Systematic Review of Adverse Events of IL-1 and IL-6 Inhibitor Use in Pediatrics

Introduction

Recently, there has been a surge in the development of biologicals, which is a diverse group of medications often produced by using living organisms such as mammalian cells, microbial agents, plants, and yeast. A subclass of these biologicals is designed to specifically target the immune response, particularly for treating immune-mediated conditions. Several biological agents have emerged that work to regulate and block the activity of cytokines.

After exposure to inflammatory stimuli such as bacterial products, the concentration of proinflammatory cytokines, such as interleukin-1 (IL-1α and IL-1β) and interleukin-6 (IL-6), increase and feed a proinflammatory signaling cascade. Animal studies demonstrated that IL-6 promotes chronic autoimmune-driven inflammation. This cytokine seems to promote differentiation of proinflammatory T-helper lymphocytes and inhibits regulatory T-lymphocyte differentiation, although it likely interacts with other interleukins in humans.¹ Autoimmune conditions, such as cryopyrin-associated periodic syndrome (CAPS) and juvenile idiopathic arthritis, have also shown elevated concentrations of IL-1β. Interleukin-1 is known to promote the differentiation and migration of cytotoxic T lymphocytes and is involved in matrix enzyme activity leading to tissue damage.² Biologicals that target cytokines such as IL-1 and IL-6 have proved effective in treating pediatric patients with severe rheumatologic autoinflammatory conditions.³ However, owing to the immunosuppressive effect of the drugs targeting IL-1 and IL-6, studies have suggested associated risks such as increased risks of new infections or reactivation of latent infections (e.g., tuberculosis), and infection related to live vaccines.^4–6 In the past, studies of IL-6 and IL-1 inhibitor use specifically in children were limited, as information was often extrapolated from adult data. As the use of these biologicals in children is more recent, the adverse effects in the pediatric population are less well outlined, and some adverse events (e.g., developmental effects) may not be possible to glean from adult studies.

The aim of this study was to systematically review the adverse events that occur during treatment with IL-6 inhibitors (e.g., sarilumab and tocilizumab) and IL-1 inhibitors (e.g., anakinra) when used in the pediatric population.

Materials and Methods

Screening and Data Extraction.

Following the search, the studies were collated and uploaded onto Covidence, a review management software, which was used to screen titles, abstracts, and full-text articles. Abstracts and full-text screening of manuscripts were carried out by 2 independent reviewers (AP, NC), based on predefined eligibility criteria, where 2707 studies were screened, following duplicate removal, and 2380 studies were excluded. Any conflicts between the 2 reviewers were resolved by a third reviewer (FG-B). During the full-text assessment stage, the reviewers assessed 327 studies for inclusion. Of these, 289 studies were excluded for the following reasons: abstract presentation; study design, study outcome, intervention, or patient populations not aligning with inclusion criteria; unavailable full text; English version unavailable; older reports of a study; and absence of separate pediatric and adult outcome data.

Following the finalization of included studies (n = 38), 2 reviewers (AP, NC) independently extracted data by using a data extraction form with characteristics such as intervention (drug, dose, method of administration, frequency), adverse effects, and frequency of adverse effects. This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of 2020, ensuring transparency and comprehensiveness in the review process (see Figure).⁷

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Results

After 2707 studies underwent initial title and abstract screening, 327 studies were assessed for eligibility through full-text screening (Figure). Of these, 38 studies fulfilled all inclusion criteria and were included in this review (Table 1.)^9–46

Table 1.Summary of Included Studies

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The ROBINS-E tool resulted in a scoring of “some concerns” or “high risk” for the risk of bias of the studies included. The main concerns were related to lack of reporting on or control of confounding variables such as concomitant medications and comorbidities. In many cases, comorbidities and other medications being taken by patients were not specified in the studies, but immunosuppressants such as corticosteroids or anti–tumor necrosis factor drugs were often discontinued prior to the study period.

Interleukin-1 Inhibitors.

Canakinumab.

