20% (1637) (Table 1). A meta-analysis of these studies revealed that the overall random-effects rate of flare after COVID-19 vaccination was 7% (95%Cl, 5%-9%; P=0.000) in RDs patients. Not surprisingly, a high level of heterogeneity existed for this result (P=0.000, I2 = 97.4%) (Figure 1).

TABLE 1
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Table 1 Summary of studies on a flare-up of RDs after COVID-19 vaccination.

FIGURE 1
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Figure 1 Total flare rate of rheumatic disease after COVID-19 vaccination.

Flare Rate in Different Vaccine Types, Doses, and Diseases

Vaccine Type

As the type of vaccine used in different studies varied, a question of whether the heterogeneity came from the difference in vaccine types was raised. Results of our meta-analysis revealed similar flare rates of RDs after mRNA vaccination and after adenovirus-based vaccination, which were 7% (95%Cl, 5%-9%; P=0.000) and 8% (95%Cl, 4%-12%; P=0.000), respectively (Supplementary Materials). Pinte et al. made direct comparisons between several different mRNA and adenovirus-based vaccines, finding no difference in terms of flare-up development (p=0.43) (25). Only 37 patients in this study received adenovirus-based vaccination, while the number of patients receiving mRNA vaccination was 371; the huge distinction in sample sizes raises the concern of unreliability. Another study conducted by Sattui et al. involved 2132 RD patients who received mRNA vaccination and 695 RD patients who received adenovirus-based vaccination. In this study, the flare rate was also similar between the two groups (28). On the other hand, a multivariable logistic regression analysis conducted by Rider et al. found that adenovirus-based vaccine was associated with higher flare risk relative to mRNA vaccine (OR1.44, 95% Cl 1.08-2.48) (29). The results of Ozdede et al. also supported this (32). As for comparing mRNA and inactive vaccines, neither showed any prone to disease flare, as similar flare rates between the two groups were observed (22, 32). Notably, most studies involved are about mRNA vaccine, and data relevant to the flare rate of RDs after inactive and adenovirus-based vaccination are still minimal.

RD Type

Different RDs can have different risks of disease flare. SLE, the typical representative of RDs, showed a flare rate ranging from 3% to 20% (16, 19, 21, 29, 31). Patients with RA, another common RD, shared similar flare rates in several studies (11.3% vs. 9.4% vs. 7.8%) (19, 21, 35). Interestingly, a generally lower frequency of flare in inflammatory arthritis compared to systemic RDs (like SLE and Behcet’s disease) was observed in the study of Fan et al. In their research, the flare rates of RA and psoriatic arthritis were 9.4% and 3.9%, respectively. In comparison, the flare rate of SLE and Behcet’s disease were 10.6% and 11.5%, respectively (19). However, this condition didn’t match the results of some other studies. In a study that involved 126 RD patients, only three patients experienced disease flare after vaccination, all of whom were diagnosed with inflammatory arthritis (27). In another study, the flare rate of inflammatory arthritis was comparable with that of systemic RDs, including SLE, SSc, Sjogren’s syndrome, and myositis (21).

Vaccine Schedule

For RD patients, protocolized two-dose vaccination schedules are needed, as the immune responses to the first dose of COVID-19 vaccine were poor due to their immunosuppressive status (38). However, in the general population, some observational studies have reported a higher prevalence of side effects after the second vaccination, especially the systemic side effects (39, 40). This condition also fits the results in RD patients (41). As for the risk of flare, most studies reported a higher risk after the second dose, while only two studies observed opposite results (16, 18, 21, 22, 2426, 34, 35). Besides, the sample sizes of the two studies with conflicting results were both limited. Combining with that patients who have experienced flares would always refuse to continue the vaccination, these results may reveal that patients without flares after the first vaccination would also experience RD flares after the second vaccination, and this risk may be even higher. Notably, Zavala-Flores et al. revealed a higher level of RD relapse after the second dose of vaccination for patients who had experienced flares between the two doses (16). Thus, continuing the vaccination schedule may not be recommended for these patients.

