This retrospective study was performed at two large academic centers in Thailand. Study candidates were patients aged <18 years before diagnosis with rheumatic disease who had regular follow-ups before November 2022 at the Pediatric Rheumatology Clinic at the Faculty of Medicine Ramathibodi Hospital and the Faculty of Medicine Siriraj Hospital, and the Pediatric Nephrology Clinic at the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. During the COVID-19 pandemic, all patients were routinely queried about their COVID-19 infection and vaccination histories. Patients with rheumatic disease who received at least one dose of the COVID-19 vaccine or had a history of COVID-19 infection with more than 6 months of follow-up time after the last vaccine dose or COVID-19 infection were included in the study. COVID-19 infection in this study was confirmed by SARS-CoV-2 positivity using polymerase chain reaction testing, rapid antigen testing, or both. The following information was extracted from medical records: demographic data, underlying rheumatic diseases, obesity, method of SARS-CoV-2 testing, number and type of COVID-19 vaccines, symptoms, clinical course and outcomes of COVID-19 vaccination and infection, treatment of COVID-19 infection and underlying disease, medications at the time of vaccination and infection, and disease activity before and after COVID-19 vaccination and infection. Body mass index (BMI) was computed as weight (kg) divided by height squared (m²) and reported as a Z-score using World Health Organization Anthro software for children aged less than 5 years (36) and AnthroPlus software for children aged 5–19 years (37). The ethics committees of the Faculty of Medicine Ramathibodi Hospital and the Faculty of Medicine Siriraj Hospital approved this multicenter research study (COA. MURA2022/695), which was conducted under the Declaration of Helsinki. The ethical committees of the institutions waived the requirement for informed consent.

During the follow-up visit, the Juvenile Arthritis Disease Activity Score-27 (JADAS-27) (38) was used to assess disease activity in patients with JIA. We used the SLE Disease Activity Index 2000 (SLEDAI-2K) (39) to measure SLE disease activity. We used disease-specific criteria to define inactive disease status: Wallace's criteria for JIA (40), the clinical SLEDAI-2K (cSLEDAI-2K) for SLE, excluding anti-double-stranded DNA and complement, and equal to zero regardless of medication (41), Pediatric Rheumatology International Trials Organization criteria for juvenile dermatomyositis (JDM) (42), and the Pediatric Vasculitis Activity Score for primary systemic vasculitis (43, 44). In other rheumatic diseases, the treating expert clinician defined the inactive condition. Remission status was defined as inactive status for at least 1 year regardless of medication.

Flare after COVID-19 vaccination or COVID-19 infection was defined as a flare that occurred within 3 months of receiving any dose of COVID-19 vaccination or having COVID-19 infection with no other flare-related factors. A flare was diagnosed if patients had new or worsening signs of underlying rheumatic disease without de-escalating concurrent medication. Flare severity was described as follows: (1) mild, self-limiting, or did not require escalation of medication; (2) mild to moderate, requiring an increase in the dosage of corticosteroids or immunosuppressants; and (3) severe, requiring an increase in dosages of both corticosteroids and immunosuppressants or biological agents. In our centers, we routinely adjusted medication after COVID-19 immunization during non-active status in accordance with The American College of Rheumatology recommendation (45). However, patients who did not receive the COVID-19 vaccine from our hospital may not have adjusted their medications after receiving the COVID-19 vaccination.

We used IBM SPSS statistics 25 software (IBM Corp., Armonk, NY, USA) and GraphPad Prism 8.3 software (GraphPad Software Inc., La Jolla, California, USA) for data analyses. Continuous variables were presented as mean and standard deviation and categorical variables were presented as numbers and percentages. Non-normally distributed variables were expressed as the median and interquartile range (IQR). The Student t-test (unpaired data) or pair t-test (paired data) was used to compare two groups with continuous data. Categorical data were compared using the χ² test or Fisher exact test. The probabilities of flare and inactive disease after flare from COVID-19 vaccination were analyzed using the Kaplan–Meier method with the log-rank test. Time to flare using the Kaplan–Meier method was indicated from the last dose of COVID-19 vaccination before symptoms of a flare. Predictive factors of flare and inactive disease after flare from COVID-19 vaccination were analyzed using Cox proportional hazards regression analysis, and the hazard ratio (HR) and confidence interval (CI) were provided. For statistical significance, a two-sided p-value of less than 0.05 was accepted.

