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Clinical Management of Primary Biliary Cholangitis—Strategies and Evolving Trends

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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.

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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

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China

    Lixia Gao

  2. Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California, Davis, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA

    Lixia Gao, Elena Woo, XiaoSong He, GaoXiang Yang, Patrick S.C Leung & M. Eric Gershwin

  3. Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Science, Beijing, China

    Li Wang

  4. Division of Gastroenterology and Hepatology, School of Medicine, University of California, Davis, CA, 95616, USA

    Christopher Bowlus

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Gao, L., Wang, L., Woo, E. et al. Clinical Management of Primary Biliary Cholangitis—Strategies and Evolving Trends. Clinic Rev Allerg Immunol 59, 175–194 (2020). https://doi.org/10.1007/s12016-019-08772-7

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