Inactivated SARS-CoV-2 vaccine does not increase the risk of relapse in patients with clinically inactive adult-onset Still’s disease

Abstract

Introduction

Adult-onset Still’s disease (AOSD) is a rare polygenic systemic autoinflammatory disorder of unknown aetiology. The pathogenesis of AOSD is associated with excessive macrophage and neutrophil activation by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), leading to an overproduction of pro-inflammatory cytokines, including IL-1β, IL-6, IL-18 and TNF-α [1]. It is possible that SARS-CoV-2 vaccines may act as PAMPs and may thus promote inflammation through the activation of Toll-like receptor pathways, leading to cytokine overproduction and immune cell activation, all of which have been associated with AOSD pathogenesis [1].

Given the ongoing coronavirus disease 2019 (COVID-19) pandemic, vaccination against SARS-CoV-2 is a powerful tool for the prevention of infection and the reduction of severe cases in the general population. Although vaccination is strongly recommended in patients with autoimmune inflammatory rheumatic diseases (AIIRDs) [2], there is little available evidence on the safety of SARS-CoV-2 vaccines in patients with AOSD, as the latter have mostly not been included in clinical trials. In addition, there have been several reports in the past 2 years of new onset or flares of AOSD after SARS-CoV-2 vaccination, with one patient even developing life-threatening macrophage activation syndrome [3–8]. These reports have raised the issue of whether SARS-CoV-2 vaccines can be safely recommended for patients with inactive AOSD [9]. However, more data are required to understand the impact of the vaccines on AOSD disease activity.

Here, we report on a prospective observational cohort study to evaluate the safety of vaccination with inactivated SARS-CoV-2 vaccines in patients with inactive AOSD.

Patients and methods

Study design and population

We conducted a prospective observational cohort study in patients with inactive AOSD in the Department of Rheumatology and Immunology, Ruijin Hospital, China. The study was conducted between 1 March 2021, and 1 June 2022. Patients who had been diagnosed with AOSD according to the Yamaguchi criteria [10] and in whom the disease had remained inactive for at least 3 months off glucocorticoid or on low-dose glucocorticoid (equivalent to prednisolone ≤7.5 mg daily) were recruited. The exclusion criteria included recent SARS-CoV-2 infection, a medical history of allergic reactions after previous vaccinations, and pregnancy. A total of 122 patients were finally enrolled and provided written informed consent to participate (Supplementary Fig. S1, available at Rheumatology online). This study was approved by the Institutional Research Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China, and was performed in compliance with the Declaration of Helsinki with written informed consent from the subjects.

Study variables

Patients without disease-related symptoms (such as fever, inflammatory arthralgia or arthritis, suggestive skin rash, myalgia, and sore throat) were considered clinically inactive. The definition of relapse in this study was as previously described [11]: specifically, the presence of at least two AOSD-related symptoms together with elevated levels of inflammatory indicators such as CRP, ESR, and ferritin, requiring treatment adjustment. Relapse was confirmed by senior rheumatologists after the exclusion of infection, allergy, or other unrelated conditions. Adverse reactions to the SARS-CoV-2 vaccine were classified into localized or systemic reactions. Localized reactions included pain, redness, itching, swelling, or tenderness at the injection site. Systemic reactions included fever, chills, headache, sore throat, fatigue, nausea, vomiting, diarrhea, joint pain, myalgia, and rash. The severity of the adverse reactions was classified as mild (did not interfere with daily activity), moderate (interfered with daily activity), or severe (required urgent medical attention or medications).

Data collection

Data on demographics, comorbidities, and clinical characteristics were collected at the time of recruitment. Due to the pandemic control policies and difficulties in visiting clinics on schedule, disease activity was primarily assessed by telephone interview or live chat. The participants were asked to contact the investigators promptly if they suffered from disease-related unwellness during the follow-up period and to inform the investigators as soon as they got vaccinated. After SARS-CoV-2 vaccination, the occurrence of localized and systemic adverse reactions within 1 week of receiving the vaccine was recorded. If individuals reported an adverse reaction to the vaccine, they were asked to rate the severity of the reaction. At the end of the study, all the participants were interviewed to evaluate the occurrence of relapse during the follow-up period.