Presentation of Flare

The flare of RDs after COVID-19 vaccination predominantly presented as joint pain, stiffness, and swelling, especially for inflammatory arthritis (16, 17, 19, 21, 26, 27, 31, 32). For SLE, except for arthritis, cutaneous and mucosal manifestations, such as malar erythema, and alopecia, were also common (16, 19, 22, 26, 31). Besides, fatigue and myalgia are commonly seen in patients with flare (21, 26, 31, 32). Several studies also reported various uncommon manifestations in different types of RD patients, such as lupus pneumonitis, leukopenia, myopericarditis, Raynaud’s syndrome, and nasal ulcer (16, 21, 22).

Most flares happened quickly after the COVID19 vaccination and were presented persistently within the first week. Barbhaiya et al. reported that only 10.9% of flares occurred later than seven days after the vaccination, while 27.7% and 61.4% of flares occurred within one day and 2-7 days after vaccination, respectively (26). Visentini et al. obtained similar results, as 83% of the flare occurred within seven days (20). In the study of Zavala-Flores et al., the average time interval between vaccination and flare was only 2.3 days (16). This time interval seems longer in the results of Connolly et al., in which the average days from the first dose of vaccination to flare rise to 6.4 (median 5, interquartile range 2-12) (21). Interestingly, this number raised to 11.4 (median 11, interquartile range, 3-20) between the second vaccination dose to flare (21).

For the severity of the flare, most patients resolved shortly after the onset (always within seven days) (16, 26, 35). Although the average resolve time in the study of Connolly et al. was up to 13 days, some patients with mild flares may not be included and extended the time to resolve, based on the fact that only flares requiring treatment were defined as involved in this study (21). On the other hand, some studies have noted that only a small part of the RD patients with flares after COVID-19 vaccination need treatment adjustment. Fan et al. found that the flare rate of disease after inactivated COVID-19 vaccination was 10%. However, less than 4% of patients required treatment escalation, much fewer comparing to the number of flare rates (19). Sattui et al. also observed a similar tendency, as flares of RDs were reported by 13.4% of patients, with only 4.6% requiring a new or increased dose of medication to treat the flare (28). In addition, the proportions of patients requiring hospitalization were even less. In the study of Zavala-Flores et al., only 10% of the SLE patients with flares needed hospitalization (16). Another study reported 151 patients with flares after vaccination, in which only 35 patients required treatment escalation, and the percentage of hospitalization even dropped to zero (21). Based on these, most of the flares after COVID-19 vaccination were mild or moderate; only a small part of the RD patients with the flare was severe. The results of Barbhaiya et al. also supported this. It founded that only 15.4% of the patients with flare reported severe symptoms after the first dose of COVID-19 vaccination, and this percentage decreased to 10.6% after the second dose (26). Besides, some studies analyzed disease activity before and after vaccination and found no significant change in the overall disease activity of RDs, thus indirectly providing evidence of non-significant flare-up (23, 34, 4147).

Risk Factors and Protective Factors for Flare

Disease Activity

In 2019, the European League Against Rheumatism (EULAR) recommended that vaccination in patients with RDs should be promoted during a quiescent state of disease to avoid flare-ups and favor a good immune response (48). For COVID-19 vaccination, Fan et al. also demonstrated that the disease under reasonable control was the protective factor for self-reported disease flare only (19). However, many RD patients with moderate-high disease activity also received the vaccination due to the severe pandemic, and an increased risk of side effects after vaccination was observed in these patients (18). Besides, RD patients with flare history within one year were consistently associated with an increased risk of flare after COVID-19 vaccination (16, 21, 25, 31). Thus, it is recommended that patients with RD are having inactive disease or low disease activity before vaccination to reduce the risk of flare (3, 48, 49).

