Introduction

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood with a chronic course. Over the past decades, pharmacotherapy of JIA has improved dramatically with the utilization of biologic agents (BAs) that control the disease activity much more effectively, thus improving the quality of life of the patients [1–3].

Biologic agents are a new sort of drugs that differ from non-biologic disease-modifying antirheumatic drugs (DMARDs) in that they are manufactured with biologic processes and target specific molecules that are expressed on cells or secreted into the extracellular space, such as tumour necrosis factor α (TNF-α), interleukin (IL) 1β, and IL-6 [4].

Essentially, all biologics are immunogenic because they are non-self; therefore, they may lead to antibody responses that give rise to neutralization of biologic activity, anaphylactoid reactions, and loss of efficacy. These effects seem to be related with host-related factors, the dose, and the route of administration [5].

There are several studies investigating the efficacy and safety of BAs with various results [6–11]. The most frequent adverse event on BAs is upper respiratory tract infections (URTIs) [6–11].

There are also concerns about the association between occurrence of serious infections, malignancies, and autoimmune diseases with exposure to BAs [4]. However, due to the difficulty of a randomized placebo-controlled study design, clinical trials are disempowered to determine whether serious infections, malignancies, and autoimmune diseases are associated with BAs [4].

Therefore, the data on the long-term safety of BAs in children are still scarce. The objective of the current study is to retrospectively analyze the adverse events in JIA patients on BAs from a pediatric rheumatology center.

Material and methods

This is a retrospective study investigating adverse events during BA treatment in children with JIA. Juvenile idiopathic arthritis patients diagnosed between August 2008 and March 2019, who were still in follow-up in our pediatric rheumatology department, were included in the study.

Diagnosis of the patients and treatment choices were designated by pediatric rheumatologists accordingly. The patients were diagnosed according to the International League of Associations for Rheumatology (ILAR) classification criteria and sub-grouped as oligoarticular JIA, rheumatoid factor (RF)-positive polyarticular JIA, RF-negative polyarticular JIA, systemic-onset JIA (soJIA), and enthesitis-related arthritis (ERA) [12].

All patients’ data were collected from the medical files of the patients. Demographic characteristics, treatment modalities, laboratory data of the patients, and the diagnosis of rheumatic disease in first-degree relatives were included in the data. Prior to study initiation, written informed consent was obtained from all the patients’ parents. Ethical approval was obtained from the Institutional Review Board of the local medical school.

The biologic agents that were received by the participants consisted of TNF-α inhibitors (etanercept, adalimumab, and infliximab), fully human monoclonal antibody targeting IL-1β (canakinumab), IL-1 receptor antagonist (anakinra), and humanized monoclonal antibody targeting IL-6 receptor (tocilizumab). Pediatric rheumatologists selected the BAs in agreement with type and activity of the disease and switched or discontinued the BAs due to adverse events or remission. The patients receiving BAs were followed up regularly by pediatric rheumatologists according to JIA subgroup, disease activity, and the type of BAs, in at least three-month intervals.

Adverse events (AEs) and serious adverse events (SAEs) were recorded from the medical files of the patients, which included comprehensive information about adverse events that were based on interrogation of symptoms, physical examination, and laboratory parameters at least quarterly during routine follow-up. Adverse events that either resulted in death, were life-threatening, required inpatient hospitalization, or resulted in persistent or significant disability/incapacity were considered as SAEs [13].

Upper respiratory tract infections (URTIs) included rhinosinusitis, pharyngitis, laryngitis, laryngotracheitis, and otitis media, which were treated in outpatient clinics. Pneumonia referred to lower respiratory tract infection with symptoms included fever, chills, and cough with sputum production and confirmed by X-ray testing. Anaphylaxis was defined according to National Institutes of Health Food Allergy and Anaphylaxis Network criteria for anaphylaxis [14].

Local injection site reactions (ISRs) were defined as having redness, itching, pain, swelling, and burning at the injection site. However, injection site reactions more than 4 cm in diameter were defined as large local reactions, which were also considered as SAEs. Microscopic analyses of midstream urine samples were used to determine urinary tract infections (UTIs). The finding of > 5 white blood cells per high-power field in a centrifuged urine specimen in a symptomatic patient was reported as a UTI.

