Unmet needs in autoimmune liver diseases

Abstract

Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis are well-defined autoimmune liver diseases, the pathophysiology of which remains enigmatic. While major therapeutic advances have been achieved for many other autoimmune diseases, precision therapy for these diseases has lagged. For example, limited data exist on the use of innovative drugs targeting the immune system, such as monoclonal antibodies that block immune checkpoint, mRNA vaccines, the influence of infections, the microbiome, and drugs on loss of tolerance in liver autoimmunity. The knowledge on recent radiological techniques, on the expanding role of artificial intelligence in medicine, and on the relationship between the pediatric and adult phenotypes also urgently needs to be advanced in liver autoimmunity. Increased patient involvement focusing on individual symptom burden is also crucial for improving long-term quality of treatment. The fourth Swiss Autoimmune Liver Disease Meeting provided a unique interdisciplinary platform for experts and patients to discuss critical gaps. This opinion paper highlights the discussions on unmet needs and potential solutions in autoimmune liver diseases.

Figure 1

An algorithm to approach suspected DI-ALH in clinical practice. Adapted from J Hepatol. 2023 Sep;79[3]:853–866. doi: 10.1016/j.jhep.2023.04.033 [66].

Figure 2. Challenges in factors contributing to loss of tolerance in the pathogenesis of AILDs.

Factors contributing to the pathophysiology of loss of tolerance, including genetic predisposition (HLA and non-HLA), post-translational and environmentally induced modifications, functional consequences of genetic variants, and events during the latency period. Additional influences include female preponderance, microbial factors, drugs (including antibiotics), diet, hormones, hygiene, immune checkpoint inactivation, and checkpoint-induced liver toxicity as a model. Key questions address the identification of autoantigens, the potential role of ASC as an early stage of PSC, and the immunological changes in pregnancy as a possible therapeutic avenue. HLA, human leukocyte antigen.

Figure 3. Treatment challenges in AILDs.

Challenges include the better treatment of patients’ symptoms. Furthermore, the use of CPIs in AILD patients and strategies for restoring tolerance through antigen-specific or polyclonal expanded regulatory T-cells (Tregs), as well as approaches targeting and harnessing the microbiota. Additional considerations include patient-reported outcomes, comparisons of second-line treatments in PBC and second- and third-line treatments in AIH, and the use of registered immunomodulatory drugs in AILD, with attention to coexisting autoimmune conditions. APC, antigen-presenting cell.