Treatment

RD patients always need therapeutic regimens, like corticosteroids, conventional disease-modifying antirheumatic drugs (cDMARDs), and biologics, to keep the disease under control. Connolly et al. reported that patients received cDMARDs (incidence rate ratio (IRR) 0.52; 95%Cl 0.34-0.8) and biologics (IRR 0.6; 95%Cl 0.39-0.93) had lower incidences of flare (21). However, the combination of cDMARDs and biologics was associated with a higher risk of flare (IRR 1.95; 95%Cl 1.41-2.68) (21). The combination therapy may suggest the higher disease activity. However, whether it is an independent risk factor for flare is still unclear. In another study, biologics didn’t show any protection against flare, as the frequency of flare within one month after vaccination shows no difference between the biological and non-biological group (22). As for the corticosteroid, bivariate analysis in the study of Pinte et al. revealed a positive association between taking corticosteroids and disease flare after vaccination (25). A similar tendency was also observed in Connolly’s study (21). Whether this means a higher disease activity or just a predictor of flare still needs to be determined. Notably, some guidelines recommended tapering the treatment for a short period before and after each vaccination dose to enhance immunogenicity (3, 49, 50). However, treatment discontinuation may increase the flare risk of RDs. Fragoulis et al. reported a marginal association between treatment discontinuation due to COVID19 vaccination with disease flare (24). Pinte et al. also reported a higher risk of flare in patients who stopped their treatment; even the difference didn’t reach a statistical significance (4/31 vs. 21/385, p=0.105) (25).

Moreover, a recent clinical trial observed more flares of RA (clinical disease activity index [CDAI] criteria >10) in the group of patients who discontinued methotrexate treatment (51). On the contrary, several studies also reported a similar flare frequency among the two groups (30, 32), and the overall change in disease activity didn’t show any significant difference (42). Based on these, weighing up the risk of disease flare is still needed before stopping the medication, even if there is no solid evidence that holding therapies would cause a higher risk of disease flare.

Other Factors

Rider et al. reported higher risks of flares for SLE, psoriatic arthritis, and polymyalgia rheumatica compared to RA (29), while some other studies found that the type of RDs had no significant effect on the occurrence of flares after vaccination (19, 21). However, another study also revealed an association between the flare-ups and having more than one RDs (25). As more than one RDs may associate with either higher disease activity or more complexity in immunity, the exact effect on disease flare is still unknown. Several other risk factors, like elderly, female, allergic history, previous infection of SARS-CoV-2, and serious reaction to a non-COVID-19 vaccine, were also reported (19, 21, 29), even though the evidence was weak.

Association Between Flare and Vaccination

Although some patients reported flare after vaccination, the comparison between patients with vaccination and those without vaccination didn’t reveal any significant association between vaccines against SARS-CoV-2 and flare. Li et al. conducted a study of 5493 RA patients, showing no significant association between arthritis flare and the complete vaccination of mRNA (adjusted IRR 0.86, 95%CI 0.73-1.01) or inactivated virus (adjusted IRR 0.87, 95%CI 0.74-1.02) COVID-19 vaccines (44). Connolly et al. also found that mRNA vaccine was not associated with flare (IRR 0.98, 95%Cl 0.72-1.32; p=0.9) (21). In Pinte’s study, the incidence of RDs flare in the vaccinated and non-vaccinated groups was comparable (6% versus 8%, p=0.302) (25). Besides, the two groups showed no significant difference even in the length of flare-up and the incidence-densities of flare-up (25).

The Flare Risk After SARS-CoV-2 Infection Compared to the Flare Risk After the COVID-19 Vaccination

COVID-19 vaccine and SARS-CoV-2 infection partly shared mechanisms for triggering RD relapse (7, 8). As shown above, the vaccine showed no direct association with flare, while SARS-CoV-2 infection was reported as an independent risk factor for RD flare in some studies (5254). The flare rate of RD after SARS-CoV-2 infection presented a vastly higher flare risk than that after vaccination (5258), with most flare rates being higher than 20% and some even higher than 40%. This may also encourage RD patients to receive the COVID-19 vaccination. It should be noted that only a limited number of RD patients got SARS-CoV-2 infection, and more studies are needed to reveal the actual situation.

Perspectives

In summary, current evidence does not support increased risk of disease flare in RD patients after COVID-19 vaccination. However, the disease flares of RDs may be triggered by COVID-19 vaccination, especially in patients with high disease activity. Most of these flares after vaccination are mild and need no treatment escalation. Considering the benefits and risks, RD patients should receive the COVID-19 vaccination but should be vaccinated when the RDs are in stable states.

However, it is advised that there are several critical questions remain to be answered in these patients. First, which type of vaccine should be used? Based on current evidence, there is no priority for each of the three types of vaccines from the perspective of disease flare risk. Most of the studies were mainly including patients receiving the mRNA vaccine, and the data about the inactivated and adenovirus vaccines are limited. Thus, more data on the flares after vaccination with the other types of vaccine are needed. Second, is it necessary to hold the RD medication for a short time? As the relationship between treatment discontinuation and flare is still ambiguous, it’s hard to weigh up the risk of flare-up and defect immunogenicity. Future in-depth studies should focus more on these questions to help make better choices for these patients.

