Safety and disease flare of autoimmune inflammatory rheumatic diseases: a large real-world survey on inactivated COVID-19 vaccines

COVID19 vaccines are of great importance in reducing SARSCoV2 infection and severe cases. Patients with autoimmune inflammatory rheumatic diseases (AIIRDs) have been strongly recommended to be vaccinated according to the novel guidance because they are more vulnerable to SARSCoV2 infection. However, patients with AIIRDs were largely excluded from vaccine trials, leading to very limited data on the safety of COVID19 vaccines. Notably, previous studies mainly focused on mRNA and adenovirus vector vaccines; however, little is known about inactivated COVID19 vaccines that also have been authorised by WHO and widely used in several most populated countries, for instance, China, Brazil, Turkey and Indonesia. A large randomised clinical trial consisting of 40 382 participants has demonstrated two inactivated COVID19 vaccines significantly reduced the risk of symptomatic COVID19. We conducted a realworld survey to evaluate the safety profiles and disease flare in patients with AIIRDs who received any dose of inactivated COVID19 vaccines in China. From 1 Aug 2021 to 15 Oct 2021, eligible participants completed a predefined 25questionbased questionnaire by invitation on social media or visiting the outpatient department. There was no restriction on the time interval from vaccination to completing the survey. In total, 1507 adults patients with AIIRDs who received inactivated COVID19 vaccine participated in this study (flow diagram in online supplemental figure 1). The median age of participants was 39 (IQR 31–51) years. There were 1166 (77.4%) female patients and 209 (13.9%) patients with selfidentified allergic history. Systemic lupus erythematosus (SLE) (614, 40.7%) was the most common AIIRD among participants, followed by rheumatoid arthritis (RA) (434, 28.8%), Behcet’s disease (BD, 122, 8.1%), psoriatic arthritis/psoriasis (PsA/PsO) (76, 5.0%), primary Sjogren’s syndrome (74, 4.9%) and ankylosing spondylitis (44, 2.9%) (online supplemental figure 2). Among all participants, 450/1507 (29.9%) participants experienced adverse events (AEs) after vaccination (table 1). Local AEs, such as pain, redness or swelling at injection site, were reported to occur in 287 (19.0%) participants. Meanwhile, 260 (17.3%) patients reported systemic AEs after vaccination. Fatigue or sleepless (123, 8.2%) was the most reported systemic AE, followed by headache (82, 5.4%) and skin rash (55, 3.6%). The median time from vaccination shot to onset of AEs was 2 days. Most AEs were mild to moderate and selflimiting. Overall, 28 Letter

Safety and disease flare of autoimmune inflammatory rheumatic diseases: a large realworld survey on inactivated COVID-19 vaccines COVID-19 vaccines are of great importance in reducing SARS-CoV-2 infection and severe cases. Patients with autoimmune inflammatory rheumatic diseases (AIIRDs) have been strongly recommended to be vaccinated according to the novel guidance because they are more vulnerable to SARS-CoV-2 infection. 1 However, patients with AIIRDs were largely excluded from vaccine trials, leading to very limited data on the safety of COVID-19 vaccines. Notably, previous studies mainly focused on mRNA and adenovirus vector vaccines; however, little is known about inactivated COVID-19 vaccines that also have been authorised by WHO and widely used in several most populated countries, for instance, China, Brazil, Turkey and Indonesia. 2 A large randomised clinical trial consisting of 40 382 participants has demonstrated two inactivated COVID-19 vaccines significantly reduced the risk of symptomatic COVID-19. 3 We conducted a real-world survey to evaluate the safety profiles and disease flare in patients with AIIRDs who received any dose of inactivated COVID-19 vaccines in China. From 1 Aug 2021 to 15 Oct 2021, eligible participants completed a predefined 25-question-based questionnaire by invitation on social media or visiting the outpatient department. There was no restriction on the time interval from vaccination to completing the survey.
Among all participants, 450/1507 (29.9%) participants experienced adverse events (AEs) after vaccination (table 1). Local AEs, such as pain, redness or swelling at injection site, were reported to occur in 287 (19.0%) participants. Meanwhile, 260 (17.3%) patients reported systemic AEs after vaccination. Fatigue or sleepless (123, 8.2%) was the most reported systemic AE, followed by headache (82, 5.4%) and skin rash (55, 3.6%). The median time from vaccination shot to onset of AEs was 2 days. Most AEs were mild to moderate and self-limiting. Overall, 28 (1.9%) patients self-reported severe AEs. There were only three patients who were hospitalised due to serious diarrhoea, headache and cough. No one reported AE of interests or fatal AE, including myocarditis, idiopathic thrombocytopenic purpura, anaphylactic shock or death.
Flare of existing AIIRDs was reported by 158 (10.5%) participants, with requirement of treatment escalation in 53 (3.5%)  figure 3). Multivariable logistic analyses demonstrated that elderly, allergic history was the risk factor for disease flare of their underlying AIIRDs, while stable disease of AIIRDs was the negative predictor for self-reported disease flare only (online supplemental table 1). Our data confirmed the safety profiles, and for the first time demonstrated the disease flare after inactivated COVID-19 vaccination in patients with AIIRDs. Overall, 29.9% of participants experienced AEs after vaccination and no fatal AEs occurred, indicating the well tolerability of inactivated COVID-19 vaccines in AIIRDs population. Importantly, our results aligned with a large real-world study supported by European League against Rheumatism(EULAR) COVID-19 database (83% mRNA vaccines), whose vaccine-related AEs were observed in 31% of patients. 4 Considering the possibility of over-activating immune system by adjuvanted vaccines, the stability of AIIRDs after vaccinations has been a principal concern. In this study, we found that although 1 in 10 reported a flare of disease after inactivated COVID-19 vaccination, fewer than 1 in 25 required treatment escalation. No episode of severe flare needing emergent hospitalisation was reported. Furthermore, we found elderly patients and those with allergic history were more likely to have disease flare after vaccinations. These call for important clinical needs for early warning of flare and close monitoring after vaccination. The incidence of AEs and AIIRD flares was generally comparable among all COVID-19 vaccines. 4-6 These may provide evidence for rheumatologists in critical discussion on vaccine acceptance.