Results

Discussion

In the present study, adverse events during BAs were retrospectively investigated in JIA patients. The most utilized biologic agents were anti-TNF-α agents, and the most encountered adverse event was URTIs in JIA patients on BAs in this study. The second most encountered adverse event was UTIs in which none of them developed pyelonephritis and required hospitalization.

In total, serious adverse events occurred with a frequency of 6.7% (n = 11) among JIA patients on BAs – in detail: 1 MAS episode in a soJIA patient on tocilizumab, 3 anaphylactic reactions in 1 oligoarticular JIA on infliximab and in 2 soJIA patients on tocilizumab, 2 lung tuberculosis in soJIA patients on canakinumab, and 3 pneumonia that required hospitalization in soJIA patients on tocilizumab, and 2 large local injection site reactions in 2 ERA patients on etanercept occurred. Although none of the patients developed malignancy or died during BAs treatment due to AEs, the short length of the study period makes the interruption difficult in this regard.

Up to now, there have been two observational retrospective studies investigated all BAs, 1 in JIA patients and the other in all pediatric rheumatic diseases [11, 15].

Cabrera et al. [11] reported a multicenter, observational, retrospective study investigating the incidence of side effects of biological agents in 813 pediatric patients with inflammatory diseases. The main diagnosis in that study was JIA with 84% frequency. The mean follow-up duration was 4.7 ±3.1 years. There was a total of 1179 BA prescriptions for 813 patients. The anti-TNF-α agents, particularly etanercept, represented 75% of all utilized BAs. A total of 419 adverse events reported in 222 patients. Adverse events were most frequently mild (46%). The frequency of severe and very severe adverse events was 15% in all patients. The incidence of adverse events was higher in JIA patients. There were two MAS episodes during tocilizumab treatment. Moreover, two serious events during etanercept treatment – one Hodgkin’s lymphoma in a RF-positive JIA patient and one death due to JIA associated pulmonary fibrosis – occurred. Furthermore, one severe sepsis requiring intensive care unit hospitalization in the non-JIA group occurred during infliximab treatment, and one demyelinating lesion appeared with canakinumab. It was concluded that the study found an overall favorable outcome for children with pediatric inflammatory rheumatic diseases treated with all BAs [11].

The other study was from Finland by Tarkiainen et al. [15]. The study included 348 consecutive patients with JIA from three centers. Oligoarticular juvenile idiopathic arthritis was the most frequent disease subgroup, and etanercept was the most utilized biologic agent. Upper respiratory tract infections were the most encountered adverse event (71.8%). A total of 121 patients (35%) experienced SAEs and 12.6% of them were serious infections. Moreover, two systemic-onset juvenile idiopathic arthritis patients on etanercept died due to serious infections. None of the patients developed lung tuberculosis and malignancy [15]. Similarly to both studies, in our study, URTIs were the most encountered adverse events during BAs. The rate of serious adverse events in the current study was 6.7%, with no sequelae or death after discontinuation of BAs, similar to the report of Cabrera et al. [11]; however, the result was lower than the Finnish study in which SAEs were reported in 35% of the patients [15].

The difference between the rates of SAEs among studies might be due to the methodology of the studies. In the Finnish study [15], at least three sources of information were used for collecting data, which may have led to more accurate data on AEs as compared to our study, in which data collection were based on medical records held by pediatric rheumatologists, similar to the report of Cabrera et al. [11]. Moreover, another explanation for the differences might be the diversity of definition of SAEs. In the Finnish study [15], adverse events, classified as serious according to the Common Terminology Criteria for Adverse Events (CTCAE) [16], which contain various organ infections and symptoms, psychiatric disorders, even elevated liver transaminase levels, neutropenia which may also lead to increased frequency of SAEs compare to our study, in which AEs either resulted in death, were life-threatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity were considered as SAEs.

Serious adverse events in the present study included anaphylaxis in 3 patients, large ISRs in 2 patients, tuberculosis in 2 patients, MAS in 1 patient, and pneumonia that required hospitalization in 3 patients.