Author Contributions

YX and YaL conducted the literature search, study selection and manuscript writing. YiL proposed the concept and revised the manuscript. All authors contributed to the article and approved the submitted version.

Funding

The study was funded by the post-doctoral research funding of West China Hospital, Sichuan University (Grant number 19HXBH036), and the Science & Technology Department of Sichuan Province funding project (No.2020YJ0022).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2022.919979/full#supplementary-material

References

1. World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard (2022). Available at: https://covid19.who.int (Accessed March 1, 2022).

Google Scholar

2. Grainger R, Kim AHJ, Conway R, Yazdany J, Robinson PC. COVID-19 in People With Rheumatic Diseases: Risks, Outcomes, Treatment Considerations. Nat Rev Rheumatol (2022) 18(4):191–204. doi: 10.1038/s41584-022-00755-x

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Curtis JR, Johnson SR, Anthony DD, Arasaratnam RJ, Baden LR, Bass AR, et al. American College of Rheumatology Guidance for COVID-19 Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: Version 3. Arthritis Rheumatol (2021) 73(10):e60–75. doi: 10.1002/art.41928

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Kroon FPB, Najm A, Alunno A, Schoones JW, Landewé RBM, Machado PM, et al. Risk and Prognosis of SARS-CoV-2 Infection and Vaccination Against SARS-CoV-2 in Rheumatic and Musculoskeletal Diseases: A Systematic Literature Review to Inform EULAR Recommendations. Ann Rheum Dis (2022) 81(3):422–32. doi: 10.1136/annrheumdis-2021-221575

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Boekel L, Hooijberg F, van Kempen ZLE, Vogelzang EH, Tas SW, Killestein J, et al. Perspective of Patients With Autoimmune Diseases on COVID-19 Vaccination. Lancet Rheumatol (2021) 3(4):e241–3. doi: 10.1016/S2665-9913(21)00037-0

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y. Infections and Autoimmunity–Friends or Foes? Trends Immunol (2009) 30(8):409–14. doi: 10.1016/j.it.2009.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Liu Y, Sawalha AH, Lu Q. COVID-19 and Autoimmune Diseases. Curr Opin Rheumatol (2021) 33(2):155–62. doi: 10.1097/BOR.0000000000000776

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Agmon-Levin N, Paz Z, Israeli E, Shoenfeld Y. Vaccines and Autoimmunity. Nat Rev Rheumatol (2009) 5(11):648–52. doi: 10.1038/nrrheum.2009.196

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Guimarães LE, Baker B, Perricone C, Shoenfeld Y. Vaccines, Adjuvants and Autoimmunity. Pharmacol Res (2015) 100:190–209. doi: 10.1016/j.phrs.2015.08.003

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Mistry P, Barmania F, Mellet J, Peta K, Strydom A, Viljoen IM, et al. SARS-CoV-2 Variants, Vaccines, and Host Immunity. Front Immunol (2022) 12:809244. doi: 10.3389/fimmu.2021.809244

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Teijaro JR, Farber DL. COVID-19 Vaccines: Modes of Immune Activation and Future Challenges. Nat Rev Immunol (2021) 21(4):195–7. doi: 10.1038/s41577-021-00526-x

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Takeuchi O, Akira S. Pattern Recognition Receptors and Inflammation. Cell (2010) 140(6):805–20. doi: 10.1016/j.cell.2010.01.022

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Muskardin TLW, Niewold TB. Type I Interferon in Rheumatic Diseases. Nat Rev Rheumatol (2018) 14(4):214–28. doi: 10.1038/nrrheum.2018.31

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Ntouros PA, Vlachogiannis NI, Pappa M, Nezos A, Mavragani CP, Tektonidou MG, et al. Effective DNA Damage Response After Acute But Not Chronic Immune Challenge: SARS-CoV-2 Vaccine Versus Systemic Lupus Erythematosus. Clin Immunol (2021) 229:108765. doi: 10.1016/j.clim.2021.108765

