Review article: experimental therapies in autoimmune hepatitis

Abstract

Summary Background Current therapeutic options for autoimmune hepatitis (AIH) are limited by adverse events associated with corticosteroids and thiopurines and the limited evidence base for second‐ and third‐line treatment options. Furthermore, current treatment approaches require long‐term exposure of patients to pharmacological agents. There have been significant advances in the understanding of the mechanisms underpinning autoimmunity and an expansion in the available therapeutic agents for suppressing autoimmune responses or potentially restoring self‐tolerance. Aim To review the mechanisms and evidence for experimental therapies that are being actively explored in the management of AIH. Methods We have reviewed the literature relating to a range of novel therapeutic immunomodulatory treatment strategies and drugs. Results Drugs which block B cell‐activating factor of the tumour necrosis factor family (BAFF) and tumour necrosis factor α are currently in clinical trials for the treatment of AIH. Experimental therapies and technologies to increase immune tolerance, such as pre‐implantation factor and regulatory T cell therapies, are undergoing development for application in autoimmune disorders. There is also evidence for targeting inflammatory pathways to control other autoimmune conditions, such as blockade of IL1 and IL6 and Janus‐associated kinase (JAK) inhibitors. Conclusions With the range of tools available to clinicians and patients increasing, it is likely that the therapeutic landscape of AIH will change over the coming years and treatment approaches offering lower corticosteroid use and aiming to restore immune self‐tolerance should be sought.

Etiopathogenesis and Diagnostic Strategies in Autoimmune Hepatitis

“…Anti-B cell-activating factor of the tumor necrosis factor family (BAFF) and anti-tumor necrosis factor (TNF) therapies, novel peptides, T regulatory cells, interleukin (IL)-1 or IL-6 blockade and Janus kinases are worth mentioning as potential players in this field. But there is still a great need for subsequent studies assessing their usefulness in AIH patients [131,132].…”

Review article: targeting the B cell activation system in autoimmune hepatitis

“…Studies evaluating the therapeutic manipulation of the B cell activation system are already underway in autoimmune hepatitis (Table 4). 97,99,100 An ongoing, randomized, placebo‐controlled, clinical trial of ianalumab (VAY736) will determine the prospect of BAFF blockade as a treatment option in autoimmune hepatitis. It will allow critical assessment of the chosen target (BAFF‐R), provide reassurances regarding treatment safety, identify knowledge gaps, and direct future investigations.…”

“…The results of the ianalumab trial will direct the next investigations in B cell depletion therapy for autoimmune hepatitis 99,100 . TACI, BCMA, and especially APRIL might warrant further investigation as alternative or complementary targets to BAFF or BAFF‐R, 56,209,268 and soluble decoy receptors might provide another, more effective, method of B cell inhibition 56,268‐272 .…”

“…Suppression of B cell activation by BAFF and APRIL can limit antigen presentation by B cells, inhibit T cell activation, reduce T cell survival, and improve the outlook of autoimmune hepatitis 145,200 . The ongoing clinical trial of monoclonal antibodies against BAFF‐R (ianalumab) is a formative step in evaluating this possibility 99,100 …”

“…Treatments based on inhibitors of BAFF or APRIL have improved the manifestations and severity of diverse autoimmune diseases in experimental models 80‐85 and patients, 86‐96 including a limited experience involving two patients with autoimmune hepatitis 97 . A fully humanized immunoglobulin G (IgG) monoclonal antibody that binds soluble BAFF has been approved as an add‐on therapy for autoantibody‐positive SLE, 56,98 and a controlled treatment trial of a monoclonal antibody against the BAFF receptor (ianalumab, also called VAY736) is underway in autoimmune hepatitis 99,100 …”