A total of 479 patients with rheumatic diseases were included in the study. Around half of the patients had JIA, which the majority of these patients having enthesitis-related arthritis (ERA), followed by systemic JIA, oligoarticular (oligo) JIA, and polyarticular JIA with rheumatoid factor (RF) positive (poly-RF-pos) and negative (poly-RF-neg). Around 40% of the participants in this study had connective tissue diseases (CTDs), the majority of whom had SLE, followed by JDM and overlapping syndromes. Nearly 10% of patients had vasculitis, with IgA vasculitis being the most prevalent, followed by Takayasu arteritis. Additional details are presented in Supplementary Table S1. From a total, 315 (65.76%) were female, with a mean age of 13.81 ± 4.30 years. The mean disease duration was 4.84 ± 4.22 years. The mean dose of prednisolone was highest in patients with CTDs. Hydroxychloroquine (HCQ), azathioprine, mycophenolate mofetil, and intravenous cyclophosphamide were frequently used in these patients. Patients with JIA typically received methotrexate (MTX), sulfasalazine, and leflunomide. Most patients with rheumatic diseases in this study did not receive biological agents. Only 65 (13.57%) of patients received biological agents. The most frequently used biological agents were tumor necrosis factor-alpha inhibitors, including adalimumab, etanercept, and infliximab. Of 479 patients included, 32 (6.68%) did not receive COVID-19 vaccination. Four hundred and twenty-nine (89.56%) patients received COVID-19 vaccines after the diagnosis of rheumatic disease, whereas 15 (3.13%) received COVID-19 vaccines within 3 months of their last dose before the diagnosis of rheumatic disease. Only 3 (0.63%) patients received COVID-19 vaccines more than 6 months after their last dose before the diagnosis of rheumatic diseases. Of 479 patients, 230 (48.01%) had no history of COVID-19 infection. Of 249 patients with confirmed COVID-19 infection, 245 (98.39%) had COVID-19 infection after the diagnosis of rheumatic diseases, and 4 (1.61%) had COVID-19 infection before the onset of rheumatic diseases. Most patients received the mRNA vaccines and two doses of COVID-19 vaccination. Additional information regarding the patient characteristics of this study is shown in Table 1.

Among 429 patients who received at least one dose of COVID-19 vaccination after having rheumatic diseases, most patients did not have side effects, with around 12% developing a fever and only 5% having pain at the injection site. The details of the side effects of the COVID-19 vaccination in each disease type are provided in Supplementary Table S2. There was no statistical difference between vaccine-associated side effects on the type of disease (p = 0.970) and the treatment (high-dose vs. low-dose prednisolone; p = 0.091). After receiving COVID-19 vaccination, 46 (10.72%) patients developed a disease flare-up (Table 2). Rheumatic diseases in patients with flare included JIA (24; 52.17%), including 2 (8.33%) patients with OligoJIA, 2 (8.33%) with poly-RF-neg, 3 (12.50%) with poly-RF-pos, 12 (50.00%) with ERA, 4 (16.67%) with systemic JIA, and 1 (4.17%) with psoriatic arthritis. Nineteen (41.30%) patients with CTDs had flare, including 17 (89.47%) with SLE and 2 (10.53%) with JDM. Two (4.35%) patients with vasculitis developed a Behçet's disease (BD) flare-up, and one (2.17%) patient had immune-mediated necrotizing myopathy.