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Souliotis VL, Vlachogiannis NI, Pappa M, Argyriou A, Ntouros PA, Sfikakis PP. DNA Damage Response and Oxidative Stress in Systemic Autoimmunity. Int J Mol Sci (2019) 21(1):55. doi: 10.3390/ijms21010055

CrossRef Full Text | Google Scholar

16. Zavala-Flores E, Salcedo-Matienzo J, Quiroz-Alva A, Berrocal-Kasay A. Side Effects and Flares Risk After SARS-CoV-2 Vaccination in Patients With Systemic Lupus Erythematosus. Clin Rheumatol (2021) 16:1–9. doi: 10.1007/s10067-021-05980-5

CrossRef Full Text | Google Scholar

17. Cherian S, Paul A, Ahmed S, Alias B, Manoj M, Santhosh AK, et al. Safety of the ChAdOx1 Ncov-19 and the BBV152 Vaccines in 724 Patients With Rheumatic Diseases: A Post-Vaccination Cross-Sectional Survey. Rheumatol Int (2021) 41(8):1441–5. doi: 10.1007/s00296-021-04917-0

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Rotondo C, Cantatore FP, Fornaro M, Colia R, Busto G, Rella V, et al. Preliminary Data on Post Market Safety Profiles of COVID 19 Vaccines in Rheumatic Diseases: Assessments on Various Vaccines in Use, Different Rheumatic Disease Subtypes, and Immunosuppressive Therapies: A Two-Centers Study. Vaccines (Basel) (2021) 9(7):730. doi: 10.3390/vaccines9070730

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Fan Y, Geng Y, Wang Y, Deng X, Li G, Zhao J, et al. Safety and Disease Flare of Autoimmune Inflammatory Rheumatic Diseases: A Large Real-World Survey on Inactivated COVID-19 Vaccines. Ann Rheum Dis (2022) 81(3):443–5. doi: 10.1136/annrheumdis-2021-221736

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Visentini M, Gragnani L, Santini SA, Urraro T, Villa A, Monti M, et al. Flares of Mixed Cryoglobulinaemia Vasculitis After Vaccination Against SARS-CoV-2. Ann Rheum Dis (2022) 81(3):441–3. doi: 10.1136/annrheumdis-2021-221248

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Connolly CM, Ruddy JA, Boyarsky BJ, Barbur I, Werbel WA, Geetha D, et al. Disease Flare and Reactogenicity in Patients With Rheumatic and Musculoskeletal Diseases Following Two-Dose SARS-CoV-2 Messenger RNA Vaccination. Arthritis Rheumatol (2022) 74(1):28–32. doi: 10.1002/art.41924

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Haslak F, Gunalp A, Cebi MN, Yildiz M, Adrovic A, Sahin S, et al. Early Experience of COVID-19 Vaccine-Related Adverse Events Among Adolescents and Young Adults With Rheumatic Diseases: A Single-Center Study. Int J Rheum Dis (2022) 25(3):353–63. doi: 10.1111/1756-185X.14279

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Braun-Moscovici Y, Kaplan M, Braun M, Markovits D, Giryes S, Toledano K, et al. Disease Activity and Humoral Response in Patients With Inflammatory Rheumatic Diseases After Two Doses of the Pfizer mRNA Vaccine Against SARS-CoV-2. Ann Rheum Dis (2021) 80(10):1317–21. doi: 10.1136/annrheumdis-2021-220503

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Fragoulis GE, Bournia VK, Mavrea E, Evangelatos G, Fragiadaki K, Karamanakos A, et al. COVID-19 Vaccine Safety and Nocebo-Prone Associated Hesitancy in Patients With Systemic Rheumatic Diseases: A Cross-Sectional Study. Rheumatol Int (2022) 42(1):31–9. doi: 10.1007/s00296-021-05039-3

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Pinte L, Negoi F, Ionescu GD, Caraiola S, Balaban DV, Badea C, et al. COVID-19 Vaccine Does Not Increase the Risk of Disease Flare-Ups Among Patients With Autoimmune and Immune-Mediated Diseases. J Pers Med (2021) 11(12):1283. doi: 10.3390/jpm11121283

