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Review
, 18 (1), 115-126

The Use of Biologics in Patients With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Affiliations
Review

The Use of Biologics in Patients With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Kate D Lynch et al. Curr Hepatol Rep.

Abstract

Purpose of review: Biologics are well established in the treatment of many immuno-inflammatory diseases including inflammatory bowel disease (IBD). However, although primary sclerosing cholangitis (PSC) is closely associated with IBD, the role of biologics in PSC remains uncertain. Many new biologics are becoming available to treat IBD, and this review aims to use the experience of biologics in PSC so far to guide more effective evaluation of emerging therapies in the future.

Recent findings: Antibodies to TNF-α were the first biologics used in IBD, and retrospective analysis suggests that they may have some benefit in PSC, even though an early randomised controlled trial (RCT) showed no effect. Mechanistic studies suggest that TNF-α may have a pathogenic role in PSC. An antibody to integrin α4β7 is effective in IBD, and there are emerging data on its effects in PSC, although no RCT data are available. Mechanistic studies suggest that interrupting the migration of lymphocytes is relevant in PSC. Two biologics, targeting vascular adhesion protein-1 (VAP-1), and lysyl oxidase-like 2 (LOXL2) have been tested in RCTs. The trial of anti-VAP1 is ongoing, whilst the anti-LOXL2 trial was negative.

Summary: Anti-TNF antibodies may benefit PSC when used to treat concomitant IBD, and this may be a direct effect on the liver in a subgroup of patients, or may be an indirect effect of treating IBD. Similarly, anti-integrin therapy may benefit a subset of patients with IBD and PSC. RCTs could decide the role of emerging biologics in PSC, although future trials should be guided by biomarkers that could predict response to the pathway being targeted.

Keywords: Crohn’s disease; Inflammatory bowel disease; Integrin alpha4beta7; Primary sclerosing cholangitis; TNF-α; Ulcerative colitis.

Conflict of interest statement

Kate Lynch reported other from Merck, other from Takeda, outside the submitted work. Satish Keshav reports grants and personal fees from ChemoCentryx, grants from Celgene, grants from GSK, grants from Merck, personal fees from Abbvie, personal fees from Dr. Falk Pharma, personal fees from Gilead, grants and personal fees from Takeda, personal fees from Vifor Pharma, personal fees from Allergan, personal fees from Amgen, personal fees from Ferring, personal fees from Genentech-Roche, personal fees from Mitsubishi Tanabe Pharma, personal fees from Pharmacosmos, outside the submitted work. Roger Chapman declares no potential conflict of interest.This article does not contain any studies with human or animal subjects performed by any of the authors.

Figures

Fig. 1
Fig. 1
Potential therapeutic drug targets in PSC. Schematic diagram of various potential therapeutic targets of biologic therapy in PSC. The image depicts a hepatic sinusoid, where gut-tropic T cells are slowed down and adhere to the sinusoidal endothelium through the interaction between CCR9 and its cognate ligand, CCL25, as well as binding of a4b7 integrin to MAdCAM-1. VAP-1 also promotes lymphocyte recruitment through multiple mechanisms, including induction of MAdCAM-1 expression. There is an excess of TNF-α seen in PSC. Four monoclonal antibodies are depicted as targeting antigens and interrupting these pathways—infliximab (TNF-α), adalimumab (TNF-α), vedolizumab (α4β7) and timolimumab (VAP-1). ADA, adalimumab; CCL25, chemokine (C-C motif) ligand 25; CCR9, C-chemokine receptor 9; IFX, infliximab; LSEC, liver sinusoidal endothelial cells; MAdCAM-1, mucosal addressin cellular adhesion molecule-1; PSC, primary sclerosing cholangitis; TNF, tumour necrosis factor; TMO, timolimumab; VAP-1, vascular adhesion protein-1; VDZ, vedolizumab. (The authors would like to acknowledge the use of some images from Servier Medical Art in the creation of Fig. 1. https://smart.servier.com/)
Fig. 2
Fig. 2
Differing ALP response to VDZ in two patients with PSC/UC. These graphs show the serum ALP level over time in two individual patients with PSC who were commenced on VDZ for their underlying UC. Both patients received VDZ according to the usual schedule as licenced with induction and maintenance. The dotted red lines show the ULN and LLN for ALP at our institution. Each open blue circle represents a measurement of serum ALP. a This patient did not attend for two of his infusions part way through his therapy, and so VDZ was inadvertently temporarily ceased. Upon recommencement, he received induction dosing again before maintenance dosing. He went into clinical and endoscopic remission of his underlying UC. b This patient remained on VDZ for 5 months before a decision was taken to cease the medication, as it had had no effect on his UC, both clinically and endoscopically. ALP, alkaline phosphatase; LLN, lower limit of normal; PSC, primary sclerosing cholangitis; UC, ulcerative colitis; ULN, upper limit of normal; VDZ, vedolizumab

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