Statistical analysis

Categorical variables were presented as frequencies (%) and were compared using the χ² test or Fisher’s exact tests. Continuous variables were represented as medians (IQR) and compared using the Mann–Whitney U test or independent t test as appropriate. A 1:1 propensity score matching (PSM) method was used to compare the relapse rate between vaccinated and unvaccinated patients matched by age, sex, and disease course, with a match tolerance of 0.02. A two-sided P-value of <0.05 was considered statistically significant. All analyses were performed using SPSS software (Version 26.0).

Results

Baseline characteristics

A total of 122 patients with AOSD were finally included in the study. Of these, 56.6% (n = 69) of patients volunteered to receive the inactivated SARS-CoV-2 vaccine, while 43.4% (n = 53) of patients were hesitant or unwilling to do so. The patients came from different areas in China and could thus have received advice about vaccination from distinct general practitioners. As a result, 7.4% (n = 9) of patients failed to receive the first dose due to the advice of general practitioners related to safety concerns for patients with AOSD. In all, 49.2% (n = 60) of the patients received the inactivated SARS-CoV-2 vaccine (Supplementary Fig. S2, available at Rheumatology online).

Demographics and medication usage were found to be comparable between vaccinated and unvaccinated participants (Table 1). The common therapeutic regimens included conventional synthetic DMARDs (vaccinated: 56.7%; unvaccinated: 67.7%) and glucocorticoid therapy (vaccinated: 28.3%; unvaccinated: 33.9%) in both groups. However, vaccinated patients exhibited longer disease durations than unvaccinated patients [55.1 (37.2, 72.3) vs 44.1 (32.8, 54.3) months, P = 0.005]. After PSM matching, all the baseline variables were found to be well balanced.

Incidence of relapses and disease characteristics

Among the vaccinated patients, 13.3% (n = 8) had elevated levels of inflammatory indicators, 6.7% (n = 4) had treatment adjustment due to flares of AOSD, and 5% (n = 3) were considered to have relapsed. The most common symptoms observed were inflammatory arthralgia and/or arthritis (13.3%). Among the unvaccinated patients, 6.5% (n = 4) reported relapse, 16.1% had elevated inflammatory indicator levels (n = 10), and 6.5% (n = 4) had treatment adjustment due to disease flares, while the most common symptoms were rash (12.9%) and arthralgia (12.9%). The incidence of relapse and occurrence of AOSD-related symptoms did not increase in vaccinated patients after the matching (Table 2, Supplementary Fig. S3, available at Rheumatology online).

Of the three patients in the vaccinated group who relapsed, all relapses occurred more than 1 month after the final vaccine dose, with two relapses occurring approximately 6 months after the last dose. The patients who relapsed after vaccination mainly presented with arthralgia and rash, both of which were relieved by treatment with low-dose prednisolone and/or conventional DMARDs.

Local and systemic adverse reactions

The participants were asked to report both localized and systemic adverse reactions within 7 days after the first SARS-CoV-2 vaccine dose (D1), the second dose (D2), and the third dose (D3) (Supplementary Table S1, available at Rheumatology online).

A total of 25% (n = 15) of patients reported adverse reactions after vaccination. The most frequent local adverse reaction was pain at the injection site (10.0%), while the most common systemic adverse reactions were joint pain (5.0%) and myalgia (3.3%). Adverse reactions that interfered significantly with daily activities were uncommon, and no severe reaction was reported.

Discussion

A recent study reported a series of cases of new onset or flares in rheumatic diseases after vaccination against SARS-CoV-2, of which the most common manifestations were related to inflammatory arthritis (n = 12, 40.0%), rheumatic polymyalgia (n = 10, 33.3%) and adult-onset Still’s disease (n = 4, 13.3%). These results aroused concern, due to a possible relationship between auto-inflammatory conditions and vaccination [12].

