Research gaps and opportunities in autoimmune hepatitis—Results of the international autoimmune hepatitis group research workshop 2022

Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that is characterised by a chronic inflammatory immune reaction directed against hepatocytes. The disease results in a substantial reduction in quality of life and potentially leads to liver‐related complications or death. The International Autoimmune Hepatitis Group (IAIHG) initiated a series of research workshops to uncover the scientific gaps and opportunities in AIH. This review summarises the results of the latest workshop in Maastricht in 2022 and reviews the current challenges in adult AIH, particularly in relation to four important aspects of AIH: diagnostics; new immunomodulatory therapies; clinical trial design; and unmet clinical needs. This review also summarises the progress made since the AIH workshop in 2017. Patients and patient representatives were actively involved in the parallel working groups alongside clinicians and researchers. Despite 40 years of experience with diagnosing and treating AIH, false diagnoses occur and treatment is still based on nonselective immunosuppression. In addition to the need for more specific diagnostic tests, prognostic markers and tailor‐based treatments, a major unmet clinical need was identified in areas of care delivery and health‐related quality of life.


| INTRODUC TI ON
Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with incidence rates ranging from 0.4 to 2.39 per 100 000. 1 AIH is a lifelong liver disease characterised by inflammation, and it can result in a substantial reduction in quality of life, including liver-related complications or death. 2

| D IAG NOS TI C S IN AUTOIMMUNE HEPATITIS
The accurate diagnosis of AIH can still be challenging since single disease-specific features for both the acute and chronic manifestations of AIH are absent. Despite hallmarks such as elevated transaminases, elevated autoantibodies (ANA, anti-SMA, anti-SLA/LP, anti-LKM, anti-LC1), polyclonal hypergammaglobulinaemia/increased IgG levels and lymphoplasmacellular infiltrates on histology, other liver diseases still have to be excluded. 19,20 In addition, the co-incidence of AIH with other liver diseases, particularly the increasingly common fatty liver diseases, also needs to be considered and recognised.

| General aspects
The problem of overlapping clinical phenotypes is most striking in the time-sensitive setting of acute severe AIH (AS-AIH) or even acute liver failure (ALF), for which existing diagnostic features have not been validated. A very important differential diagnosis for acute AIH is drug-induced liver injury (DILI) because specific diagnostic tests are also lacking for this entity. However, for ALF, the identification of prognostic parameters indicating transplantfree survival or steroid response might be more relevant than the precise distinction between AIH and non-AIH liver disease. 12 In uncertain acute cases, for example, manifestations without highgrade fibrosis or cirrhosis indicating pre-existing subclinical AIH and/or relevant drug exposure within recent months hinting at DILI, steroids should be started. However, after the initial treatment response, careful steroid withdrawal should be undertaken.
A recurrence of hepatitis after or during the weaning of steroids supports the diagnosis of AIH, and long-term immunosuppression with azathioprine can be avoided. 21

Key points
• Newly developed diagnostic auto-antibody cut-offs and pathological criteria need to be validated in all clinical settings and in all age groups, sexes and ethnicities.
• Future AIH treatment studies should focus on novel immunomodulatory therapies that precisely target aberrant inflammatory pathways such the TNFα, IL-6, IL-12 and JAK/STAT pathways.
• A main priority is the development of an AIH-specific questionnaire assessing quality of life that can be included in clinical trials.
• Unmet clinical needs should be a standard topic in every rare liver disease research workshop, preferably led by patients or patient representatives.

| Autoantibodies
Multiple diagnostic assays are used to detect autoantibodies for autoimmune liver diseases worldwide without sufficient standardisation. These platforms include classical indirect immunofluorescence on rodent tissue sections (stomach, kidney, liver) or on HEp2 cells as well as enzyme-linked immunosorbent assays (ELISAs) and immunoblots. Future studies should aim to establish an TA B L E 1 Key issues and outcome after the workshop in 2017.

Key issues 4 Effort Outcome
Need for better understanding of disease pathogenesis Single-centre feasibility pilot study 5 Regulatory T-cell (Treg) therapy is potentially curative in patients with autoimmune liver diseases Single-centre cohort study 6 Immuno-next-generation immunosequencing reveals a persisting T-cell bias in AIH internationally comparable standardisation of these assays. A machine learning approach could help to standardise the assessment of patterns and titre levels of indirect immunofluorescence and spread the experience from a few reference centres to more international diagnostic centres. Although immunofluorescence is considered the gold standard for autoantibody detection in autoimmune liver diseases, a recent study revealed comparable accuracies of indirect immunofluorescence and immunoassays but with assay-specific cutoff values. 9 In addition, new serological tests with putatively higher accuracy than conventional autoantibodies, such as assays to quantify the polyreactivity of IgGs, 10 should be further explored in multicentre studies and in clinically challenging situations (acute AIH vs. DILI vs. other acute liver injuries). Beyond that, efforts should be undertaken to validate AIH-specific cut-offs for ELISA-based immunoassays. The previously revised cut-offs for ANA and anti-SMA for the diagnosis of AIH were developed with the use of control groups in studies on chronic liver disease, such as fatty liver disease, but need to be validated in the setting of acute hepatitis such as DILI or acute liver failure. 9 Since this is not achievable for all centresespecially smaller centres-the need for reference laboratories for liver serology should be discussed in the future.