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Barbhaiya M, Levine JM, Bykerk VP, Jannat-Khah D, Mandl LA. Systemic Rheumatic Disease Flares After SARS-CoV-2 Vaccination Among Rheumatology Outpatients in New York City. Ann Rheum Dis (2021) 80(10):1352–4. doi: 10.1136/annrheumdis-2021-220732

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Spinelli FR, Favalli EG, Garufi C, Cornalba M, Colafrancesco S, Conti F, et al. Low Frequency of Disease Flare in Patients With Rheumatic Musculoskeletal Diseases Who Received SARS-CoV-2 mRNA Vaccine. Arthritis Res Ther (2022) 24(1):21. doi: 10.1186/s13075-021-02674-w

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Sattui SE, Liew JW, Kennedy K, Sirotich E, Putman M, Moni TT, et al. Early Experience of COVID-19 Vaccination in Adults With Systemic Rheumatic Diseases: Results From the COVID-19 Global Rheumatology Alliance Vaccine Survey. RMD Open (2021) 7(3):e001814. doi: 10.1136/rmdopen-2021-001814

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Rider LG, Parks CG, Wilkerson J, Schiffenbauer AI, Kwok RK, Noroozi Farhadi P, et al. Baseline Factors Associated With Self-Reported Disease Flares Following COVID-19 Vaccination Among Adults With Systemic Rheumatic Disease: Results From the COVID-19 Global Rheumatology Alliance Vaccine Survey. Rheumatol (Oxford) (2022) 23:keac249. doi: 10.1093/rheumatology/keac249

CrossRef Full Text | Google Scholar

30. Tzioufas AG, Bakasis AD, Goules AV, Bitzogli K, Cinoku II, Chatzis LG, et al. A Prospective Multicenter Study Assessing Humoral Immunogenicity and Safety of the mRNA SARS-CoV-2 Vaccines in Greek Patients With Systemic Autoimmune and Autoinflammatory Rheumatic Diseases. J Autoimmun (2021) 125:102743. doi: 10.1016/j.jaut.2021.102743

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Felten R, Kawka L, Dubois M, Ugarte-Gil MF, Fuentes-Silva Y, Piga M, et al. Tolerance of COVID-19 Vaccination in Patients With Systemic Lupus Erythematosus: The International VACOLUP Study. Lancet Rheumatol (2021) 3(9):e613–5. doi: 10.1016/S2665-9913(21)00221-6

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Ozdede A, Guner S, Ozcifci G, Yurttas B, Toker Dincer Z, Atli Z, et al. Safety of SARS-CoV-2 Vaccination in Patients With Behcet's Syndrome and Familial Mediterranean Fever: A Cross-Sectional Comparative Study on the Effects of M-RNA Based and Inactivated Vaccine. Rheumatol Int (2022) 4:1–15. doi: 10.1007/s00296-022-05119-y

CrossRef Full Text | Google Scholar

33. Boekel L, Kummer LY, van Dam KPJ, Hooijberg F, van Kempen Z, Vogelzang EH, et al. Adverse Events After First COVID-19 Vaccination in Patients With Autoimmune Diseases. Lancet Rheumatol (2021) 3(8):e542–5. doi: 10.1016/S2665-9913(21)00181-8

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Izmirly PM, Kim MY, Samanovic M, Fernandez-Ruiz R, Ohana S, Deonaraine KK, et al. Evaluation of Immune Response and Disease Status in Systemic Lupus Erythematosus Patients Following SARS-CoV-2 Vaccination. Arthritis Rheumatol (2022) 74(2):284–94. doi: 10.1002/art.41937

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Bixio R, Bertelle D, Masia M, Pistillo F, Carletto A, Rossini M. Incidence of Disease Flare After BNT162b2 Coronavirus Disease 2019 Vaccination in Patients With Rheumatoid Arthritis in Remission. ACR Open Rheumatol (2021) 3(12):832–3. doi: 10.1002/acr2.11336

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Firinu D, Perra A, Campagna M, Littera R, Fenu G, Meloni F, et al. Evaluation of Antibody Response to BNT162b2 mRNA COVID-19 Vaccine in Patients Affected by Immune-Mediated Inflammatory Diseases Up to 5 Months After Vaccination. Clin Exp Med (2021) 5:1–9. doi: 10.1007/s10238-021-00771-3