When we classified patients into flare and non-flare groups, we observed that age, sex, BMI Z-scores, and disease duration before receiving the first COVID-19 vaccination were comparable across the two groups. Substantially distinct frequencies of disease status were observed in the flare and non-flare groups before the first dose of COVID-19 vaccination was received. The vaccine type was the mRNA vaccine, and patients frequently received two to three vaccine doses. Most side effects occurred after receiving the first dose of COVID-19 immunization, and fever was the most common side effect in both groups. The dose of prednisolone at the time of vaccination was substantially higher in the flare group than in the non-flare group (Table 2). The flare group more frequently received sulfasalazine than the non-flare group. The use of other medications (disease-modifying antirheumatic drugs and biological agents) was comparable between the two groups. JADAS-27 and SLEDAI-2K scores before vaccination were similar between patients with flare and non-flare. However, JADAS-27 and SLEDAI-2K scores after vaccination significantly increased in the flare group compared with those in the non-flare group (Table 2). At the end of the study, the mean time to flare after COVID-19 vaccination based on the Kaplan–Meier method was longer in patients receiving prednisolone <10 mg/day compared with that in patients receiving prednisolone ≥10 mg/day (20.47 months, 95% CI: 19.86–21.07 vs. 16.51 months, 95% CI: 14.80–18.22, p = 0.003; Figure 1). Univariate analysis identified two significant covariates: use of prednisolone ≥10 mg/day before vaccination and non-active status (i.e., inactive disease and remission status). After multivariate analysis adjusted for age, sex, obesity, disease duration, disease status, and treatment, the only predictor of flare following the COVID-19 vaccine was the use of prednisolone ≥10 mg/day before vaccination (HR: 2.04, 95% CI: 1.05–3.97, p = 0.037), as shown in Table 3.

In the flare group, the mean time to flare after the last dose of COVID-19 vaccination and before flare symptoms was 1.95 ± 0.14 months. Of 46 patients, flare occurred predominantly after the second vaccine dose (26; 56.52%), followed by the first (11; 23.91%) and third (9; 19.57%) doses. The features of flare were as follows: arthritis (52.17%), thrombocytopenia (13.00%), anemia (6.52%), inflammatory or vasculitis rash (10.87%), progressive weakness (2.17%), hepatitis (2.17%), and systemic inflammation (10.87%). Flare severity was mostly mild to moderate (52.17%), followed by mild (26.09%) and severe (21.74%). For the treatment of flares, patients mostly required increased doses of the following therapies: immunosuppressants other than corticosteroids (34.78%), corticosteroids (17.39%), both corticosteroids and immunosuppressants (13.04%), and biologic agents (8.70%). Of 46 flare patients, 26 (56.52%) achieved inactive clinical status after disease flares in a mean time of 5.60 ± 3.15 months. At the end of the study, the mean time to reach clinically inactive disease after disease flare using the Kaplan–Meier method was longer in the patients with active disease before receiving the COVID-19 vaccine than in patients with inactive disease status (12.65 months, 95% CI: 10.18–15.13 vs. 6.34 months, 95% CI: 4.70–8.06, p = 0.002; Figure 1). We conducted a multivariate analysis by selecting significant covariates in the univariate analysis. After adjusting for age, sex, obesity, disease duration, disease status, and treatment, the analysis showed that the predictor of achieving inactive status after disease flare was non-active disease before receiving COVID-19 vaccination (HR: 2.95, 95% CI: 1.04–8.40, p = 0.043; Table 4).

Of 447 patients who received at least one dose of COVID-19 vaccination, 15 (3.36%) developed a new onset of rheumatic disease after receiving the vaccine. Most were patients with JIA [8; 53.33%; including ERA (4; 50.00%), poly-RF-pos (2; 25%), poly-RF-neg (1; 12.5%), and OligoJIA (1; 12.5%)], followed by CTDs patients [6; 40.00%; including SLE (4; 66.67%), JDM (1; 16.67%), Sjögren's syndrome (1; 16.67%)], and one (6.67%) patient with neuromyelitis optica (i.e., other rheumatic diseases). All patients received the mRNA vaccine BNT162b2. Of 15 patients, 10 (66.67%) and 5 (33.33%) developed a new onset of rheumatic disease after the second and first COVID-19 vaccine doses, respectively. Three patients had fevers after receiving the first dose of the COVID-19 vaccination. The median time from the last COVID-19 vaccination to the new onset of disease was 2.50 (1.73–2.77) months. The median patient age was 11.50 years (IQR: 10.34–13.72). Two-thirds of patients were female and 26.67% were obese, and the median Z-score was 0.45 (IQR: −0.66–2.23).