| Histology
Liver histology is still considered to be essential and a standard for the diagnosis of AIH. However, pathognomonic histological features are missing, although some features have previously been proposed to be more specific for AIH, such as emperipolesis, rosetting or the pronounced presence of plasma cells. [26][27][28] Most of these features seem to reflect the severity of liver damage or liver regeneration rather than aetiology. Indeed, the histological features of acute AIH with a more lobular pattern are distinct from those of chronic liver disease with a more portal pattern of inflammation. Over time and after the introduction of the current diagnostic scores of AIH, the pattern of centrilobular necrosis has been associated with acute AIH and was probably previously misinterpreted as DILI. 29 In addition, the given histological criteria are not based on a structured consensus process of several international liver pathologists. To update the histological features of AIH and to propose, for the first time, histological criteria for acute manifestations, an international consensus statement from liver pathologists was published recently. 11 A validation study is planned to confirm these criteria in a set of AIH patients with acute and chronic manifestations and relevant control groups, such as DILI patients.

| NE W IMMUN OMO DUL ATORY THER APIE S FOR AUTOIMMUNE HEPATITIS
AIH is an immune-mediated liver disease; however, the precise aetiology remains unknown. 3

| New approaches in AIH treatment
Current treatment regimens for patients with AIH are based on nonselective immunosuppressive therapy. 19,38,39 However, standard immunosuppressive drugs are associated with many adverse effects and reduced health-related quality of life (HRQoL). [40][41][42] Therefore, novel immunomodulatory agents targeting precisely aberrant inflammatory pathways are urgently needed. The innovation of immunobiology, which led to pathway-specific therapies for other autoimmune disorders, [43][44][45] illustrates what needs to be achieved in the spectrum of AIH management. In an effort to address this unmet need, and since recent technological advances and biologics allow us to explore new approaches to the treatment of AIH, 46,47 several candidates have been proposed (Figure 1).

| Cytokine, chemokine, signalling pathways and beyond
The inflamed hepatic microenvironment in AIH is enriched with TNFα,

| CLINI C AL TRIAL S IN AUTOIMMUNE HEPATITIS
Approximately 15%-20% of AIH patients require alternative treat-

| Pitfalls of clinical trials for AIH
There are several challenges involved to conducting trials for AIH.
AIH is a rare disorder, and recruiting patients requires a multicentre approach involving many sites. Clinical investigator-driven research has become difficult given the complex regulatory framework and lack of funding for research on AIH, although drug development for rare diseases has become more interesting for pharmaceutical industries in recent years. Although patients are very willing to participate in trials, as they believe that research is needed to improve treatment options, preferably corticosteroid-free options, 75 low recruitment rates have resulted in the discontinuation of several studies.
In addition, a number of trial programmes have been discontinued because of a lack of efficacy of the tested compound in the treatment of other autoimmune disorders. For example, a recent phase 2 study was stopped due to disappointing results of the effect of RO7049665 in ulcerative colitis (Clini calTr ials.gov: NCT04790916).
It is important to wait for the effectiveness of new treatments to be established in other autoimmune disorders before setting up a clinical trial in AIH to avoid clinical trial discontinuations.

| Trial design
A clinical trial that is designed for treatment of a first and acute manifestation of AIH differs from a trial that targets the maintenance phase due F I G U R E 1 Novel candidate therapies for autoimmune hepatitis. FMT, faecal microbiota transplant; MHC, major histocompatibility complex; TNFα, tumour necrosis factor alpha; IL, interleukin; CXCL-10, C-X-C motif chemokine 10; IP-10, interferonγinducible protein-10; Treg, regulatory T cell. BAFF, B-cell activation factor. Created with BioRe nder.com to divergent patient selection, choice of first-line/second-line therapies and choice of primary outcomes (short term vs. long term). A newly initiated study focusing on AIH treatment-naïve patients randomly assigned patients to azathioprine or mycophenolate mofetil, both combined with prednisolone, for the induction of remission. 14 The primary endpoint of this study was the normalisation of serum ALT and IgG levels after remission and intolerance to treatment, but did not include non-invasive markers of liver fibrosis or patient-reported outcomes.

| Future goals
The unanswered questions, including those related to the most effective first-line/second-line treatment, need to be resolved at the population level using clinical trials. Alternative approaches, such as international cohort studies with propensity score matching or N = 1 trials, should also be explored to achieve clinical evidence of therapies in subgroups (variant syndromes, third-line therapies and severe acute AIH).

| Improvement in clinical practice
Thorough discussions were held between patient representatives and physicians during this workshop regarding how we could improve clinical care for adult and paediatric AIH patients. To better address the unmet clinical needs of AIH patients, we propose several actions: (1) screen for the presence of symptoms that limit the quality of life of the patient by using standardised, disease-specific questionnaires in the outpatient clinic; (2)

| Future goals
The large caveat in AIH is the lack of disease-specific questionnaires that can be used to monitor symptoms in AIH patients and included in clinical trials. Therefore, the next step is to execute qualitative and quantitative studies on HRQoL and unmet clinical needs in AIH patients that will identify the most affected domains. Patient representatives from ERN RARE-LIVER have initiated a project to assess the unmet clinical needs in AIH, in which the most relevant problems and difficulties for our patients will be identified. In addition, a large multicentre, international study of HRQoL in patients with AIH and variant syndromes is currently ongoing and will determine the relationship between HRQoL and factors associated with HRQoL, including depression, corticosteroid use and medication adherence.
The results of these studies will support the development of an AIHspecific questionnaire and the design of specific interventional studies aimed at HRQoL domains that are affected by AIH. One example of such an intervention is the Q.RARE.LI project, which was funded in 2020 by the European Joint Programme on Rare Diseases (EJP RD) to provide social support for patients with rare liver diseases including AIH. Finally, regular meetings should be initiated between physicians and patient representatives to promote interaction, facilitate means to improve patient-physician relationship and continue to work on unmet clinical needs.

| CON CLUS ION
The vibrancy of the field is evident by the numerous studies con-