Interleukin 1 (IL-1), a critical proinflammatory cytokine produced by monocytes and macrophages, comprises two distinct ligands: interleukin 1α (IL-1α) and interleukin 1β (IL-1β) (Nur Sunar Yayla et al., 2024; Salmon et al., 2022). Both IL-1α and IL-1β bind to the IL-1 type 1 receptor (IL-1R1), inducing a wide range of secondary inflammatory mediators and playing critical roles in regulating immune and inflammatory processes, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (Kim and Lee, 2024; Xu et al., 2024; Wu et al., 2022).

In 2001, the U.S. Food and Drug Administration (FDA) approved the first IL-1 blocker, anakinra, for the treatment of RA, cryopyrin-associated periodic syndromes (CAPS), and deficiency of IL-1 receptor antagonist (DIRA); this agent is a recombinant form of the IL-1R antagonist (IL-1Ra) that competitively inhibits the binding of IL-1α and IL-1β to the IL-1R1, thus blocking IL-1 signaling and mitigating its inflammatory effects (Arnold et al., 2022). In 2009, the FDA approved canakinumab, a human monoclonal antibody that specifically and selectively targets IL-1β, for treating periodic fever syndromes, including familial Mediterranean fever (FMF), CAPS, and Still’s disease (Sanz-Cabanillas et al., 2023). Rilonacept, another FDA-approved IL-1 blocker, was excluded from this study due to insufficient safety data. Although anakinra and canakinumab offer significant therapeutic benefits for numerous autoinflammatory diseases (AIDs), adverse drug reactions, including injection site reactions (ISRs) and infections, have been observed both during and after treatment (Giancane et al., 2022; Baverez et al., 2022; Lopalco et al., 2022; Cota-Arce et al., 2021; Qiu et al., 2024). Additionally, some studies have reported severe adverse events (AEs), such as macrophage activation syndrome (MAS), pneumonia, and liver failure (Cota-Arce et al., 2021; Kullenberg et al., 2016; Sota et al., 2018; Taylor et al., 2016). Multicenter observational studies in Europe have demonstrated that anakinra and canakinumab were frequently utilized beyond their approved indications in clinical settings, treating a spectrum of conditions from monogenic AIDs to various polygenic and multifactorial disorders, including Blau syndrome, Behçet’s disease, idiopathic uveitis, and idiopathic recurrent acute pericarditis (Vitale et al., 2016; Del Giudice et al., 2022; Rossi-Semerano et al., 2015). Significantly, this off-label use has not been accompanied by a long-term comprehensive risk assessment. Given these findings, a systematic analysis of extensive samples and real-world AEs is essential to ensure their safety.

The FDA Adverse Event Reporting System (FAERS) database, which gathers spontaneous AE reports from healthcare professionals, pharmaceutical manufacturers, patients, and others from diverse regions, is an invaluable resource for post-market surveillance and the early detection of drug safety issues (Zou et al., 2024). We conducted this pharmacovigilance study to assess the potential correlation between IL-1 blockers—anakinra and canakinumab—and AEs, utilizing real-world data from FAERS and a variety of signal quantification techniques to offer valuable insights for clinical decision-making, regulatory safety, and future comprehensive research.

This study represented the first systematic analysis of the safety of IL-1 blockers in a real-world population through a pharmacovigilance approach. Our analysis not only confirmed established safety information but also identified novel risk signals, thus providing a more comprehensive and accurate foundation for future public health decision-making and drug safety regulation. An in-depth discussion of the findings follows.

This study identified that subcutaneous injection emerged as the prevalent administration mode for both drugs (anakinra 72.64%; canakinumab 69.24%), followed by intravenous injection (anakinra 0.70%; canakinumab 0.83%). Although the proportion of intravenous injections was relatively low, one study demonstrated that among gout patients, intravenous administration of anakinra proved more effective than subcutaneous administration among patients with higher BMI and significant edema (Thueringer et al., 2015). Saunders et al. observed that intravenous administration of anakinra facilitated more rapid mitigation of cytokine storms in cases of adult MAS (Saunders et al., 2023). The determination of the optimal administration mode for specific indications of IL-1 blockers warrants further investigation. In addition, the significant proportion of “other” administration routes (anakinra 26.11%; canakinumab 29.21%) may obscure the risks associated with specific routes, such as intra-articular administration (Brown et al., 2011; Chevalier et al., 2009; Brown et al., 2010). Regarding the reports with established AE timing, AEs associated with anakinra most frequently occurred within 30 days of dosing (32.74%), while those for canakinumab displayed a broader temporal distribution; this discrepancy may stem from anakinra’s higher incidence of early, transient ISRs (Kaiser et al., 2012). This underscored the necessity of early and ongoing monitoring of AEs associated with anakinra and canakinumab, and indicated that future safety studies related to canakinumab may require prolonged follow-up. Regarding the countries of reporting, the majority of anakinra (71.13%) and canakinumab (41.78%) reports originated from the United States, which may not accurately reflect the global occurrence of adverse reactions, especially in regions like Asia, due to regional and racial variations. Enhanced multinational pharmacovigilance cooperation is necessary to achieve a comprehensive understanding of adverse reaction profiles worldwide.