Of 245 patients who had COVID-19 infection, 8 (3.27%) had a disease flare after COVID-19 infection (Table 5). No patients with rheumatic diseases in this study developed multisystem inflammatory syndrome in children after COVID-19 infection. When patients were classified into the flare or non-flare groups, most patients in the flare group had SLE (4; 50%), followed by JIA (2; 25%; one with systemic JIA and one with poly-RF-pos), and vasculitis (2; 25%; one with microscopic polyangiitis and one with IgA vasculitis). Age, the percentage of female patients, and BMI Z-score were comparable between the flare and non-flare groups. Most patients in the flare and non-flare groups had a similar disease status before the COVID-19 infection. JADAS-27 and SLEDAI-2K scores before infection were comparable between patients with flare and non-flare. Nevertheless, the JADAS-27 and SLEDAI-2K scores after infection were significantly higher in the flare group compared with those in the non-flare group (Table 5). The predominant vaccine type was the mRNA vaccine, and patients frequently received two doses of COVID-19 vaccines. Disease duration before COVID-19 infection was similar between the two groups. The amount of prednisolone during COVID-19 infection and the proportion of patients receiving immunosuppressants other than AZA were comparable between the two groups. In the flare group, no patients received biological agents. The symptoms of COVID-19 infection in both groups were fever, cough, and sore throat. The most frequent anti-viral drug was favipiravir, and patients did not require hospital admission. All patients recovered after COVID-19 infection, which lasted fewer than five days based on COVID-19 symptoms. No significant parameters—including doses of prednisolone and disease status before COVID-19 infection—were associated with flares following COVID-19 infection.

In the flare group, the mean time to flare following COVID-19 infection was 1.13 ± 0.94 months. The features of flares included glomerulonephritis (3; 37.5%), inflammatory or vasculitis rash (2; 25%), arthritis (2; 25%), and autoimmune hemolytic anemia (1; 12.5%). Flare severity was mainly mild to moderate (62.5%), followed by severe (37.5%). In the treatment of the underlying rheumatic disease after the flare, patients primarily required increased doses of the following therapies: immunosuppressants other than corticosteroids (50%), corticosteroids and immunosuppressants (37.5%), and corticosteroids alone (12.5%). Of 8 patients, 5 (62.5%) achieved inactive disease status with a mean duration of 4.26 ± 2.41 months.

Regarding the COVID-19 course, there was no statistical difference between the specific diseases (Supplementary Table S3) and the treatment, including patients receiving high-dose and low-dose prednisolone (Supplementary Table S4) and patients with and without biological treatment (Supplementary Table S5). In addition, the course of COVID-19 infection in patients who developed an infection after vaccination was comparable to that in patients who had COVID-19 infection prior to vaccination (Supplementary Table S6). Most patients had a mild infection with only upper respiratory tract symptoms and recovery within five days. Only three COVID-19 patients had a moderate infection with mild pneumonia and needed only an oxygen canular. All of them were treated with favipiravir. They had already received the vaccination, and none of them had a disease flare. The first case was an inactive SLE who had taken only HCQ. Her recovery time took around 2 weeks. The second case was inactive SJIA, who had taken low-dose prednisolone and MTX. She recovered within 10 days. The third case is inactive oligo JIA, who had taken MTX. Her recovery time was five days.

Of 249 patients who had confirmed COVID-19 infection, 4 (1.61%) developed a new onset of rheumatic disease—including ERA, OligoJIA, JDM, and SLE—after having COVID-19 illness. Two patients (50.00%) did not receive a COVID-19 vaccination. The other patients received two doses of BNT162b2; the last dose of the COVID-19 vaccine was received more than 6 months before the onset of symptoms of new rheumatic disease. The mean time between the onset of symptoms of new rheumatic diseases and COVID-19 infection was 2.59 ± 0.23 months. The mean patient age was 11.86 ± 1.65 years, with a similar representation of male and female patients. All patients had normal weight and the mean Z-score was 1.11 ± 0.98. The symptoms of COVID-19 infection of the four patients included fever (100%), cough (50%), sore throat (50%), nasal congestion (25%), and diarrhea (25%). No patient required hospital admission during COVID-19 illness. Two patients received favipiravir, and one patient received herbal medicine. Symptoms of COVID-19 infection resolved for all patients within 5 days of infection.