To the Editor:

Avacopan, a C5a receptor (C5aR) inhibitor, has emerged as a novel treatment for antineutrophil cytoplasmic antibody–associated vasculitis (AAV), providing an alternative to glucocorticoids (GCs).1 Despite its promising potential, severe liver dysfunction associated with avacopan has been reported in Japan.2,3 Given the relatively recent approval of avacopan, there is lack of real-world evidence detailing its adverse events. We thus sought to elucidate the clinical differences between patients with and without avacopan hepatotoxicity treated at Nagasaki University Hospital, Japan Community Healthcare Organization (JCHO) Isahaya General Hospital, and Sasebo City General Hospital. Patients with AAV treated with avacopan from June 2022 to December 2023 were enrolled. We retrospectively reviewed all patient cases to confirm the AAV diagnosis. No other diagnoses could account for the findings of AAV.

This study was approved by the institutional review boards of Nagasaki University Hospital (approval no. 15072753), JCHO Isahaya General Hospital (approval no. 89), and Sasebo City General Hospital (approval no. 2023-A033). An opt-out strategy was chosen for the enrolled patients.

We classified patients using the 2022 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria for granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis,4-6 and compared the baseline characteristics, Birmingham Vasculitis Activity Score version 3,7 and immunosuppressive treatment between the patients who developed hepatotoxicity due to avacopan and those who did not. Avacopan-induced hepatotoxicity was defined as serum aspartate aminotransferase or alanine aminotransferase > 5× the upper limit of normal (ULN) or alkaline phosphatase > 2× ULN due to avacopan, as referenced in the American Association for the Study of Liver Diseases practice guidance on drug, herbal, and dietary supplement-induced liver injury.8 Categorical variables were compared using Fisher exact test, and continuous variables were compared using Wilcoxon rank-sum test.

Thirty-eight patients were eligible for the study; 2 patients were excluded because of an inability to distinguish hepatotoxicity caused by avacopan or sulfamethoxazole/trimethoprim. Table 1 summarizes the characteristics of the 36 patients with AAV. Six patients (16.7%) developed liver abnormalities due to avacopan; their liver dysfunction findings are summarized in Table 2. These 6 patients had no liver abnormalities, history of viral hepatitis, other liver diseases, or alcohol use disorder before the initiation of avacopan. They were negative for hepatitis C, and none had a chronic hepatitis B virus (HBV) infection. HBV reactivation was not observed in the patients with prior HBV exposure. Table 2 provides the results of other viral laboratory tests and imaging tests performed in relation to liver damage. These results were negative and varied among the patients. Two of the 6 patients (patients 1 and 4) had severe drug-induced liver injury (DILI) with jaundice. After cessation of avacopan, all 6 patients showed improvement in liver function. The range of scores of the updated Roussel Uclaf Causality Assessment Method (RUCAM) in the patients who developed DILI is 3 to 8 points, indicating at least possible causality.9 Significant differences in GC use were observed between the patients who developed avacopan-induced hepatotoxicity and those who did not (P = 0.045; Table 1).

Comparison of clinical and laboratory characteristics as well as treatment between patients with AAV who did and did not develop avacopan-induced liver injury.

Summary of clinical and laboratory characteristics of the 6 patients who developed avacopan-induced liver injury.

Of the 36 patients, 83.3% were treated with concomitant GCs, which is comparable to the result of the ADVOCATE trial,1 in which 75.2% of the patients in the avacopan group used GCs during the screening period. Although we have found no prior studies suggesting that GCs reduce the risk of any type of DILI, we speculate that GC use may mitigate the risk of avacopan-induced liver dysfunction in patients with AAV.

The pathophysiology of prolonged avacopan-induced liver dysfunction remains unknown. Daveau et al suggested that C5aR is upregulated during liver regeneration, and that C5a, through C5aR, induces a growth response in hepatocytes.10 Gonther et al recently described a beneficial role of C5aR in the recovery phase of acetaminophen-induced liver injury.11 Taken together, these findings suggest that one of the reasons for avacopan-induced liver dysfunction, especially in severely prolonged jaundice cases,2,3 may be that the blockade of C5aR by avacopan inhibits hepatocyte regeneration.

Another point of discussion is the racial differences in the proportion of patients with avacopan-induced liver dysfunction. Compared with the ADVOCATE trial,1 in which 278 of the 330 patients were White and 5.4% of the patients in the avacopan group experienced serious adverse events related to abnormalities in liver function, our study revealed a relatively higher incidence of avacopan-induced liver abnormalities. Research on DILI in Japanese patients has suggested that the frequency of the causes of DILI in Japan differs from those in Europe and North America.12 The difference in the proportion of patients with liver dysfunction due to avacopan use may be influenced by racial and genetic backgrounds.

Limitations of our study are its small sample size and the possible existence of confounding factors regarding the concomitant use of GCs with avacopan. The absence of both data on liver fibrosis evaluated by ultrasound and histopathological findings of liver specimens is also a limitation.

Our findings suggest a potential association between the absence of GC use concomitant with avacopan and DILI associated with avacopan.