Analysis of indications, with the exception of unknown product uses, revealed that RA (26.56%), Still’s disease (15.47%), and juvenile idiopathic arthritis (12.54%) were the prevalent indications for anakinra, while for canakinumab, common indications included Still’s disease (16.57%), CAPS (12.83%), and pyrexia (11.18%). Notably, both drugs demonstrated a significant frequency of off-label use, especially anakinra. The emerging recognition that IL-1 plays a pivotal role in the immune-driven mechanisms of inflammatory diseases, and that IL-1 blockers inhibit proinflammatory pathways in these conditions through a highly specific mode of action, has prompted the increased use of targeted modulatory IL-1 therapies across various inflammatory diseases (Sota et al., 2018). Recent systematic reviews have shown that anakinra and canakinumab both provide significant clinical benefits in treating CAPS, FMF, gout, RA, and systemic juvenile idiopathic arthritis (Arnold et al., 2022). In alignment with our findings, multicenter observational studies from Europe have revealed that, due to limited licensed indications, anakinra and canakinumab were frequently administered off-label, particularly anakinra (Vitale et al., 2016; Rossi-Semerano et al., 2015). Anakinra was employed as a first-line biologic agent in a larger patient cohort, potentially explaining the drug’s comparatively higher rate of off-label prescribing (Vitale et al., 2016). Indeed, the current experience with IL-1 blockers in off-label settings proves inadequate due to the absence of comprehensive long-term monitoring. Our exploration of AEs using real-world data offers critical evidence towards ensuring their safety.

A series of risk signals were identified in this study; based on disproportionality analysis at the SOC level, AEs associated with anakinra were primarily linked to infections and infestations, while those associated with canakinumab predominantly involved congenital, familial and genetic disorders and infections and infestations. Of note, the majority of AERs were submitted by consumers, rather than healthcare professionals. Considering the potential lack of reliability and comprehensiveness in consumer reports compared to professional submissions, as well as the differences in focus—such as patients potentially excelling at reporting subjective experiences—we subsequently analyzed a subset of reports submitted by both healthcare and non-healthcare professionals, comparing these with the overall findings. The results indicated only minor changes in the rankings of the most frequently reported SOC signals, suggesting minimal impact of reporting bias on our conclusions, further affirming the reliability of our findings.

At the PT level, both anakinra and canakinumab exhibited significant signals of AEs related to infections and ISRs. These AEs generally aligned with the information provided in the drug insert and clinical safety data. Although previous studies reported favorable safety profiles for anakinra and canakinumab (Atas et al., 2021; Arnold et al., 2022), our findings indicated that occurrences of death were documented in AER outcomes. Further analysis of these reports revealed that Still’s disease and cardioembolic event prophylaxis were the primary indications reported by health professionals for anakinra and canakinumab, respectively. AEs such as septic shock, acute respiratory distress syndrome, and condition aggravated occurred frequently, suggesting that the poorer general clinical status of the underlying disease, its complications, and further deterioration may be the principal contributors to mortality.

ISRs represent the most common and consistently reported AEs for IL-1 blockers. A retrospective observational study demonstrated that canakinumab was associated with a lower rate of ISRs compared to other IL-1 blockers (Nur Sunar Yayla et al., 2024). Consistent with these observations, we found that a greater number of ISRs was associated with anakinra, attributable to the shorter half-life of anakinra and the requirement for daily subcutaneous injections. In contrast, canakinumab, with its longer half-life, does not require frequent injections or high dosages, potentially contributing to better skin tolerance of canakinumab (Dhimolea, 2010). Furthermore, the analysis indicated that both drugs were linked to improper drug use, particularly anakinra. Anakinra is comparatively inconvenient compared with canakinumab, which requires injections every 4 or 8 weeks. The more frequent ISRs associated with anakinra may also have impeded patient compliance.

As with all biologics, infections represent a worrisome adverse effect of IL-1 blockers. Cabral et al. observed that 129 (5.1%) of 2,896 RA patients treated with anakinra developed serious infections, primarily in the respiratory tract (Cabral et al., 2016). A meta-analysis demonstrated a dose-dependent increase in the incidence of serious infections among 2,062 RA patients undergoing treatment with anakinra (Salliot et al., 2009). Furthermore, numerous observational studies have disclosed that infections, particularly upper respiratory tract infections (URTIs), are the most common AEs in canakinumab-treated pediatric rheumatic diseases (Kilic Konte et al., 2024; Coşkuner et al., 2023; Iwata et al., 2023). In alignment with prior findings, this study identified a high frequency of infection-related AEs with strong signal intensity; sinusitis and nasopharyngitis were the most frequent infection-related AEs associated with anakinra and canakinumab, respectively. Importantly, the present study did not detect a safety signal for tuberculosis infection or reactivation. Previous evidence indicated that opportunistic infections, specifically those caused by Mycobacterium tuberculosis, were rare in patients treated with IL-1 blockers, even among populations at high risk for reactivation of latent infections (Cavalli and Dinarello, 2018; Cantarini et al., 2015; Dumaine et al., 2020; Lima et al., 2023). IL-1 appears to be associated with late hypersensitivity reactions to M. tuberculosis. However, this association does not play a fundamental role in infection control, potentially explaining the minimal or absent risk of tuberculosis in patients treated with IL-1 blockers (Lima et al., 2023). Nonetheless, given the elevated risk of infection associated with IL-1 blockers, it is recommended that thorough assessments be conducted for active and latent infections before initiating treatment, and that indicators of infection are closely monitored during therapy to minimize the risk of severe infectious events.

