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Clinical Management of Primary Biliary Cholangitis—Strategies and Evolving Trends

  • Lixia Gao
  • Li Wang
  • Elena Woo
  • XiaoSong He
  • GaoXiang Yang
  • Christopher Bowlus
  • Patrick S.C LeungEmail author
  • M. Eric GershwinEmail author
Article

Abstract

PBC is a chronic progressive autoimmune disorder involving the destruction of intrahepatic small bile ducts, cholestasis, fibrosis, and ultimately cirrhosis if left untreated. It is largely driven by the autoimmune response, but bile acids and the intestinal microbiota are implicated in disease progression as well. The only drugs licensed for PBC are UDCA and OCA. UDCA as a first-line and OCA as a second-line therapy are safe and effective, but the lack of response in a significant portion of patients and inadequate control of symptoms such as fatigue and pruritus remain as concerns. Liver transplantation is an end-stage therapy for many patients refractory to UDCA, which gives excellent survival rates but also moderate to high recurrence rates. The limited options for FDA-approved PBC therapies necessitate the development of alternative approaches. Currently, a wide variety of experimental drugs exist targeting immunological and physiological aspects of PBC to suppress inflammation. Immunological therapies include drugs targeting immune molecules in the B cell and T cell response, and specific cytokines and chemokines implicated in inflammation. Drugs targeting bile acids are also noteworthy as bile acids can perpetuate hepatic inflammation and lead to fibrosis over time. These include FXR agonists, ASBT inhibitors, and PPAR agonists such as bezafibrate and fenofibrate. Nonetheless, many of these drugs can only delay disease progression and fail to enhance patients’ quality of life. Nanomedicine shows great potential for treatment of autoimmune diseases, as it provides a new approach that focuses on tolerance induction rather than immunosuppression. Tolerogenic nanoparticles carrying immune-modifying agents can be engineered to safely and effectively target the antigen-specific immune response in autoimmune diseases. These may work well with PBC especially, given the anatomical features and immunological specificity of the disease. Nanobiological therapy is thus an area of highly promising research for future treatment of PBC.

Keywords

Primary biliary cholangitis Clinical trial Nanomedicine Tolerogenic nanoparticle 

Abbreviations

PBC

Primary biliary cholangitis

UDCA

Ursodeoxycholic acid

OCA

Obeticholic acid

ALP

Alkaline phosphatase

AMA

Anti-mitochondrial antibody

BEC

Biliary epithelial cells

BA

Bile acids

FDA

Food and Drug Administration

NASH

Nonalcoholic steatohepatitis

6-ECDCA

6 Alpha-ethyl-chenodeoxycholic acid

CDCA

Chenodeoxycholic acid

FXR

Farnesoid X receptor

CYP7A1

Cholesterol 7-alpha-hydroxylase

FGF19

Fibroblast growth factor 19

ULN

Upper limit or normal

LT

Liver transplantation

LPA

Lysophosphatidic acid

ATX

Autotaxin

IBAT

Ileal bile acid transporter

ASBT

Apical sodium-dependent bile acid transporter

PDC-E2

Pyruvate dehydrogenase complex-E2

Ig

Immunoglobulin

Foxp3

Forkhead box P3

TGF-β

Transforming growth factor beta

TNF-α

Tumor necrosis factor alpha

IL

Interleukin

APC

Antigen-presenting cell

CTLA-4

Cytotoxic T lymphocyte antigen-4

Tregs

Regulatory T cells

CXCL

Chemokine (C-X-C motif) ligand

CXCR

Chemokine (C-X-C motif) receptor

BAFF

B cell activating factor

S1P

Sphingosine-1-phosphate

FKN

Fractalkine

CAR

Constitutive androstane receptor

PXR

Pregnane X receptor

LXR

Liver X receptor

TGR5

Transmembrane G-protein-coupled receptor 5

GPBAR1

G-protein-coupled bile acid receptor 1

PPAR

Peroxisome proliferator-activated receptor

nor-UDCA

Norursodeoxycholic acid

NF-κB

Nuclear factor κB

PSC

Primary sclerosing cholangitis

MMTV

Mouse mammary tumor virus

SAMe

S-adenosyl-L-methionine

GGT

Gamma glutamyl transferase

NADPH

Nicotinamide adenine dinucleotide phosphate hydrogen

NOX

Nicotinamide adenine dinucleotide phosphate hydrogen oxidase

LOXL2

Lysyl oxidase like 2

tNPs

Tolerogenic nanoparticles

TIMP

Tolerogenic immune-modifying nanoparticle

EAE

autoimmune encephalomyelitis

PLGA

Poly(D,L-lactide-co-glycolide)

MOG

Myelin oligodendrocyte glycoprotein

PLP

Proteolipid protein

OVA

Ovalbumin

GM-CSF

Granulocyte/macrophage-colony-stimulating factor

DCs

Dendritic cells

rhMBP

Recombinant human myelin basic protein

T1D

Type 1 diabetes

AhR

Aryl hydrocarbon receptor

ITE

2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester

ds-DNA

Double strands DNA

SLE

Systemic lupus erythematosus

CII

Type II collagen

PD-L1

Programmed death ligand 1

PLG

Poly(lactide-co-glycolide)

MCP-1

Monocyte chemoattractant protein 1

CX3CR1

Chemokine CX3C motif receptor 1

MHC

Major histocompatibility complex

MSC

Mesenchymal stem cell

MDR3

Multidrug resistance protein 3

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors do not have any conflict of interest on this paper.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Rheumatology and ImmunologyThe Second Hospital of Hebei Medical UniversityShijiazhuangChina
  2. 2.Division of Rheumatology, Allergy and Clinical Immunology, School of MedicineUniversity of California, DavisDavisUSA
  3. 3.Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital (PUMCH)Chinese Academy of Medical ScienceBeijingChina
  4. 4.Division of Gastroenterology and Hepatology, School of MedicineUniversity of CaliforniaDavisUSA

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