CrossRef Full Text | Google Scholar

37. Dimopoulou D, Spyridis N, Vartzelis G, Tsolia MN, Maritsi DN. Safety and Tolerability of the COVID-19 Messenger RNA Vaccine in Adolescents With Juvenile Idiopathic Arthritis Treated With Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol (2022) 74(2):365–6. doi: 10.1002/art.41977

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Prendecki M, Clarke C, Edwards H, McIntyre S, Mortimer P, Gleeson S, et al. Humoral and T-Cell Responses to SARS-CoV-2 Vaccination in Patients Receiving Immunosuppression. Ann Rheum Dis (2021) 80(10):1322–9. doi: 10.1136/annrheumdis-2021-220626

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Lee YW, Lim SY, Lee JH, Lim JS, Kim M, Kwon S, et al. Adverse Reactions of the Second Dose of the BNT162b2 mRNA COVID-19 Vaccine in Healthcare Workers in Korea. J Korean Med Sci (2021) 36(21):e153. doi: 10.3346/jkms.2021.36.e153

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Andrzejczak-Grządko S, Czudy Z, Donderska M. Side Effects After COVID-19 Vaccinations Among Residents of Poland. Eur Rev Med Pharmacol Sci (2021) 25(12):4418–21. doi: 10.26355/eurrev_202106_26153

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Machado PM, Lawson-Tovey S, Strangfeld A, Mateus EF, Hyrich KL, Gossec L, et al. 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 (2022) 81(5):695–709. doi: 10.1136/annrheumdis-2021-221490

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Tedeschi SK, Stratton J, Ellrodt JE, Whelan MG, Hayashi K, Yoshida K, et al. Rheumatoid Arthritis Disease Activity Assessed by Patient-Reported Outcomes and Flow Cytometry Before and After an Additional Dose of COVID-19 Vaccine. Ann Rheum Dis (2022). doi: 10.1136/annrheumdis-2022-222232. annrheumdis-2022-222232.

CrossRef Full Text | Google Scholar

43. Picchianti-Diamanti A, Aiello A, Laganà B, Agrati C, Castilletti C, Meschi S, et al. Immunosuppressive Therapies Differently Modulate Humoral- and T-Cell-Specific Responses to COVID-19 mRNA Vaccine in Rheumatoid Arthritis Patients. Front Immunol (2021) 12:740249. doi: 10.3389/fimmu.2021.740249

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Li X, Tong X, Yeung WWY, Kuan P, Yum SHH, Chui CSL, et al. Two-Dose COVID-19 Vaccination and Possible Arthritis Flare Among Patients With Rheumatoid Arthritis in Hong Kong. Ann Rheum Dis (2021) 81(4):567–8. doi: 10.1136/annrheumdis-2021-221571. annrheumdis-2021-221571.

CrossRef Full Text | Google Scholar

45. Verstappen GM, de Wolff L, Arends S, Heiermann HM, van Sleen Y, Visser A, et al. Immunogenicity and Safety of COVID-19 Vaccination in Patients With Primary Sjögren's Syndrome. RMD Open (2022) 8(1):e002265. doi: 10.1136/rmdopen-2022-002265

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Geisen UM, Berner DK, Tran F, Sümbül M, Vullriede L, Ciripoi M, et al. Immunogenicity and Safety of Anti-SARS-CoV-2 mRNA Vaccines in Patients With Chronic Inflammatory Conditions and Immunosuppressive Therapy in a Monocentric Cohort. Ann Rheum Dis (2021) 80(10):1306–11. doi: 10.1136/annrheumdis-2021-220272

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Fornaro M, Venerito V, Iannone F, Cacciapaglia F. Safety Profile and Low Risk of Disease Relapse After BNT162b2 mRNA SARS-CoV-2 Vaccination in Patients With Rare Rheumatic Diseases. J Rheumatol (2022) 49(3):334–5. doi: 10.3899/jrheum.210863

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, van Assen S, Bijl M, et al. 2019 Update of EULAR Recommendations for Vaccination in Adult Patients With Autoimmune Inflammatory Rheumatic Diseases. Ann Rheumatol Dis (2021) 79:39–52. doi: 10.1136/annrheumdis-2019-215882

