1 INTRODUCTION

For almost 2 years, our planet has been suffering from coronavirus disease-2019 (COVID-19) caused by a novel coronavirus named severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2). Although scientists worldwide are mainly focused on the pandemic, there is still no available therapeutic option that may provide sufficient cure, and COVID-19 remains a significant global health concern. Thus, preventive strategies such as face masks, social distancing, personal hygiene, and vaccination come into prominence. Recently, several studies have shown newly developed vaccines to be effective and safe tools for the fight against COVID-19.1, 2

In the early days of the pandemic, children were considered to have an asymptomatic or a mild COVID-19 disease course in contrast to adults.3 However, a growing number of pediatric cases with multi-system inflammatory syndrome in children (MIS-C) caused by SARS-CoV-2 have been described with devastating consequences such as intensive care unit admission or even death.4, 5 Therefore, vaccination strategies are needed to be well-established for children, as well as for adults.

There is a vulnerable group such as immunocompromised patients among the pediatric population that merits to be prioritized for the vaccination. Patients with inflammatory rheumatic diseases (IRD) are considered to be in this group, due to their immune-disturbed conditions caused by their medications and chronic inflammatory states. However, it is still debated whether IRD increases the risk of severe COVID-19 due to conflicting findings of current studies.6-11

Although patients with IRD and those under immunosuppressive treatment were mainly excluded from the clinical trials of recent vaccines, they were widely vaccinated.12 Since they may be at increased risk of worse outcomes from vaccine-preventable diseases, and due to limited source of vaccines in most of the developing countries, they were considered to be a prioritized group by authorities.13, 14 Yet there is no sufficient safety data, particularly for the vaccination of children with IRD.

There are 2 different kinds of COVID-19 vaccines, CoronaVac inactive SARS-CoV-2 and BNT162b2 messenger RNA (mRNA) COVID-19 (Pfizer-BioNTech), which are currently available in our country. Considering the concerns regarding COVID-19 vaccine safety among pediatric patients with IRD due to a lack of data, an urgent need for studies evaluating safety profiles of vaccines emerged. We designed this cross-sectional study to examine the vaccine-related adverse events among this group of patients.

2 MATERIALS AND METHODS 2.1 Patients and data collection

In our country, in January 2021, healthcare professionals, and in February 2021, patients with chronic health conditions, those older than 18, were started to be vaccinated by 2 doses of CoronaVac inactive SARS-CoV-2 with a 1-month interval. Afterward, the third dose was allowed for both groups in July 2021. Citizens were able to choose their vaccine type, as CoronaVac inactive SARS-CoV-2 or BNT162b2 mRNA COVID-19 (Pfizer-BioNTech). Finally, the fourth dose was approved for both groups in August 2021. Again, individuals were free to prefer their vaccine type.

In mid-August 2021, CoronaVac inactive SARS-CoV-2 and BNT162b2 mRNA COVID-19 vaccines started being administered to children older than 12 with chronic medical conditions and healthy children older than 15 in our country. Then, at the beginning of September 2021, vaccine administration against the novel coronavirus was launched for all children under 12, regardless of their underlying disease.

We conducted a web-based survey in mid-September 2021. Questionnaires regarding the data of the rheumatic diseases, COVID-19 vaccination status, disease flares within 1 month after the vaccines, and experienced adverse events (due to vaccines) of the participants were prepared in Google Forms and circulated through several social media platforms.

Healthy children under 18 and patients under 21 with an at least 1-year follow-up period in our department for a childhood-onset rheumatic disease were included in the study. While data of the rheumatic patients were verified by their medical records, data of COVID-19 vaccination status and experienced adverse events of the participants were verified by phone calls and national registries. Subjects whose data could not be verified by phone calls, registries or medical records were excluded from the study due to a lack of data.

Redness, warmth, regional pain, and tenderness at the injection site due to COVID-19 vaccines were considered as local reactions. While permanent disabilities, hospitalization or an extended hospital stay (if vaccinated while in the hospital), life-threatening illness, birth defects (congenital anomalies), and death were considered severe adverse events, the rest of the adverse events were considered non-severe adverse events, based on the recommendations of Vaccine Adverse Event Reporting System (VAERS) which is co-managed by the Centers for Disease Control and Prevention and the US Food and Drug Administration.15

Subjects were categorized into 3 different groups. Children with no underlying disease were considered the healthy control group. While rheumatic patients who were receiving at least one of the biologic agents such as etanercept, infliximab, adalimumab, anakinra, canakinumab, tocilizumab, and rituximab during their vaccination periods were considered the biologic group, the rest of the rheumatic patients were considered the non-biologic group.