While biologic agents have revolutionized the therapies for chronic inflammatory, neoplastic, and autoinflammatory disease, like other pharmaceutical agents, they can cause anaphylactic reactions. Anaphylaxis has been reported with various BAs, including rituximab, infliximab, and tocilizumab in pediatric rheumatic diseases [17–21]. Anaphylactic reactions to BAs can occur on the first dose or after multiple exposures [22].

In the present study we encountered anaphylaxis in 3 patients – 2 during tocilizumab and 1 during infliximab treatment. Anaphylaxis was reported in 4 (1.1%) patients during infliximab treatment in the study of Tarkiainen et al. [15]. To our knowledge, there is only one study evaluating severe hypersensitivity reactions to biological agents in children with all rheumatic diseases from Turkey [23].

In that study, 128 patients using eight different BAs with all rheumatic diseases were evaluated. The frequency of anaphylaxis was reported to be 3.9% in children with all rheumatic diseases and 4% in JIA patients [23]. In the present study, the frequency of anaphylaxis was lower (1.9%) than the previous report among JIA patients. Unlike our study, the previous study enrolled patients with all rheumatic diseases, which might explain the higher frequency of anaphylaxis among patients receiving BAs in the previous study.

The most important complication of the soJIA is MAS, and it can be deadly. Macrophage activation syndrome occurs in almost 10% of soJIA patients and may occur even under BAs [24–26]. In the present study we encountered one MAS episode at the sixth dose of tocilizumab treatment in a soJIA patient. In regard to macrophage activation syndrome, Cabrera et al. [11] also reported two MAS episodes during tocilizumab treatment in JIA patients. However, in the other previous study, they did not report any MAS episode during follow-up, rather than soJIA activation [15].

The risk of tuberculosis development or activation is an area of concern in BA-administered patients [27]. In regard to tuberculosis, in this study 2 siblings with soJIA under canakinumab treatment were diagnosed with lung tuberculosis. However, they were also given methotrexate, methylprednisolone concomitantly, and had a long-lasting disease that led to being given various BAs before canakinumab treatment. Therefore, it is difficult to conclude that these side effects are solely related to canakinumab administration.

There are diverse clinical studies investigating the safety of BAs as well as the effectiveness of BAs in the treatment of pediatric rheumatic diseases, particularly JIA [6–11]. In those studies, BAs were found to be well tolerated and the most encountered infections were the URTIs which were treated at outpatient clinics. In the present study, the most frequent AEs were also URTIs with a frequency of 54.3%, which were also treated at outpatient clinics, similarly to the literature.

However, there is only one prospective study investigating the occurrence of infections in JIA patients on all BAs from Turkey [6]. A total of 307 juvenile idiopathic arthritis patients, mainly oligoarticular JIA, were included the study. Juvenile idiopathic arthritis patients on BAs were examined by a pediatric infectious disease specialist every 2 months during 1 year. The most frequently administered BA was etanercept. During the study period, 57% of the patients developed infection. Upper respiratory tract infections were the most frequently encountered infections, in which none of the patients required hospitalization. The rate of urinary tract infections was similar to our findings, with 18.8% frequency. Chickenpox was diagnosed in 7 patients (2.2%), none of whom were hospitalized or developed any complications. During one-year follow-up, pneumoniae was diagnosed in 12 patients (3.9%), in whom two required hospitalization. Lung tuberculosis occurred in 2 patients (0.6%) during etanercept and adalimumab treatments. The findings of our study and the previous study are comparable in terms of encountered infections, and most of the encountered AEs were easily treated at outpatient clinics.

The main limitation of the present study is the retrospective design, which might lead to miss-collection of some adverse events. Moreover, the relatively small number of each BA group and juvenile idiopathic arthritis subgroups make the interpretation of statistical analyses difficult between groups. Therefore, further, multicenter, prospective studies are needed for the identification of the real-life incidence of side effects of BAs in pediatric rheumatic diseases. However, we still think that the data on SAEs give us important knowledge about JIA patients on BAs.

Conclusions

In the current study, upper respiratory tract infections were the most frequently encountered adverse event in JIA patients using BAs. In total, the frequency of SAEs was 1.9%. Although serious adverse events are rare in clinical practice and can be managed easily either with discontinuation of therapy or with treatment of AEs, we suggest that patients on BAs should be monitored and interrogated for the possibility of various adverse events.