Nine studies assessed canakinumab as an intervention (Table 2). Treatment doses were either 150 mg or 2 to 4 mg/kg. This treatment was studied in patients with CAPS, colchicine-resistant familial Mediterranean fever, hyperimmunoglobulin D syndrome–mevalonate kinase deficiency, systemic juvenile idiopathic arthritis (JIA), idiopathic recurrent pericarditis, pyoderma gangrenosum, and sickle cell anemia. The number of patients in each study ranged from 16 to 177, with an overall total number of 560, and a median number of 47 patients per study. Study duration was a mean of 32.3 (range, 6–90) months, for studies that provided this information. Adverse events included infections (e.g., upper and lower respiratory tract infections) (n = 58 patients or 122 events in studies not reporting number of patients). Other reported events included local injection site reactions (n = 2, events = 1), fever (n = 76), headache (n = 63), arthralgia (n = 50), diarrhea (n = 42), and rash (n = 30). Elevated transaminase concentration (n = 6), thrombocytopenia (n = 12), neutropenia (n = 13), and leukopenia (n = 1) were also reported. More rarely reported events included abscess following appendicitis, anaphylaxis, mast cell activation syndrome (MAS), urticaria, and splenic cyst. Studies that identified serious adverse events reported 95 events (rate = 0.17, of 560 total studied patients).

Table 2.Reported Adverse Events With IL-1 and IL-6 Inhibitor Use in Children

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Anakinra.

Twelve studies included anakinra as an intervention. Treatment doses ranged from 0.5 to 4 mg/kg, with 1 study allowing up to 11 mg/kg and a maximum dose of 100 mg/day. Conditions treated included CAPS, chronic infantile neurological cutaneous and auricular syndrome, Muckle-Wells syndrome, recurrent pericarditis, systemic JIA, juvenile rheumatoid arthritis, Kawasaki disease, and neonatal-onset multisystem inflammatory disease. The overall total number of patients was 299 and the median number of patients was 22 per study. Study duration was a mean of 22.5 (range 1.5–60) months. Commonly reported adverse events include local injection site reactions (n = 42 patients, and 16 events in studies that did not report number of patients), headache (n = 52), arthralgia (n = 18), fever (n = 43, events = 40), infection (including upper respiratory tract infections) (n = 107, events = 235), rash (n = 28, events = 59), ocular hyperemia (n = 12), fatigue (n = 10), diarrhea (n = 19, events = 1), nausea/vomiting (n = 9, events = 26), oropharyngeal pain (n = 9), musculoskeletal pain (events = 118), and elevated liver enzymes (n = 2, events = 13). More rarely reported events included weight gain, oral aphthosis, urticaria, post–lumbar puncture syndrome, chest pain, convulsion, neutropenia, serious infection (such as parainfluenza and pneumonia), hepatitis, abdominal pain, MAS, and other serious adverse events.²⁴ Studies that identified serious adverse events reported 45 events (rate = 0.15, of a total of 299 studied patients).

Rilonacept.

Two studies included rilonacept as a treatment. They used a dose of 2.2 mg/kg or 4.4 mg/kg and both involved systemic JIA, with a total number of 60 patients, or 36 and 24 patients per study, respectively. Study duration was 19 and 27 months. Reported adverse events included liver enzyme elevation (n = 4 patients), abdominal pain (events = 4), headache (events = 5), nausea/vomiting (events = 10), cough (events = 4), rash (events = 4), infection (n = 16, events = 16), and a grouped set of reactions including fatigue, pyrexia, and injection site reactions (n = 18). Serious adverse events included infection such as gastroenteritis (n = 1) and varicella (n = 1), arthritis (events = 2), liver function abnormality (n = 1), mental status change (n = 1), and hemophagocytic histiocytosis (n = 1). Serious adverse events included 16 events (rate = 0.27, of 60 total studied patients).

Discussion

The objective of this systematic review was to summarize the adverse events occurring with IL-1 and IL-6 inhibitor treatment, when used in a pediatric population. The review identified a total of 38 studies, and the study designs included prospective cohort, cross-sectional, case series, and case-control studies.

