Natural history and management of refractory autoimmune hepatitis

Short abstract

Content available: Author Interview and Audio Recording

Answer questions and earn CME

Watch the interview with the author.

Listen to an audio presentation of this article.

Autoimmune hepatitis (AIH) is a chronic liver disease that can result in hepatic fibrosis and progress to cirrhosis and need for liver transplantation. Corticosteroids and azathioprine (AZA) are recommended as first‐line therapies for induction and maintenance therapy and are successful in the majority of cases. ¹ , ² The goal of treatment is biochemical remission (normalization of serum aspartate aminotransferase, alanine aminotransferase, and immunoglobulin G levels) and histological remission if biopsy is pursued. However, 10% to 20% of patients have treatment failure (worsening laboratory values or histological findings) or insufficient response to treatment, which is defined as failure to normalize aminotransferases by 6 months. ² Patients who do not achieve remission require urgent action because refractory disease is associated with disease progression and increased risk for liver‐related death or need for liver transplant. ³

Guidelines on treatment decisions for the 10% to 20% of difficult‐to‐treat patients are limited because there are few randomized controlled trials. Practice is widely variable and often based on retrospective or single‐center experiences. In this review, we will explore the mechanism of action (Table 1) and evidence for available treatments of AIH refractory to standard first‐line therapies.

TABLE 1.

Mechanism of action for second‐ and third‐line therapies for AIH

Drug name/class	Mechanism of action	Dosing
MMF	Prodrug metabolized in the liver to mycophenolic acid, which inhibits purine biosynthesis, resulting in antiproliferative effects on T and B cells	20‐40 mg/kg/day
CNIs	Suppresses IL‐2 synthesis, which decreases T cell proliferation and differentiation	Tacrolimus: 2‐6 mg/kg/day, trough 1‐10 ng/mL
		CsA: 4‐10 mg/kg/day, trough 150‐200 ng/mL
mTOR inhibitors	Decrease T cell activation and expand regulatory T cells	Sirolimus: 1‐2 mg/kg/day, trough 2.5‐8 ng/mL
Anti B‐cell therapies
Rituximab	Monoclonal antibody against CD20 resulting in B cell depletion	375 mg/m2, repeat dosing based on aminotransferases and CD19 counts; other considerations include premedication with acetaminophen, diphenhydramine, and corticosteroids to prevent infusion reaction; can administer 1 g/kg intravenous immunoglobulin after infusion as infection prophylaxis
B cell activating factor (BAFF) inhibitors	Monoclonal antibody against BAFF or BAFF receptors, which inhibit B cell differentiation	Clinical trial with three experimental arms ongoing

MYCOPHENOLATE MOFETIL

Recent guidelines from the American Association for the Study of Liver Diseases (AASLD) and European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) support the use of mycophenolate mofetil (MMF) as an alternative first‐line or second‐line treatment for patients who are intolerant of AZA or who have refractory disease. ¹ , ² MMF is the most widely used second‐line treatment for AIH and generally has a favorable side‐effect profile. MMF is a prodrug of mycophenolic acid that inhibits de novo purine biosynthesis to inhibit T cell and B cell proliferation. Typically, patients who show good disease response to AZA but have intolerance because of side effects will have an improved response rate to MMF over those patients with AZA treatment failure. A meta‐analysis demonstrated the pooled response rate in these patients treated with MMF was 82%, while it was 32% for patients who were treated with MMF after AZA treatment failure. ⁴ There is also evidence that calcineurin inhibitors (CNIs) can be a successful second‐line therapy, but MMF is preferred because of a favorable side‐effect profile compared with CNIs (Table 2).

TABLE 2.

Side effects for second‐ and third‐line therapies for AIH

Drug name or class	Adverse effects
MMF	Leukopenia, diarrhea, teratogenicity
CNIs	Nephrotoxicity, hypertension, neurotoxicity, metabolic syndrome, gum hyperplasia and hypertrichosis (CsA)
mTOR inhibitors	Myelosuppression, hyperlipidemia, aphthous ulcers, proteinuria
Anti–B cell therapies	Infusion reaction, bacterial and viral infections

CALCINEURIN INHIBITORS

CNIs (e.g. cyclosporine [CsA] and tacrolimus) act by suppression of interleukin‐2 (IL‐2) synthesis and T cell proliferation. In a recent review of reported AIH cases where CsA (n = 133) or tacrolimus (n = 13) was used as first‐ or second‐line agent, success rates were more than 90% for both drugs. ⁵ When specifically used as second‐ or third‐line treatments, the outcomes are still positive, albeit lower. Pape et al. ⁶ reviewed outcomes in 20 adult and pediatric cases where CNIs were used after first‐line therapy failed. In these patients where CNIs were used as second‐line (n = 7) or third‐line (n = 13) therapy, transaminases normalized in 57% and 53.8%, respectively. A recent meta‐analysis of second‐line agents in pediatric AIH found six studies where CNIs were used and compared response rates at 6 months. In a total of four studies (n = 15 patients), there was an 83% response to CSA. Two studies (n = 4 patients) showed 50% response to tacrolimus. ⁷

