Drug-induced liver injury secondary to anakinra in a patient with systemic juvenile idiopathic arthritis—Case report and literature overview

Abstract

Background:

Anakinra, an interleukin-1 receptor antagonist, is widely used to manage systemic juvenile idiopathic arthritis (sJIA) and related inflammatory conditions. While generally well tolerated, rare cases of drug-induced liver injury (DILI) have been reported.

Methods:

In addition to a literature review, we present a pediatric case of severe DILI attributed to anakinra. The case is of a 14-year-old male with sJIA complicated by macrophage activation syndrome (MAS) who developed DILI following the initiation of anakrina.

Results:

Anakrina was started after initial corticosteroid treatment. Following dose escalation, he developed a marked elevation in liver enzymes and cholestasis. Extensive workup, including a liver biopsy, excluded other causes and supported a diagnosis of anakinra-induced DILI. Discontinuation of anakinra led to the gradual normalization of liver function. Subsequent treatment with cyclosporine and tocilizumab was well tolerated.

Conclusions:

Differentiating the liver enzyme elevation to MAS versus DILI is challenging but critical, as management strategies differ. Anakinra-induced liver injury appears to be an idiosyncratic, immune-mediated phenomenon that resolves on drug withdrawal. Our case highlights the importance of monitoring liver function during anakinra therapy and the role of liver biopsy in complex cases.

Lay Summary

Anakinra is a medication used to treat children with a type of arthritis called systemic juvenile idiopathic arthritis (sJIA), which causes joint inflammation and other symptoms. Although anakinra is usually safe, it can cause liver damage in rare cases. We describe a 14-year-old boy with sJIA who developed serious liver problems after starting anakinra. Tests and a liver biopsy confirmed the medication was the cause. After stopping anakinra, his liver improved, and he was successfully treated with other medicines. This case shows that doctors should carefully watch liver tests in children on anakinra to catch any liver injury early and adjust treatment as needed.

Introduction

Anakinra is a recombinant interleukin-1 receptor antagonist (IL-1RA) that inhibits the biological activity of both IL-1α and IL-1β, controlling active inflammation (1). It is commonly prescribed for systemic juvenile idiopathic arthritis (sJIA), macrophage activation syndrome (MAS), refractory Kawasaki disease (KD), and some periodic fever syndromes (2). Adverse reactions are usually not serious and include injection-site reactions, respiratory infections, headaches, and, less commonly, abdominal pain and diarrhea (1). Hepatotoxicity and hepatic events have also been reported in pediatric patients with sJIA and KD (3–5) as rare side effects of anakinra in isolated case reports and in small case series. Hepatotoxicity has also been described as a side effect of anakinra in adult patients with rheumatoid arthritis and Still's disease (6).

Along with a literature review, we describe a pediatric patient with drug-induced liver injury (DILI) secondary to the initiation of anakinra for severe sJIA with MAS.

Case Report

A 14-year-old male was referred to pediatric rheumatology with two months of upper- and lower-limb polyarthritis and two weeks of a quotidian fever pattern. On initial assessment, he exhibited a bilateral, evanescent erythematous maculopapular rash on the upper extremities and torso, with coalescing lesions. Additional findings included generalized lymphadenopathy, hepatosplenomegaly, and extensive small- and large-joint polyarthritis.

Laboratory evaluation revealed neutrophilic leukocytosis, elevated inflammatory markers, ESR >100 mm/h (normal: 0–10) and CRP >200 mg/L (normal: 0–7), and mild hypoalbuminemia (albumin 32 g/L; normal: 35–45). Features consistent with MAS were present: hyperferritinemia (ferritin 2953 µg/L; normal: 20–200), hypertriglyceridemia (1.3 mmol/L; normal: 0.40–1.00), hypofibrinogenemia (1.6 g/L; normal: 1.8–3.5), elevated soluble IL-2 receptor (2766 pg/mL; normal: 195–666), and elevated CD163 (2253 pg/mL; normal: 215–1217). The liver enzymes were initially normal but later became elevated: ALT 86 U/L (normal: 8–60), AST 70 U/L (normal: 10–40), GGT 554 U/L (normal: 10–50), ALP 483 U/L (normal: 63–270), and total bilirubin 64 µmol/L (normal: 2–22), attributed to MAS. The rheumatoid factor, ANA, and infectious workup were negative. Abdominal ultrasound showed hepatosplenomegaly with normal liver echotexture and patent hepatic vessels. Echocardiography revealed a small pericardial effusion.

Based on clinical and laboratory features, the patient was diagnosed with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS. He was started on IV pulse methylprednisolone, followed by oral prednisone, subcutaneous anakinra at 2 mg/kg/day, and acetaminophen for fever. He initially tolerated treatment but had an incomplete response. Anakinra was increased to 4 mg/kg/day (100 mg twice daily).

Following dose escalation, liver enzymes rose significantly. Three weeks after anakinra initiation, ALT increased to 1400 U/L and AST to 834 U/L. He developed severe cholestasis with total bilirubin 109 µmol/L (normal: 0–9) and direct bilirubin 24 µmol/L (normal: 0–5). Liver synthetic function remained intact (INR 0.9; albumin 37 g/L), but persistent MAS markers raised concerns for ongoing MAS or possible DILI. Further investigations, including a comprehensive infectious and autoimmune hepatitis workup, were negative. The differential diagnosis included MAS-related hepatitis, Wilson disease, autoimmune hepatitis, and DILI secondary to methylprednisolone, prednisone, or anakinra. A liver biopsy was performed, revealing lobular hepatitis with zone 3 necrosis, parenchymal loss, moderate inflammatory activity, and no significant fibrosis (Figure 2). There were no histological features of Wilson disease or MAS.