Although hepatotoxicity associated with IL-1 blockers is rare, it cannot be ignored. Multiple case reports have documented hepatotoxicity related to anakinra use in both adult and pediatric patients, particularly in those with Still’s disease or predisposing factors, such as a history of elevated liver enzymes (Martins et al., 2023; Murray et al., 2021; Giancane et al., 2022). Taylor et al. reported a case wherein a teenager with adult-onset Still’s disease developed severe acute hepatic failure attributed to anakinra use (Taylor et al., 2016). Canakinumab exerts minimal impact on hepatic metabolism compared to anakinra and has not been linked to any clinically significant cases of acute liver injury (Gülez et al., 2020). However, multiple large registration trials have reported ALT elevations in 1%–3% of patients treated with canakinumab (Lachmann et al., 2009; So et al., 2010; Schlesinger et al., 2012; Ruperto et al., 2018; Feist et al., 2018). This study identified significant signals of hepatocellular injury and hepatomegaly in anakinra-associated AEs, as well as hepatomegaly and transaminase elevation in canakinumab-associated AEs, thus confirming the association between IL-1 blockers and liver injury. Notably, these signals predominantly occurred in minors. The absence of systematic liver function monitoring in FAERS data could result in detection bias and an underestimation of risk since mild or transient liver enzyme elevations might be undocumented. Consequently, these results must be interpreted with caution. The mechanisms underlying hepatic injury caused by anakinra and canakinumab remain elusive and are potentially linked to their effects on the immune system or the IL-1 pathway, crucial for regulating inflammation and cellular damage. Although severe hepatic injury AEs are rare, monitoring liver function during IL-1 blocker therapy is essential, particularly in minors. Further research is required to elucidate the direct connection between anakinra, canakinumab, and liver injury.

The study also identified numerous significant risk signals not outlined in the drug labels, including clubbing, Waldenström’s macroglobulinemia, hepatosplenic T-cell lymphoma, body height below normal, and decreased gastric pH associated with anakinra use; and deafness, pulmonary thrombosis, brain edema, clubbing, increased intracranial pressure, adenocarcinoma of the colon, papillary thyroid cancer, and squamous cell carcinoma of the lung related to canakinumab use. All of these AEs occurred infrequently; their mechanisms have yet to be fully elucidated, and certain side effects may be a general result of impaired IL-1 pathways. It is noteworthy that we identified rare tumor-associated AEs with both anakinra and canakinumab. A multicenter study reported Waldenström’s macroglobulinemia in two patients with Schnitzler’s syndrome, attributed to anakinra use (Néel et al., 2014). The literature still lacks a conclusive association between IL-1 blockers and malignancy; though the frequency of malignancy-associated AEs is low, prospective, long-term multicenter studies remain necessary.

Although the comprehensive characterization of anakinra and canakinumab-associated AEs in this study provided robust evidence for their safety, several limitations persist. First, the FAERS database depends on a spontaneous reporting system, which carries inherent risks such as irregular and incomplete reporting, potentially leading to reporting bias. Second, the signal of AEs detected by the study using the disproportionality method elucidates only a statistical correlation with the targeted AEs, not representing a biological causal link; further clinical studies are therefore necessary to explore this causal relationship. Additionally, the scarcity of detailed clinical patient information and medication information hindered control over confounding variables, including comorbidities, medication dosage, and other health-affecting factors, as well as the ability to assess efficacy. Finally, given the voluntary reporting nature of the FAERS database, it is not possible to determine the total number of individuals treated and thus the exact incidence of AEs and mortality outcomes.

Our comprehensive pharmacovigilance analysis of the FAERS database contributes real-world evidence supporting the clinical safety management of anakinra and canakinumab. Overall, the safety profile of anakinra and canakinumab was generally favorable, characterized primarily by ISRs and infections. No significant safety signals were detected for tuberculosis infection or reactivation, and the incidence of hepatic injury and malignancy-associated AEs was low. Furthermore, we observed that both anakinra and canakinumab were frequently used beyond their approved indications. In this context, the multilevel analysis of this study serves as a crucial reference for clinicians to optimize drug selection and enhance safety regulatory efforts. Future research, including more rigorous prospective, multicenter clinical trials and epidemiological studies, is necessary to validate our findings and facilitate a more precise assessment of the safety risks associated with anakinra and canakinumab.