Efficacy of rituximab in difficult-to-manage autoimmune hepatitis: Results from the International Autoimmune Hepatitis Group

Abstract

Graphical abstract Highlights• Study of rituximab therapy in 22 patients with autoimmune hepatitis over a follow-up period of 24 months.• No serious adverse events were noted during followup in patients treated with rituximab.• Rituximab therapy improved liver enzymes significantly during the 2 years of follow-up.• Prednisolone dose reductions were seen in 62% of patients at 12-month follow-up.• A total of 71% of patients were free of AIH flares during the 24 months of follow-up. Lay summaryAutoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to firstor second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome.Background & Aims: Treatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH.Methods: Clinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period.Results: Twenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19-79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3-28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p <0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1-10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded. Conclusion:In patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated w...

The future of autoimmune liver diseases – Understanding pathogenesis and improving morbidity and mortality

“…28 Rituximab, a B-cell depleting agent, has been shown to induce remission in hard-to-treat AIH patients with lower complication rates. 29 Another B-cell depleting monoclonal antibody targeting the B-cell activation factor receptor is under investigation in a phase II/III trial in AIH patients who do not respond to SOC. 30 Furthermore, there is a reduced balance of regulatory and effector T cells in patients with AIH who do not achieve remission.…”

Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease

“…Moreover, in adult AIH, rituximab treatment resulted in increased tissue and/or circulating Treg numbers. 172 Additionally, a recent report showed that rituximab could improve liver enzymes and reduce the dose of prednisone in 22 difficult-to-treat AIH patients without severe side effects, 173 which was associated with biochemical, histological and immunological remission and a significant reduction in flares in more than 70% of the patients in a two-year follow-up. 173 In PBC patients, alterations in the B cell repertoire have been observed.…”

“…172 Additionally, a recent report showed that rituximab could improve liver enzymes and reduce the dose of prednisone in 22 difficult-to-treat AIH patients without severe side effects, 173 which was associated with biochemical, histological and immunological remission and a significant reduction in flares in more than 70% of the patients in a two-year follow-up. 173 In PBC patients, alterations in the B cell repertoire have been observed. Analysis of B cell clonal diversity showed a marked reduction in clonal diversity and somatic hypermutations in class-switched sequences, which were more prominent in PBC patients with cirrhosis.…”

Review article: experimental therapies in autoimmune hepatitis

“…Rituximab, an anti‐CD20 monoclonal antibody, is an established therapy in autoimmune disorders and may have a role in the treatment of AIH 77‐79 . A recent retrospective report collating outcomes for 22 patients in Northern Europe and Canada demonstrated an improvement in liver biochemistry and reduction in corticosteroid doses following two 1000 mg doses of rituximab given 2 weeks apart (five patients received repeat dosing), 80 suggesting that therapeutic targeting of B cells might be a useful approach in AIH.…”