Avacopan-associated drug-induced liver injury (DILI) in children requires careful management because of its potential for rapid exacerbation. Avacopan is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis drug that selectively inhibits the C5a receptor, allowing for lower prednisolone (PSL) doses [1]. Because of this mechanism of action, avacopan could be effective against other diseases and may be more broadly used in the future [2]. However, to the best of our knowledge, reports on adverse avacopan reactions are limited, and there are no detailed reports about pediatric patients. Although the disease is not age-specific, the possibility that the drug dosage and reactions may vary according to pediatric characteristics should be considered. Herein, we present a pediatric case of severe DILI that developed rapidly and was thought to have been caused by avacopan.

A 10-year-old boy was referred to our hospital with prolonged vasculitis symptoms. He had experienced recurrent episodes of abdominal pain, diarrhea, gingivitis, sinusitis, and conjunctivitis over the previous 5 months. One month before, due to purpura, hematochezia, and hematuria, the patient was started on an oral steroid therapy; however, symptoms did not improve. At the time of his first visit to our hospital, his Birmingham Vasculitis Activity Score (BVAS) was 16 (purpura, conjunctivitis, sinusitis, abdominal pain, and hematuria). Blood tests revealed Proteinase-3 (PR3) ANCA > 350 U/mL (above the limit of measurement), eosinophils < 1%, aspartate aminotransferase (AST) 13 IU/L, alanine aminotransferase (ALT) 12 IU/L, and γ-glutamyltranspeptidase (γ-GTP) 26 IU/L. Urinalysis revealed a urine protein/creatinine ratio of 0.16 g/gCr, red blood cell (RBC) counts of 20–29/high power field, and positive RBC casts. Additional kidney histology, head magnetic resonance imaging plus angiography, spirometry, audiometry, and electrocardiography revealed no abnormal findings; however, chest computed tomography revealed a diffuse alveolar hemorrhage. The patient was diagnosed with granulomatosis with polyangiitis (GPA) and was immediately treated with three courses of methylprednisolone pulse therapy. Induction therapy was planned to consist of rituximab (RTX) once a week for a total of four weeks and three avacopan 10 mg capsules administered twice daily, since he was a child and PR3-ANCA positive. Figure 1 illustrates the patient’s progress. On day 31 after avacopan initiation, the patient was asymptomatic. However, blood tests revealed sudden liver function test abnormalities; AST 723 IU/L, ALT 1145 IU/L, γ-GTP 616 IU/L, total-bilirubin 0.56 mg/dL, ammonia 58 μg/dL, prothrombin time/internationally normalized ratio 0.86, and activated partial thromboplastin time 24.7 seconds. Blood and throat swab specimens collected at the onset of liver function test abnormalities were tested; polymerase chain reaction tests for severe acute respiratory syndrome coronavirus 2 and serum IgM for adenovirus, cytomegalovirus, Epstein-Barr virus, and varicella-zoster virus were all negative. From the time before avacopan initiation throughout the liver function tests to the period after the abnormalities were identified, hepatitis B and C viruses were continuously tested for HBs antigen, HBc antibody, HBs antibody, HCV antibody, and HBV-DNA amounts for reactivation monitoring, and no abnormalities were detected. Drug-induced lymphocyte stimulation test results were negative for avacopan and RTX. Avacopan and the fourth round of RTX were discontinued, but PSL, sulfamethoxazole-trimethoprim, alfacalcidol, and teprenone were continued. Subsequently, the patient’s liver injury improved, and he did not have an elevated BVAS.

Fig. 1
figure 1

Course of a child with granulomatosis with polyangiitis treated with avacopan. Avacopan and other induction therapy drugs are indicated in the upper row. The vertical axis of the graph shows the proteinase-3 (PR-3) anti-neutrophil cytoplasmic antibody (ANCA) and liver enzyme levels. The horizontal axis shows the number of days elapsed following administration of avacopan. Liver enzyme levels were normal on day 26 of treatment; however, a sharp increase was observed on day 31. The patient’s liver enzyme levels improved after drug discontinuation. The Birmingham Vasculitis Activity Score of the patient remained unrelated to liver enzyme levels. PSL, prednisolone; IVMP, intravenous methylprednisolone; RTX, rituximab; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyltranspeptidase

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Notably, severe liver function test abnormalities suspected to be avacopan-related developed rapidly in this child with GPA. Although the time of DILI onset was unknown, it was detected early because the patient was on scheduled treatment with RTX. Avacopan-induced liver function test abnormalities are well known. In a randomized controlled trial on ANCA-associated vasculitis, the incidence was higher in the avacopan group (5.4%) than in the PSL group (3.7%) [1]. Therefore, the Food and Drug Administration and other agencies have issued warnings regarding liver function abnormalities. However, the frequency at which follow-up should be performed was not indicated. Several detailed reports on liver function test abnormalities following avacopan administration in adults have been published. In one patient, with the shortest confirmed test interval, liver function values were normal 2 weeks prior, but increased to a maximum ALT of 624 U/L on day 32 of avacopan [3]. Although it is undeniable that the previously reported patient experienced DILI in a period shorter than 2 weeks, our patient had a normal ALT 5 days earlier, which increased to a maximum of 1254 IU/L. The mechanisms of DILI due to avacopan have not yet been elucidated, and childhood factors may have played a role in the rapid progression of the disease. Currently, there are only two detailed reports of avacopan use in children [2, 4]. The first case included an 11-year-old with C3 glomerulonephritis who was treated with avacopan for 41 months, including an 8-week withdrawal period according to the trial. The second was a 9-year-old with GPA who was treated with avacopan for 35 months. These children benefited from the dosage of three 10 mg avacopan capsules administered twice daily; this treatment was chosen based on a phase II study. In the present case, we chose a similar avacopan dose; however, the patient developed severe liver function test abnormalities. In contrast, a phase I study in which 48 adult volunteers received 1, 3, 10, 30, or 50 mg capsules of avacopan administered twice daily, or a placebo, experienced no dose-dependent adverse drug reactions [5]. However, the long-term relationship between adverse drug reactions and dose is still being determined because of the short 7-day trial period. Since the pharmacokinetics of avacopan are dose-dependent [5], there may be an optimal dose for children who are underweight compared to adults. In this child, whose detailed infectious disease tests revealed negative results for viral hepatitis, the liver function test abnormalities resolved spontaneously after discontinuation of avacopan. The BVAS, which was used to assess the GPA activity during the observation period, remained unchanged. These trends indirectly support the possibility that avacopan was related to the observed abnormalities.

The cause of the liver function test abnormalities in this case report cannot be definitively stated, as there is a possibility that it may have been caused by other drugs in the treatment regimen, including RTX. However, there is a paucity of patients with ANCA-associated vasculitis medicated with RTX who have shown liver function test abnormalities [6]. Additionally, other drugs were continued without any association with liver function transitions. Therefore, DILI caused by avacopan was suspected. The course presented by this child will be useful in future practice.

In summary, DILI caused by avacopan may be rapid and severe in children. As more reports accumulate, it will be easier to elucidate the pathogenesis associated with the liver function test abnormalities, and optimal drug dosing and follow-up intervals in children should be established.

Summary

What is new?

  • Avacopan for granulomatosis with polyangiitis in pediatric patients may induce rapidly severe liver function test abnormalities. Herein, aspartate aminotransferase level was normal before reaching approximately 1200 IU/L 5 days later.