The institutional ethics committee of our center approved the study protocol (03/09/21-29430533-903.99-175245). The recommendations of the Declaration of Helsinki for biomedical research involving human subjects were followed. At least one of the family members of all the participants provided informed consent.

2.2 Statistical analysis

The statistical analysis was performed using SPSS for Windows, version 21.0 (SPSS Inc). Categorical variables were expressed as numbers (percentages). Ages of the patients were given as median (minimum-maximum), based on their distribution which was measured by using the Kolmogorov-Smirnov test. Categorical variables were compared by using Chi-square test or Fisher's exact test, when available. Ages of the patients were compared using the Mann-Whitney U or Kruskal-Wallis test, when appropriate. Statistical significance was defined as P <.05. Prism software (Prism 8, GraphPad Software) was used to analyze and graph data.

3 RESULTS 3.1 Study population

Following the link of our web-based survey that was shared on our clinic's online social media platforms, 466 participants fulfilled the questions. Those who stated that they were not vaccinated (n = 181) were not included in the study. Among those who stated they were vaccinated, those who could not be reached by phone (n = 19), whose follow-up period was <1 year (n = 8) and whose data could not be verified via the national registries, medical records of our department or phone calls (n = 12) were excluded.

Finally, 246 subjects (141 females) were eligible for the study. The median age was 15.34 (12.02-20.92) years. Twenty-three participants whose parents stated in the survey that they did not have any chronic diseases, and whose medical records were checked and confirmed by phone calls that they did not have any underlying disease or long-term medication were considered the healthy control (HC) group.

In the study group there were 126 patients with autoinflammatory diseases (AID) (familial Mediterranean fever [FMF], 123; cryopyrin-associated periodic syndrome [CAPS], 2; Blau syndrome [BS]), 54 patients with juvenile idiopathic arthritis (JIA) (oligoarticular JIA [oJIA], 43; juvenile spondylarthritis [jSPA], 8; polyarticular JIA [pJIA]), 30 patients with connective tissue disease (CTD) (systemic lupus erythematosus [SLE], 16; dermatomyositis [DM], 10; scleroderma, 3; Sjögren’s syndrome, 1), 9 patients with vasculitis (Behçet’s disease [BD], 2; deficiency of adenosine deaminase 2 [DADA2], 2; Takayasu arteritis [TA], 2; granulomatous polyangiitis [GPA], 1; Henoch-Schönlein purpura [HSP], 2; Kawasaki disease [KD]) and 4 patients with acute rheumatic fever (ARF) (Table 1).

TABLE 1. Baseline characteristics of the study population

Healthy controls

(n = 23)

Patients with AID

(n = 126)

Patients with JIA

(n = 54)

Patients with CTD

(n = 30)

Patients with vasculitis

(n = 9)

Patients with ARF

(n = 4)

Age, y (median, min-max) 15.67 (12.04-19.94) 15.09 (12.06-20.72) 15.41 (12.06-20.64) 16.89 (12.49-20.64) 15.58 (12.02-20.92) 15.42 (13.71-18.1) Gender Female, n (%) 10 (43.5%) 68 (54%) 35 (64.8%) 19 (63.3%) 6 (66.7%) 3 (75%) Male, n (%) 13 (56.5%) 58 (46%) 19 (35.2%) 11 (36.7%) 3 (33.3%) 1 (25%) Diagnoses (n) -

FMF (123)

CAPS (2)

BS (1)

oJIA (43)

jSPA (8)

pJIA (3)

SLE (16)

DM (10)

Scleroderma (3)

Sjögren (1)

BD (2)

DADA2 (2)

TA (2)

GPA (1)

HSP (1)

KD (1)

