An update on the pharmacological management of autoimmune hepatitis

ABSTRACT

Introduction: Autoimmune hepatitis (AIH) is an immune mediated, inflammatory disease affecting the liver as a result of environmental triggers in susceptible individuals leading to loss of self-tolerance. The immunopathogenesis of AIH is not fully understood, which limits targeted therapeutic options.

Areas covered: In this review, the authors provide an overview of current practice in the management of AIH, which include induction therapy with corticosteroids (± thiopurines), followed by maintenance therapy. Lack of early response to treatment may serve as a predictor of those at risk of requiring treatment escalation to second- and third-line agents such as mycophenolate mofetil (MMF), calcineurin inhibitors or biologics. Evidence for third-line agents from small retrospective studies or individual centers are reviewed. The nuances of AIH treatment in pregnancy, overlap syndromes, and drug induced liver injury (DILI) warrant further consideration.

Expert opinion: Augmenting the balance of regulatory T cells (Treg) and effector T cells is an appealing therapeutic target with a multitude of agents in development. Many of the challenges in AIH research are due to its rarity and lack of randomized data. Management of AIH should strive towards individualized care through risk stratification and use of the best therapeutic modality for each patient.

KEYWORDS:

• Autoimmune hepatitis
• immunosuppression
• overlap syndrome
• pregnancy
• drug induced liver injury
• autoimmune pancreatitis
• Tregs

Abbreviations

AASLDAmerican Association for the study of liver diseases

AIHAutoimmune hepatitis

AIPAutoimmune pancreatitis

AISCAutoimmune sclerosing cholangitis

ALFAcute liver failure

ALPAlkaline phosphatase

ALTAlanine aminotransferase

APCAntigen presenting cells

ASAIHAcute severe autoimmune hepatitis

ASTAspartate aminotransferase

AMAAnti-mitochondrial antibody

ANAAnti-nuclear antibody

BAFFB-cell activating factor

BRBiochemical remission

BSGBritish Society of Gastroenterology

CMVCytomegalovirus

CNICalcineurin inhibitors

CTLACytotoxic T lymphocyte-associated antigen 4

CXCR3Chemokine receptor-3

CXCLChemokine receptor-3 ligands

DCDendritic cells

DILIDrug induced liver injury

EASLEuropean Association for the Study of the Liver

FOXP3Forkhead/winged helix transcription factor

GGTGamma-glutamyl transferase

GMPSGuanosine monophosphate synthetase

HAIHepatitis activity index

HILIHerb induced liver injury

HLAHuman leukocyte antigen

HPRTHypoxanthine guanine phosphoribosyl transferase

IAIHGInternational Autoimmune Hepatitis group

IBDInflammatory bowel disease

IFXInfliximab

IgGImmunoglobulin G

IMPDHInosine monophosphate dehydrogenase

INRInternational normalized ratio

JAKJanus kinases

LC1Anti-liver cytosol-1

LKMAnti-liver kidney microsome

LTLiver transplantation

mAbMonoclonal antibody

MELD-NaModel for end-stage liver disease-sodium

MMFMycophenolate mofetil

6-MMP6-Methyl mercaptopurine

6-MMPR6-Methyl mercaptopurine ribonucleotides

MPMercaptopurine

MSCMesenchymal stem cells

mTORMammalian target of rapamycin

NAFLDnonalcoholic fatty liver disease

OOIOther organ involvement

PBCPrimary biliary cholangitis

PSCPrimary sclerosing cholangitis

RARheumatoid arthritis

RCTRandomized control trials

RUCAMRoussel Uclaf causality assessment method

SCBUSpecial care baby unit

SLA/LPAnti-soluble liver antigen/liver pancreas

SMAAnti-smooth muscle antibody

STAT-5Signal transducers and activator of transcription-5

TfhT-follicular helper cell

TGTioguanine

6-TGN6 tioguanine nucleotide

ThT helper

6-TIMP6-thioinosine monophosphate

TLR4Toll-like receptor-4

TNFαTumor necrosis factor α

TPMTThiopurine S-methyltransferase

TregRegulatory T cells

UDCAUrsodeoxycholic acid

UKELDUnited Kingdom end-stage liver disease score

ULNUpper limit of normal

Article highlights

• Autoimmune hepatitis is a heterogeneous condition with a complex immunopathogenesis.

• Environmental triggers in genetic susceptible individuals result in loss of self-tolerance due to dysregulation of T cells.

• Current immunosuppressive therapy carries a significant side effect burden and there is a need for targeted therapies.

• Novel therapeutic agents currently being explored aim to augment the regulatory T cell and effector T cell balance.

• In future, endeavor should be made to provide individualized care through better prognostication and use of the best therapeutic agents for a given patient.

This box summarizes key points contained in the article.

Declaration of interest

MA Heneghan is supported by the European Association for the Study of the Liver Registry Grant (Liver Disease in Pregnancy), The King’s College Hospital NHS Trust Charity (Orpin Bequest), and The Kelly Group. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This manuscript was not funded.