MAMMALIAN TARGET OF RAPAMYCIN INHIBITORS

Mammalian target of rapamycin (mTOR) inhibitors are useful immunosuppressants because they both decrease T cell activation and function to expand regulatory T cells. Dysfunction of regulatory T cells is known to occur in AIH. Drugs such as sirolimus were first successfully used in the setting of posttransplant AIH but are now also considered for patients with refractory AIH. In a study by Chatrath et al., ⁸ five adult patients were treated with sirolimus as second‐ or third‐line therapy, and 40% (n = 2) had complete response, while 80% (n = 4) had a partial response, which was defined as a 50% decrease in baseline alanine aminotransferase. In a study by Kurowski et al. ⁹ of four pediatric patients with AIH who had unsuccessful standard therapy, 50% (n = 2) were successfully treated with sirolimus.

ANTI–B CELL THERAPIES

Historically, AIH has been primarily understood to be T cell mediated; however, there is growing evidence that supports the role of B cells in AIH pathogenesis through antigen presentation and stimulation of T cells, as well as inflammatory cytokine production. ¹⁰ Although limited, there are published reports showing a favorable response and safety profile of B cell–depleting therapies. Rituximab, an anti‐CD20 monoclonal antibody, is already used in multiple autoimmune diseases. Up until recently, literature on the use of rituximab for AIH was limited to case reports and case series. ¹¹ , ¹² , ¹³ In 2019, the largest cohort of patients with AIH treated with rituximab was published with 22 subjects across multiple centers internationally. Patients with a median age of 40 years (range 19‐79 years) had 71% freedom from AIH flares for 2 years, and 62% (n = 12) of patients were able to reduce the dose of prednisone.

B cell activating factor (BAFF), a cytokine in the tumor necrosis factor (TNF) family needed for B cell development and differentiation, is elevated in multiple autoimmune diseases, including AIH. ¹⁴ Inhibition of BAFF is currently being explored as a potential therapy for AIH. BAFF receptors are expressed on mature B cells, and there is an ongoing multicenter, randomized, double‐blinded, placebo‐controlled phase 2–3 clinical trial using ianalumab, a BAFF receptor inhibitor, in patients with AIH with incomplete response to standard therapy (ClinicalTrials.gov: NCT03217422). The study's estimated completion date is 2025. Belimumab, an anti‐BAFF monoclonal antibody, is FDA approved for the treatment of systemic lupus erythematous. Arvaniti et al. ¹⁵ described two cases of refractory AIH with favorable response to belimumab.

TNF‐α INHIBITORS

Monoclonal antibodies to TNF‐α have been successfully used to treat refractory AIH in children and adults. ¹⁶ , ¹⁷ However, based on the lack of sufficient data and the risk for infections and drug‐induced liver injury, neither ESPGHAN nor AASLD currently include this class as a recommended treatment for AIH. ¹ , ² Anti‐TNF‐α–triggered drug‐induced liver injury can present with an AIH‐like phenotype, including positive autoantibodies and interface hepatitis on liver biopsy. ¹⁸ , ¹⁹ The highest incidence is in patients taking infliximab and generally is associated with a favorable prognosis.

AIH WITH CIRRHOSIS

Up to 33% of adults and 38% of children with AIH have cirrhosis at diagnosis. ¹ Currently available treatment guidelines are slightly different compared with patients without cirrhosis. For example, budesonide is not recommended by AASLD or ESPGHAN as an alternative steroid to prednisone in this population. ¹ , ² Previous studies have shown budesonide to be ineffective in patients who have not achieved remission on prednisone. ²⁰ There is concern that portosystemic shunting and bypass of hepatic metabolism may reduce drug efficacy. In addition, patients with cirrhosis are more likely to have cytopenias, and because AZA can cause myelosuppression, it is not recommended in the AASLD guidelines in patients with decompensated cirrhosis who instead are likely better served by transplantation if appropriate. ¹ However, successful treatment of AIH can improve liver fibrosis, even in cases where cirrhosis is present at diagnosis. ²¹ In addition, retrospective studies comparing treated versus untreated patients with cirrhosis at diagnosis have shown improved outcomes in the treated group. ²² , ²³ Based on the clinical and histopathological improvements, medical management should be attempted if possible.

Refractory AIH is an important cause of chronic liver disease because failure to achieve remission is associated with significant morbidity, including need for liver transplantation. Current available guidelines do not include a specific algorithm for third‐line and rescue therapy. Decisions on alternative agents should be made based on possible risks of therapy and individual patient characteristics. For example, medications associated with myelosuppression should be used with caution in patients with cytopenias, mTOR inhibitors should be avoided in patients being considered for surgical interventions given the negative impact on wound healing, and the risk for metabolic syndrome with CNIs should be weighed against the potential benefit. Continued research on the immunopathogenesis of AIH is critical to the development of targeted therapies.

CONFLICT OF INTEREST

Nothing to report.

Whitehead B, Kriegermeier A. Natural history and management of refractory autoimmune hepatitis. Clinical Liver Disease. 2022;20:120–123. 10.1002/cld.1231