- Ongoing treatments Colchicine, n (%) - 125 (99.2%) - - 3 (33.3%) - Steroid, n (%) - - 10 (18.5%) 9 (30%) 2 (22.2%) - ASA, n (%) - - - 5 (16.7%) 1 (11.1%) - bDMARDs Anakinra, n (%) - 2 (1.6%) - - - - Canakinumab (n, %) - 8 (6.3%) - - - - Tocilizumab, n (%) - - 2 (3.7%) 2 (6.7%) 2 (22.2%) - Etanercept, n (%) - - 12 (22.2%) 2 (6.7%) 2 (22.2%) - Adalimumab, n (%) - - 10 (18.5%) - - - Rituximab, n (%) - - - 1 (3.3%) - - cDMARDs MTX, n (%) - - 12 (22.2%) 10 (33.3%) - - Leflunomide, n (%) - - 9 (16.7%) 1 (3.3%) - - Cyclosporine, n (%) - - - 3 (10%) - - Cyclophosphamide, n (%) - - - 1 (3.3%) - - HCQ, n (%) - - - 21 (70%) - - MMF, n (%) - - - 6 (20%) - - COVID-19 history before vaccination, n (%) 7 (30.4%) 18 (14.1%) 9 (17.3%) 6 (20%) 1 (11.1%) 3 (75%) Vaccination info Vaccination type mRNA, n (%) 19 (82.6%) 109 (86.5%) 49 (90.7%) 27 (90%) 6 (66.7%) 4 (100%) Inactive, n (%) 3 (13%) 16 (12.7%) 5 (9.3%) 3 (10%) 1 (11.1%) - Mix, n (%) 1 (4.3%) 1 (0.8%) - - 2 (22.2%) - Adverse events None, n (%) 12 (52.2%) 68 (54%) 33 (61.1%) 21 (70%) 3 (33.3%) 2 (50%) Non-severe, n (%) 10 (435%) 56 (44.4%) 21 (38.9%) 9 (30%) 6 (66.7%) 2 (50%) Severe, n (%) 1 (4.3%) 2 (1.6%) - - - - Local reactions, n (%) 3 (13%) 8 (6.3%) 8 (14.8%) 1 (3.3%) - - Disease flare within 1 month Yes, n (%) - 15 (11.9%) 10 (18.5%) 2 (6.7%) - - No, n (%) - 111 (88.1%) 44 (81.5%) 28 (93.3%) 9 (100%) 4 (100%) Abbreviations: AID, autoinflammatory diseases; ARF, acute rheumatic fever; ASA, acetylsalicylic acid; BD, Behçet disease; bDMARDs, biologic disease-modifying antirheumatic drugs; BS, Blau syndrome; CAPS, cryopyrin-associated periodic syndromes; cDMARDs, conventional disease-modifying antirheumatic drugs; CTD, connective tissue disease; DADA2, deficiency of adenosine deaminase 2; DM, dermatomyositis; FMF, familial Mediterranean fever; GPA, granulomatous polyangiitis; HCQ, hydroxychloroquine; HSP, Henoch-Schönlein purpura; JIA, juvenile idiopathic arthritis; jSPA, juvenile spondylarthritis; KD, Kawasaki disease; MMF, mycophenolate mofetil; MTX, methotrexate; oJIA, oligoarticular juvenile idiopathic arthritis; pJIA, polyarticular juvenile idiopathic arthritis; SLE, systemic lupus erythematosus; TA, Takayasu arteritis.

During their vaccination periods, 128 patients were receiving colchicine (FMF, 123; CAPS, 2; BD, 2; DADA2, 1); 49 conventional disease-modifying antirheumatic drugs (cDMARDs) (methotrexate [MTX], 22 [JIA, 12; DM, 7; scleroderma, 2; SLE, 1]; hydroxychloroquine [HCQ], 21 [SLE, 16; DM, 3; Sjögren, 1; scleroderma, 1]; leflunomide, 10 [JIA; 9; SLE, 1]; mycophenolate mofetil [MMF]; 6 [SLE, 3; scleroderma, 2; DM, 1]; cyclosporine; 3 [DM; 3]; cyclophosphamide, 1 [SLE; 1]), 43 biologic disease-modifying antirheumatic drugs (bDMARDs) (etanercept, 16 [JIA, 12; DM, 2; DADA2, 2]; adalimumab, 10 [JIA, 10]; canakinumab, 8 [FMF, 7; CAPS, 1]; tocilizumab, 6 [JIA; 2; TA, 2; scleroderma, 2]; anakinra, 2 [FMF, 1; CAPS, 1]; rituximab, 1 [SLE, 1]); 21 systemic steroids (JIA, 10; SLE, 6; DM, 2; DADA2, 1; BD, 1; scleroderma, 1); and 6 patients were receiving acetyl-salicylic acid (SLE, 5; DADA2, 1) (Table 1). Four patients with ARF were under penicillin prophylaxis. Twenty-two patients with IRD excluding the ARF were in remission, and they were not receiving any treatment except non-steroidal anti-inflammatory drugs.