Letters
Higher serum levels of short-chain fatty acids are associated with non-progression to arthritis in individuals at increased risk of RA Transition from the autoimmune to the clinical phase of rheumatoid arthritis (RA) is a critical step that is yet insufficiently understood. Identification of factors that facilitate the progression from this prodromal RA at-risk state to clinical RA may open new possibilities for preventive interventions. In this context, nutritional factors may be critical. Short-chain fatty acids (SCFAs) are intestinal microbial metabolites that result from nutritional fibre digestion and exert immune regulatory properties. 1 SCFAs have shown to effectively inhibit the onset of experimental arthritis. 2 Furthermore, serum butyrate levels decrease shortly before the onset of arthritis. 2 Whether SCFA levels may play a role in the transition from the autoimmune to the clinical phase of RA in humans, however, has not been studied to date.
To address this concept, we measured serum SCFA levels in a prospective cohort of 82 individuals with an increased risk to develop RA. 3 At inclusion, these individuals were positive for anti-citrullinated protein antibodies (ACPA) and had musculoskeletal pain but no clinical signs of arthritis (joint swelling). Baseline characteristics are shown in online supplemental table 1. Following a median follow-up of 72 months, 39 patients (48%) had developed clinical arthritis after a median of 6 months. Baseline serum samples were analysed for SCFA concentrations as previously described. 4 At-risk individuals not progressing to arthritis had significantly higher mean baseline serum levels of total SCFA (ie, the sum of acetate, butyrate, propionate or pentanoate), butyrate and acetate as compared by t-test to individuals who progressed to arthritis (figure 1). In contrast, levels of propionate and pentanoate did not significantly differ (figure 1). Univariable Cox regression analyses revealed significant association between lower total SCFA levels and progression to arthritis (p=0.029), while for the individual SCFA, we found significant associations concerning butyrate (p=0.038) and acetate (p=0.039) levels, but not regarding pentanoate or propionate (online supplemental table 2). Statistical significance remained after adjusting for age, sex, symptom duration, rheumatoid factor status, ACPA levels and CRP levels (total SCFA p=0.030; butyrate p=0.009 and acetate p=0.045, online supplemental table 2).
These data suggest that SCFA, in particular butyrate and acetate, influences the risk for the transition from the autoimmune to the clinical phase of RA. Although most p values would not remain significant after correction for multiple testing, the data are in line with previous findings in animal models 2 and thus confirm our prespecified hypothesis. As SCFAs are produced by intestinal microbiota on fermentation of dietary fibres, our findings strengthen the concept that nutritional factors could influence the onset of RA. SCFAs are critical for the barrier function