The IL-1 and IL-6 inhibitors, including canakinumab, anakinra, tocilizumab, and rilonacept, were studied for a range of conditions such as CAPS, colchicine-resistant familial Mediterranean fever, hyperimmunoglobulin D syndrome–mevalonate kinase deficiency, systemic JIA, idiopathic recurrent pericarditis, pyoderma gangrenosum, and sickle cell anemia. Canakinumab and anakinra displayed some common adverse events including infections (rate = 0.19), headaches (rate = 0.13), local site injection reactions (n = 0.05), and fever (rate = 0.14). Rilonacept showed adverse events such as liver enzyme elevation (rate = 0.25), abdominal pain (rate = 0.25, using n = 4 events), and infections (rate = 0.27). Studies including the administration of tocilizumab reported adverse events including neutropenia (rate = 0.02), elevated transaminase concentration (rate = 0.03), and infections (rate = 0.09). There were also serious adverse events reported at a rate of 0.25, although multiple events may have occurred in individual patients. Given the variability of the format in which adverse events were reported across studies for both types of inhibitors, it is difficult to draw definitive conclusions about their safety profiles or whether some drugs are better tolerated. Regarding concomitant disease and drug interactions, information in the literature is limited, and these were not clearly reported in most of the reviewed studies. Synergistic effects with other immunosuppressants such as tumor necrosis factor-alpha inhibitors, leading to increased infection risk, have been suggested.⁴⁷ However, several included studies did discontinue use of other immunosuppressants prior to the study period.

However, the findings of this review provide additional evidence summarizing some of the most reported and serious adverse events observed in patients after the intake of these medications and corroborate our knowledge of their safety profiles in children specifically. The reported adverse events highlight the need for careful monitoring, individualized management, and an assessment of the risk and benefits for the administration of the medicine for each patient. The administration of interleukin inhibitors in children should be made after a thorough evaluation of patients’ medical conditions, disease severity, and previously reported adverse events for the medication. There is currently a paucity of evidence regarding monitoring strategies in this population, but screening of immunization status, tuberculosis screening, baseline blood tests (e.g., complete blood counts and liver function tests), and regular follow-up monitoring of bloodwork is generally encouraged. The evaluation of adverse events noted in this review may suggest the need for further research on monitoring strategies, regular screening for infectious symptoms, or patient/parent education regarding when to seek medical care if specific symptoms are observed.^48,49

While the medications reviewed are also used in adult patients, comparison of the nature and incidence of adverse events is difficult owing to the differences in diseases (and comorbidities) treated in children versus adults. However, many adverse events seem to be similar and have similar incidences (taking into account that, in general, pediatric trials were smaller and often focused on specific types of pediatric diseases that involve some degree of immunosuppression and/or inflammation). Notably, a relatively common incidence of infections and hematologic adverse events can be observed in both populations, as well as hypersensitivity reactions for biologicals. Perhaps the main differences among age groups can be observed for canakinumab, which can produce hyperuricemia and vertigo more commonly in adults than in children (possibly because adults have higher risk for predisposing comorbidities such as kidney impairment).⁵⁰ Rilonacept and tocilizumab did not seem to cause hyperlipidemia in children, as opposed to adults, but the experience in children is much more limited.^51,52 Finally, there is a suggestion that canakinumab-related infections are more frequent in children, with the caveat that many of the children receiving this medication had some form of congenital autoinflammatory condition with an immune dysfunction component.²¹

There are several limitations to be considered in this systematic review. Included studies had different designs, data collection methods, sample sizes, and reporting of adverse events. Some studies also did not categorize their reported adverse events as serious or nonserious events. Some studies reported only the number of patients with adverse events, and some reported only the number of adverse events. These factors may introduce heterogeneity into the results and potential bias while making comparisons. Studies with smaller sample sizes also could affect the generalizability of the data reported and limit the statistical power required to detect rare adverse events in children. Where available, the duration of study observation was averaged and few studies reported on safety profiles for long-term data exceeding 3 years. There has also been considerable variability with the reporting format of adverse events across different studies, which prevented the ability to conduct a meta-analysis and could affect the reliability of the data owing to differences in terminology and grading scales. Lastly, for studies that did not separate pediatric and adult data, the decision was made to include studies with a mean age of less than 18 years because the data were relevant to this review. Despite the inclusion of adult adverse events from these studies, capturing this pediatric data reduces the likelihood that pediatric adverse events are missed in this review. Specific trends related to sex or age within pediatrics were not elucidated within studies included in this review.

Despite these limitations, this review holds importance owing to the evidence gap it addresses and its clinical implications. It will help clinicians and health care providers assess the risks and safety profiles of administering interleukin inhibitors to a pediatric population. It will assist pediatricians to make evidence-based treatment decisions and have informed discussions with patients about possible therapeutic routes. It also serves as a reference for health care professionals to help with the monitoring, and early detection of adverse events after the administration of the medication. However, further research is warranted to provide more conclusive data in the pediatric population, such as with randomized controlled trials. Furthermore, long-term studies are also required to expand our understanding of the long-term safety outcomes of interleukin inhibitors in children.