Rituximab Is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A Phase 2 Randomized Controlled Trial

Khanna, Amardeep; Jopson, Laura; Howel, Denise; Bryant, Andrew; Blamire, Andrew M.; Newton, Julia L.; Jones, David

doi:10.1002/hep.30099

Cited by 57 publications

(34 citation statements)

References 37 publications

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“…Regardless of why it arises, it is likely to hamper recovery from fatigue unless it is addressed. [49][50][51] Central Pathways: To generate symptoms in CLD, including fatigue, activation of peripheral signalling pathways must lead to changes within the brain. Numerous neurotransmitter systems and brain regions have been implicated in the regulation of central fatigue ( Figure 3); however, there is a growing body of evidence that links central fatigue to dysfunction in the basal ganglia within the brain.…”

Section: Pathophysiologymentioning

confidence: 99%

Fatigue in chronic liver disease: New insights and therapeutic approaches

Swain

Jones

2018

Liver International

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The management of fatigue associated with chronic liver disease is a complex and major clinical challenge. Although fatigue can complicate many chronic diseases, it is particularly common in diseases with an inflammatory component. Fatigue can have both peripheral (i.e., neuromuscular) and central (i.e., resulting from changes in neurotransmission within the brain) causes. However, fatigue in chronic liver disease has strong social/contextual components and is often associated with behavioural alterations including depression and anxiety. Given the increasing awareness of patient-reported outcomes as important components of treatment outcomes and clinical research, there is a growing need to better understand and manage this poorly understood yet debilitating symptom. Although several pathophysiological mechanisms for explaining the development of fatigue have been generated, our understanding of fatigue in patients with chronic liver disease remains incomplete. A better understanding of the pathways and neurotransmitter systems involved may provide specific directed therapies. Currently, the management of fatigue in chronic liver disease can involve a combined use of methods to beneficially alter behavioural components and pharmacological interventions, of which several treatments have potential for the improved management of fatigue in chronic liver disease. However, evidence and consensus are lacking on the best approach and the most appropriate biochemical target(s) whilst clinical trials to address this issue have been few and limited by small sample size. In this review, we outline current understanding of the impact of fatigue and related symptoms in chronic liver disease, discuss theories of pathogenesis, and examine current and emerging approaches to its treatment.

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Section: Pathophysiologymentioning

confidence: 99%

Fatigue in chronic liver disease: New insights and therapeutic approaches

Swain

Jones

2018

Liver International

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“…Modulators of T-cell function and of T-cell recruitment have been studied with negative results. Limited data have shown improvement in ALP with significant improvement in pruritus with rituximab but with no improvement in fatigue [79,80]. The risks of stem cell transplantation, which has been evaluated in several studies, has failed to show clinically significant benefit and does not appear to be worth the risks of such an invasive procedure.…”

Section: Immune System Modulationmentioning

confidence: 99%

“…Interleukin modulation with ustekinumab has also been found ineffective. B-cell depletion with rituximab lacks long-term efficacy and is not beneficial for the treatment of fatigue, but may improve pruritus [79,80]. Other biologic therapies including invasive measures such as stem cell transplantation have also lacked significant enough benefit to be worth the potential side effects.…”

Section: Other Agentsmentioning

confidence: 99%

Emerging therapies for PBC

Chascsa

Lindor

2020

J Gastroenterol

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Primary biliary cholangitis is an uncommon cholestatic liver disease predominantly affecting middleaged women. Left untreated, there is a high risk of progression to end-stage liver disease. Few treatment options exist. To date, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only medical therapies approved for use, other than symptomatic treatments and liver transplantation, the latter of which is reserved for those developing complications of cirrhosis or with intractable pruritus. UDCA improves outcomes, but many patients do not adequately respond. OCA therapy may improve response, but long-term data are limited. New therapies are desperately needed, but evaluation has been limited by the fact that the disease is heterogeneous, hard end points take years to develop, and there are different criteria in use for determining therapeutic response based on surrogate biomarkers. Fibrates appear to be the most promising new therapy and have beneficially affected surrogate end points and are beginning to show improvement in clinical end points.

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“…67 However, a subsequent open-label study, including 14 patients, demonstrated only a mild improvement in liver tests (although pruritus decreased in 60%), 68 and a phase II randomised controlled trial with improvement in fatigue as the primary outcome failed to demonstrate efficacy at 12 months. 69 The overall conclusion is that rituximab has limited efficacy in PBC and is not recommended despite a good short-term safety profile.…”

Section: Immunological Agentsmentioning

confidence: 99%

New treatments/targets for primary biliary cholangitis

2019

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Primary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.

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Rituximab Is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A Phase 2 Randomized Controlled Trial

Cited by 57 publications

References 37 publications

Fatigue in chronic liver disease: New insights and therapeutic approaches

Fatigue in chronic liver disease: New insights and therapeutic approaches

Emerging therapies for PBC

New treatments/targets for primary biliary cholangitis

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