Before their vaccinations, 44 subjects recovered from COVID-19 (FMF, 18; JIA, 9; HC, 7; SLE, 5; ARF, 3; DM, 1; GPA, 1) (Table 1). While 4 of the recovered ones (HC, 2; JIA, 1; SLE, 1) had asymptomatic infection, the rest had mild COVID-19 symptoms. None of them had a severe clinical course.

While 214 subjects received BNT162b2 mRNA vaccine (FMF, 106; JIA, 49; HC, 19; SLE, 14; DM, 10; ARF, 4; CAPS, 2; scleroderma, 2; KD, 1; HSP, 1; BD, 1; DADA2, 1; Sjögren, 1; TA, 1; GPA, 1; BS, 1), 28 received inactivated SARS-CoV-2 vaccine (FMF, 16; JIA, 5; HC, 3; SLE, 2; DADA2, 1; scleroderma, 1), and 4 received both (FMF, 1; BD, 1; TA, 1; HC, 1) (Table 1).

Out of 246 subjects, 145 received a single dose of BNT162b2 mRNA vaccine, 19 received a single dose of inactivated SARS-CoV-2 vaccine, 69 received double doses of BNT162b2 mRNA vaccine, 8 received double doses of inactivated SARS-CoV-2 vaccine, 3 received double doses of inactivated SARS-CoV-2 vaccine plus a single dose of BNT162b2 mRNA vaccine, 1 received double doses of inactivated SARS-CoV-2 vaccine plus double doses of BNT162b2 mRNA vaccine, and 1 received 3 doses of inactivated SARS-CoV-2 vaccine.

3.2 Adverse events

COVID-19 vaccine-related adverse events reported by the participants and their families were as follows: fatigue (n = 68, 27.6%), headache (n = 44, 17.9%), myalgia (n = 38, 15.4%), arthralgia (n = 38, 15.4%), fever (n = 35, 14.2%), nausea-vomiting (n = 19, 7.7%), diarrhea (n = 16, 6.5%), anorexia (n = 16, 6.5%), chest pain (n = 14, 5.7%), abdominal pain (n = 11, 4.5%), rhinorrhea (n = 8, 3.3%), arthritis (n = 8, 3.3%), cough (n = 8, 3.3%), dyspnea (n = 6, 2.4%), throat ache (n = 5, 2%), rash (n = 3, 1.2%), anosmia (n = 2, 0.8%), hypertension (n = 1, 0.4%), and hypotension (n = 1, 0.4%) (Figure 1).

SARS-CoV-2 vaccination-related adverse events among our participants

Three subjects were considered to have severe adverse events, since they required hospitalization and additional treatment: 20.2 years-aged female patient with FMF who developed hypertension (2 weeks remained) after the second dose of BNT162b2 mRNA vaccine; 12.1 years-aged female with no underlying disease who experienced severe rash after the first dose of BNT162b2 mRNA vaccine; and 13.7 years-aged male patient with FMF who developed pre-syncope due to hypotension after the first dose of BNT162b2 mRNA vaccine.

All the adverse events but hypertension recovered in THE first 4 days. There was no adverse event after the administration of the second dose of CoronaVac inactive SARS-CoV-2 vaccine. Adverse event frequencies according to days and vaccine doses are given in Figure 2. Local reactions after the vaccines were seen in 20 subjects (JIA, 8; FMF, 7; HC, 3; DM, 1; BS, 1). Local reaction frequencies according to vaccine doses are also given in Figure 2.