Figure 2: Lobular predominant hepatitis with zone 3 necrosis and parenchymal loss.

Histologic findings include patchy chronic lobular inflammation with necrosis and parenchymal loss (*) surrounding a central vein (CV); relatively preserved hepatocytes are seen in the top left (#) (magnification 400×)

Anakinra was discontinued after 4 weeks and replaced with cyclosporine; steroids were continued. Liver enzymes remain elevated for 1 week post-discontinuation but returned to baseline with the resolution of cholestasis by week 12 (Figure 1). Tocilizumab was added at week 8. The patient tolerated the tocilizumab–cyclosporine combination well, with resolution of systemic symptoms, improved arthritis, and the normalization of liver parameters.

Figure 1: Laboratory values at disease onset and resolution of transaminitis.

Discussion

Liver enzyme elevation is common in sJIA and may be linked to disease activity, MAS, or DILI. Differentiating the cause is challenging, as MAS often requires escalated therapy, while DILI necessitates stopping the offending drug, which can worsen disease management. Interpreting labs is complicated, as ferritin, liver enzymes, and CD163 can be elevated in both MAS and DILI.

Anakinra-induced liver injury, though rare, is a significant concern in sJIA management. Our report adds to the limited literature on this topic. Table 1 summarizes the reported cases. The first series described three sJIA patients developing acute hepatitis on anakinra (3). Similar cases were reported by Murray et al, who noted improvement in liver enzymes after stopping anakinra, although no biopsies were performed (5). A 2023 case series reported pediatric cases of anakinra-induced DILI in KD and sJIA (4). Taylor et al described acute liver failure in an adolescent with Still's disease, with full recovery after discontinuation (6). Similar associations are reported in adults with adult-onset Still's disease (AOSD) and in patients with rheumatoid arthritis, with resolution of hepatotoxicity after drug withdrawal (7–9). Our case is novel in that the liver biopsy confirmed DILI and ruled out other causes. Liver enzymes also improved in our patient after stopping anakinra.

Table 1:

Case reports: Hepatotoxicity associated with anakinra

Study reported	Total patients Age range	Sex	Diagnosis	Peak enzymes	Outcome
Canna et al3	n = 3 13 mo to 8 y	NR	Acute hepatitis	AST Levels Patient 1: 1200 U/L Patient 2: 3000 U/L Patient 3: 2400 U/L	In two patients, transaminitis resolved within 1 week of discontinuing IL-1RA, the third improved in 1 month
Murray et al5	n = 1 13 y	M	Severe hepatotoxicity	ALT: 12000 U/L AST: NR	Resolved after discontinuation of anakinra
Martins et al4	n = 3 Patient1: 12 y Patient 2 y Patient 3: 4 y	M	Acute hepatitis	Patient 1: AST: 1900 IU/L ALT: 4050 IU/L Patient 2: AST: 110 IU/L ALT: 910 IU/L Patient 3: AST: 900 IU/L ALT: 1575 IU/L	Resolved after discontinuation of anakinra
Aly et al8	n = 1 20 y	M	Subacute liver failure	ALT: 1128 U/L	ALT gradually decreased following cessation of anakinra
Ahmed et al7	n = 1 46 y	F	Acute liver failure	AST: 927 IU/L and ALT: 1414 IU/L	Liver enzymes stabilized after 1 week of discontinuing anakinra
Taylor et al6	n = 1 16 y	M	Severe acute liver failure	AST: 2271 U/L and ALT of 2002 U/L	Liver enzymes returned to normal at his 1-year follow-up
Mahamid et al9	n = 2 46 y 49 y	F	Steatosis and steatohepatitis	Patient 1: WNL Patient 2: AST 30 U/L and ALT 50 U/L	In patient 2, liver enzymes returned to normal 3 weeks after discontinuing anakinra

NR = Not reported

Anakinra-induced liver injury is likely idiosyncratic and immune-mediated, not dose-dependent. IL-1 blockade may disrupt cytokine balance, impairing hepatocyte survival and promoting apoptosis. Histology often shows hepatocellular injury with eosinophilic infiltration and necrosis, supporting an immune-driven mechanism (10). Typically, the injury resolves after the discontinuation of anakinra, though the mechanism remains unclear. Immune dysregulation is likely central, as noted in case series and in the LiverTox publication (1,10). Although anakinra has shown hepatoprotective effects in some contexts (eg, improving hepatitis in AOSD, promoting regeneration post-hepatectomy, and preventing liver failure in rat models), it has also been linked to liver injury (11–13). These contradictory effects underscore the complex, context-dependent role of IL-1ra (14).

Conclusion

Our case report reinforces that anakinra-induced DILI should be considered in sJIA patients with elevated liver enzymes. Liver function monitoring is advised, particularly during early therapy or dose escalation. A liver biopsy can help clarify the etiology in complex cases involving MAS and liver enzyme abnormalities.

Funding Statement

N/A

Contributions:

Conceptualization, MP Jariwala, S Mannala, M Kehar; Data curation, MP Jariwala, S Mannala, L Samson, A Poulin; Formal Analysis, MP Jariwala, S Mannala, L Samson, M Kehar; Investigation, MP Jariwala, T Kerr, A Poulin; Writing – Original Draft, MP Jariwala, S Mannala, L Samson, M Kehar; Writing – Review & Editing, MP Jariwala, S Mannala, M Kehar, T Kerr; Supervision, M Jariwala.

Ethics Approval:

N/A

Informed Consent:

Consent was obtained from the patient and family for this case report. No personal information of the patient is included.

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

N/A

Funding:

N/A

Disclosures:

The authors have no conflicts of interest to disclose. There was no financial support or competing interests involved.

Peer Review:

This manuscript was peer reviewed.

Animal Studies:

N/A