Long-Term Safety of Anti-Interleukin-1 Medications in Children with Rheumatic Diseases: a Systematic Review.

Background: Anti-interleukin-1 (IL-1) biologic disease-modifying anti-rheumatic drugs are the mainstay for several childhood rheumatic and autoinflammatory diseases. Long-term medication safety is a key consideration for chronic disease management.

Aim: The objective was to synthesise evidence on the long-term safety of anti-IL-1 medications in children and young people with rheumatic diseases, including autoinflammatory diseases.

Methods: The study protocol was registered prospectively (PROSPERO CRD420251000272). Original full text studies of at least ten patients presenting safety data on anti-IL-1 medications in children with rheumatic diseases were eligible for inclusion. Medline, Embase and Web of Science were searched from inception to 27 February 2025. The methodological index for non-randomized studies (MINORS) tool was used to assess risk of bias. All relevant safety outcomes were presented and synthesised. Meta-analysis was not performed owing to study heterogeneity.

Results: A total of 1660 unique records were screened, and 57 unique studies (3690 patients) were included. In total, 31 were retrospective cohort studies, and 10 were prospective interventional trials. Most studies were of moderate (n = 31) or high (n = 25) risk of bias. Rates of adverse events varied significantly between studies. Injection site reactions (particularly with anakinra) and minor infections were common. Infections were the most common type of serious adverse event. Drug reaction with eosinophilia and systemic symptoms (n = 3) and interstitial lung disease (including related conditions) (n = 9) were reported in patients with systemic onset juvenile arthritis only. Deaths (n = 16) and malignancies (n = 7) were uncommon, often occurring long after anti-IL-1 medication discontinuation and were often deemed to be unrelated to the anti-IL-1 medication.

Conclusions: Our results are consistent with the known safety profile of anti-IL-1 medications and show that they are generally safe for use in the context of childhood rheumatic and autoinflammatory diseases. This review of clinical trial and real-world data will help inform clinical decision-making and family counselling when initiating anti-IL-1 medications in children.