Adverse event frequencies according to days and vaccine types

Twenty-seven patients experienced disease flare within 1 month after the vaccination (after the first dose of BNT162b2 mRNA vaccine, 17; after the second dose of BNT162b2 mRNA vaccine, 7; after the first dose of CoronaVac inactive SARS-CoV-2 vaccine, 3) (FMF, 15; JIA, 10; SLE, 2). Among those who experienced disease flare, all patients with FMF presented with typical attacks (fever, abdominal pain, chest pain, and/or arthralgia), and all JIA patients developed new-onset arthritis. In addition to increased inflammatory markers, 1 of 2 patients with SLE had cutaneous involvement, and bicytopenia was seen in the other.

3.3 Comparison of the participant groups

There were no significant differences between the HC group, biological group and non-biological group in terms of age, gender, vaccine types, and frequencies of pre-vaccination COVID-19 histories, local reactions and adverse events. Moreover, the frequency of disease flares within 1 month after vaccines was not different between the biological group and the non-biological group. Detailed data Are given in Table 2.

TABLE 2. Comparison between the characteristics of healthy children, biologic group, and non-biologic group

Healthy control group

(n = 23)

Non-biologic group

(n = 180)

Biologic group

(n = 43)

P Age, y (median, min-max) 15.67 (12.04-19.94) 15.14 (12.02-20.72) 16.09 (12.19-20.92) .124 Gender Female, n (%) 10 (43.5%) 106 (58.9%) 25 (58.1%) .369 Male, n (%) 13 (56.5%) 74 (41.1%) 18 (41.9%) Pre-vaccination COVID-19 history Yes, n (%) 7 (30.4%) 28 (15.6%) 9 (20.9%) .182 No, n (%) 16 (69.6%) 152 (84.4%) 34 (79.1%) Vaccination type mRNA, n (%) 19 (82.6%) 160 (88.9%) 35 (81.4%) .301 Inactive, n (%) 3 (13.0%) 18 (10.0%) 7 (16.3%) Mix, n (%) 1 (4.3%) 2 (1.1%) 1 (2.3%) Local reaction Yes, n (%) 3 (13.0%) 14 (7.8%) 3 (7.0%) .581 No, n (%) 20 (87.0%) 166 (92.2%) 40 (93.0%) Disease flare within 1 montha Yes, n (%) - 21 (11.7%) 6 (14.0%) .680 No, n (%) - 159 (88.3%) 37 (86.0%) Adverse events None, n (%) 12 (52.2%) 101 (56.1%) 26 (60.5%) .579 Non-severe, n (%) 10 (43.5%) 77 (42.8%) 17 (39.5%) Severe, n (%) 1 (4.3%) 2 (1.1%) 0 (0.0%) 3.4 Assessment of the risk factors for vaccine-related adverse events

There was no significant relationship between adverse event frequency and age, gender, the existing diseases, ongoing treatments (except acetylsalicylic acid [ASA]) and pre-vaccination COVID-19 histories. While the adverse event frequency was significantly lower in those who were receiving ASA during their vaccination period (P = .037), it was significantly higher in those who received the BNT162b2 mRNA vaccine (P < .001). Detailed data were given in Table 3.

TABLE 3. Comparison of the patients with and without COVID-19 vaccine-related adverse events according to the baseline characteristics Adverse events P

Yes

(n = 107)

No

(n = 139)

Age, y (median, min-max) 15.55 (12.02-20.92) 15.11 (12.18-20.72) .376 Gender Female, n (%) 65 (60.7%) 76 (54.7%) .340 Male, n (%) 42 (39.3%) 63 (45.3%) Disease Healthy control, n (%) 11 (10.3%) 12 (8.6%) .323 Patients with AID, n (%) 58 (54.2%) 68 (48.9%) FMF, n 57 66 CAPS, n 1 1 BS, n - 1 Patients with JIA, n (%) 21 (19.6%) 33 (23.7%) oJIA, n 15 28 jSPA, n 4 4 pJIA, n 2 1 Patients with CTD, n (%) 9 (8.4%) 21 (15.1%) SLE, n 4 12 DM, n 4 6 Scleroderma, n 1 2 Sjögren, n - 1 Patients with vasculitis, n (%) 6 (5.6%) 3 (2.2%) BD, n 2 - DADA2, n 1 1 TA, n 1 1 GPA, n 1 - HSP, n - 1 KD, n 1 - Patients with ARF, n (%) 2 (1.9%) 2 (1.4%) Presence of a rheumatic disease, n (%) 96 (89.7%) 127 (%91.4) .827 Ongoing treatments