Introduction: Avacopan, an oral C5a receptor antagonist, has been demonstrated to be effective in inducing and maintaining remission in microscopic polyangiitis (MPA), with the additional benefit of reducing glucocorticoid exposure and associated toxicity. Among its side effects, liver injury is the most common, occurring in 16. 7-40. 9% of cases in Japanese cohorts. Methods: A patient in her 90s was undergoing treatment for hypertension and diabetes but was referred for further evaluation due to worsening renal function. MPO-ANCA was elevated to 300 IU/mL and renal function remained stable at the same level for a while. Renal involvement was considered an organ manifestation of vasculitis, and prednisone (PSL) 0. 5 mg/kg/day was initiated. After starting PSL, renal function declined. Judging that disease activity could not be controlled with steroids alone, rituximab was added. Two months after starting steroids, the patient was hospitalized with acute pyelonephritis. Avacopan was introduced with the goal of early steroid withdrawal. Four months after treatment initiation, she got herpes zoster and was prescribed amenamevir. She presented with skin jaundice and anorexia and was admitted with liver dysfunction and jaundice (T-Bil 21. 2 mg/dL). Avacopan was discontinued due to difficulty with oral intake while MPO-ANCA was decreased to 4. 7 IU/mL. Based on this course, druginduced hepatitis was suspected. Two courses of steroid pulse therapy (mPSL 500 mg) were administered, and fresh frozen plasma was supplemented when prothrombin was decreased. The patient progressed from subacute hepatitis to fulminant hepatitis and passed away. Results: Avacopan is metabolized by the liver, and hepatic impairment as an adverse effect has been reported in the ADVOCATE trial. Liver dysfunction was not observed within the first 6 weeks after abvacopan initiation. This was considered a drug-induced liver injury caused by amenamevir or avacopan. Avacopan-induced liver dysfunction can manifest after more than 4 weeks of administration. It remains unclear whether the combination was inappropriate or if the 6-week timing after initiation coincided with the onset of liver dysfunction, compounded by the time lag between jaundice onset and hospital presentation. Both avacopan and amenamevir are metabolized in the liver by CYP3A4. Abacopan has moderate inhibitory effects on CYP3A4, while amenamevir induces CYP3A4 making interaction possible. Although avacopan was discontinued during amenamevir administration, prior avacopan use before starting amenamebvir may have led to increased amenamevir blood levels. Conclusion: ANCA-associated vasculitis is a systemic disease causing multi-organ dysfunction, necessitating therapeutic intervention. Recent advances in molecularly targeted therapies, such as rituximab and avacopan, have expanded treatment options. Clinicians involved in future management must select optimal treatment strategies, considering both therapeutic timing, dosage, and administration methods, while also weighing healthcare economics. I have no potential conflict of interest to disclose. I did not use generative AI and AI-assisted technologies in the writing process.
Suzuki et al. (Wed,) studied this question.