CrossRef Full Text | Google Scholar

49. Moutsopoulos HM. A Recommended Paradigm for Vaccination of Rheumatic Disease Patients With the SARS-CoV-2 Vaccine. J Autoimmun (2021) 121:102649. doi: 10.1016/j.jaut.2021.102649

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Arnold J, Winthrop K, Emery P. COVID-19 Vaccination and Antirheumatic Therapy. Rheumatol (Oxford) (2021) 60(8):3496–502. doi: 10.1093/rheumatology/keab223

CrossRef Full Text | Google Scholar

51. Araujo CSR, Medeiros-Ribeiro AC, Saad CGS, Bonfiglioli KR, Domiciano DS, Shimabuco AY, et al. Two-Week Methotrexate Discontinuation in Patients With Rheumatoid Arthritis Vaccinated With Inactivated SARS-CoV-2 Vaccine: A Randomised Clinical Trial. Ann Rheum Dis (2022) 81(6):889–97. doi: 10.1136/annrheumdis-2021-221916. annrheumdis-2021-221916.

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Fike A, Hartman J, Redmond C, Williams SG, Ruiz-Perdomo Y, Chu J, et al. Risk Factors for COVID-19 and Rheumatic Disease Flare in a US Cohort of Latino Patients. Arthritis Rheumatol (2021) 73(7):1129–34. doi: 10.1002/art.41656

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Abualfadl E, Ismail F, Shereef RRE, Hassan E, Tharwat S, Mohamed EF, et al. Impact of COVID-19 Pandemic on Rheumatoid Arthritis From a Multi-Centre Patient-Reported Questionnaire Survey: Influence of Gender, Rural-Urban Gap and North-South Gradient. Rheumatol Int (2021) 41(2):345–53. doi: 10.1007/s00296-020-04736-9

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Felten R, Scherlinger M, Guffroy A, Poindron V, Meyer A, Giannini M, et al. Incidence and Predictors of COVID-19 and Flares in Patients With Rare Autoimmune Diseases: A Systematic Survey and Serological Study at a National Reference Center in France. Arthritis Res Ther (2021) 13;23(1):188. doi: 10.1186/s13075-021-02565-0

CrossRef Full Text | Google Scholar

55. Hügle B, Krumrey-Langkammerer M, Haas JP. Infection With SARS-CoV-2 Causes Flares in Patients With Juvenile Idiopathic Arthritis in Remission or Inactive Disease on Medication. Pediatr Rheumatol Online J (2021) 19(1):163. doi: 10.1186/s12969-021-00653-8

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Di Iorio M, Cook CE, Vanni KMM, Patel NJ, D'Silva KM, Fu X, et al. DMARD Disruption, Disease Flare, and Prolonged Symptom Duration After Acute COVID-19 Among Participants With Rheumatic Disease: A Prospective Study. medRxiv (2022). doi: 10.1101/2022.02.08.22270696. 9:2022.02.08.22270696.

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Ye C, Cai S, Shen G, Guan H, Zhou L, Hu Y, et al. Clinical Features of Rheumatic Patients Infected With COVID-19 in Wuhan, China. Ann Rheum Dis (2020) 79(8):1007–13. doi: 10.1136/annrheumdis-2020-217627

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Schioppo T, Argolini LM, Sciascia S, Pregnolato F, Tamborini F, Miraglia P, et al. Clinical and Peculiar Immunological Manifestations of SARS-CoV-2 Infection in Systemic Lupus Erythematosus Patients. Rheumatol (Oxford) (2022) 61(5):1928–35. doi: 10.1093/rheumatology/keab611

CrossRef Full Text | Google Scholar

Keywords: COVID-19, SARS-CoV-2, vaccine, rheumatic disease, flare

Citation: Xie Y, Liu Y and Liu Y (2022) The Flare of Rheumatic Disease After SARS-CoV-2 Vaccination: A Review. Front. Immunol. 13:919979. doi: 10.3389/fimmu.2022.919979

Received: 14 April 2022; Accepted: 30 May 2022;
Published: 04 July 2022.

Edited by:

Natasa Toplak, Univerzitetnega Kliničnega Centra Ljubljana, Slovenia

Reviewed by:

Haralampos M Moutsopoulos, National and Kapodistrian University of Athens, Greece

Copyright © 2022 Xie, Liu and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yi Liu, liuyihuaxi@126.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.