In this study, we evaluated the impact of vaccination with inactivated SARS-CoV-2 vaccines on disease activity in patients with inactive AOSD and identified no increased risk of relapse compared with unvaccinated patients. No incidents of severe relapse or hospitalization were reported. Local and systemic reactions were found to be mild and self-limiting. These findings are consistent with those of a previous study on immune-mediated inflammatory diseases (IMIDs) involving patients with AOSD (n = 24) that showed an acceptable safety profile for SARS-CoV-2 vaccination [13]. Overall, severe vaccine-related adverse reactions were rare, and there was no significantly increased risk of relapse observed after receiving inactivated SARS-CoV-2 vaccines in clinically inactive AOSD patients.

Over 10 cases with new-onset AOSD or flares in AOSD have been reported within the past 2 years. Indeed, four of these patients had been previously diagnosed with AOSD and found to develop flares less than 1 month after the last dose of the SARS-CoV-2 vaccine [3–6]. Of these patients with flares, one was mild, while the other three required hospitalization and were treated with intravenous corticosteroids and biologic agents. Interestingly, Knabl and colleagues conducted a transcriptomic analysis of a patient who experienced disease flares both before and after vaccination, observing that the vaccination seemingly activated the type I IFN pathway as well as multiple inflammatory mediators [3]. However, we found no relapse within 1 month after receiving inactivated SARS-CoV-2 vaccines. The risk of relapse after vaccination thus appears to be tolerable. Consistent with these results, it has been reported that post-vaccination disease activity also remained stable in most patients with familial Mediterranean fever, the most common hereditary autoinflammatory disease [14]. It should be noted that, in our study, all the participants were clinically inactive for a long period of time, and some of them were still taking low doses of steroids or DMARDs, which might have reduced the risk of relapse even when they were exposed to potential triggers. In addition, the inactivated SARS-CoV-2 vaccines may help to provide the anticipated protective antibodies and regulate T cell response while avoiding triggering disease flares compared with mRNA vaccines.

This is the first prospective study evaluating the risk of relapse in patients with AOSD after receiving inactivated SARS-CoV-2 vaccines. However, there are several limitations associated with this study. First, vaccination was not randomized among these participants, which may have introduced bias, although we performed PSM to reduce bias. In addition, the participants in the study cohort received vaccines containing inactivated SARS-CoV-2, which cannot be generalized to other vaccine types. Specifically, further studies on the safety of mRNA vaccines may be warranted. In addition, long-term follow-up is required to reveal the possible association between SARS-CoV-2 vaccination and the risk of relapse in these patients.

Overall, our results demonstrated that vaccination with inactivated SARS-CoV-2 did not lead to an increased risk of relapse in patients with inactive AOSD, and serious vaccine-related adverse reactions were rare. These findings may help to overcome vaccine hesitancy and increase vaccine confidence among AOSD patients. Thus, vaccinations should not be withheld because of misguided fears of precipitating AOSD flares, and patients should be provided with proper advice about the benefits of vaccination.

Supplementary material

Supplementary material is available at Rheumatology online.

Data availability statement

The data underlying this article will be shared on reasonable request to the corresponding author.

Contribution statement

All authors made substantive intellectual contributions during the study. H.C. has full access to all the data included in this article and takes responsibility for the integrity of the data and the accuracy of the analyses. All authors approved the final version of the manuscript. Substantial contributions to the conception or design of the work: H.C., J.T., X.H., C.Y. and H.P.; acquisition of data: X.H., H.C., Y.Su, Y.Sun, H.L., X.Cheng, J.Y., H.S., Q.H., J.M., Z.Z., J.J., T.L., M.W., F.W., X.Chen, Z.T., Y.M., H.Z., Y.Y., D.Z. and L.C.; analysis and interpretation of data: X.H., H.C. and H.P.; drafting the work and revising it critically for important intellectual content: X.H., H.C., J.T. and C.Y.

Funding

This work was supported by the National Natural Science Foundation of China (82101883, 82171769), the Shanghai Sailing Program. (21YF1426300) and Shanghai Science and Technology Innovation Action (20Y11911500).

Disclosure statement: The authors have declared no conflicts of interest.

References

Author notes