Anti-TNF therapy for inflammatory bowel disease in patients with neurodegenerative Niemann-Pick disease Type C

Isabelle Williams; Sumeet Pandey; Wolfram Haller; Hien Quoc Huynh; Alicia Chan; Gesche Düeker; Ruth Bettels; Laurent Peyrin-Biroulet; Chinenye R Dike; Catherine DeGeeter; David Smith; Nada Al Eisa; Nick Platt; Thorsten Marquardt; Tobias Schwerd; Frances M Platt; Holm H Uhlig

doi:10.12688/wellcomeopenres.16986.1

Anti-TNF therapy for inflammatory bowel disease in patients with neurodegenerative Niemann-Pick disease Type C

Wellcome Open Res. 2022 Jan 11:7:11. doi: 10.12688/wellcomeopenres.16986.1. eCollection 2022.

Authors

Isabelle Williams¹, Sumeet Pandey¹, Wolfram Haller², Hien Quoc Huynh³, Alicia Chan⁴, Gesche Düeker⁵, Ruth Bettels⁶, Laurent Peyrin-Biroulet^{7

8}, Chinenye R Dike⁹, Catherine DeGeeter⁹, David Smith¹⁰, Nada Al Eisa^{10

11}, Nick Platt¹⁰, Thorsten Marquardt⁶, Tobias Schwerd¹², Frances M Platt¹⁰, Holm H Uhlig^{1

13

14}

Affiliations

¹ Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
² Birmingham Children's Hospital, UK, Birmingham, UK.
³ Department of Paediatrics, Stollery Children's Hospital, University of Alberta, Alberta, Canada.
⁴ Division of Clinical Genetics, Stollery Children's Hospital, University of Alberta, Alberta, Canada.
⁵ University Children's Hospital Bonn, Bonn, Germany.
⁶ Children's Hospital Munster, Munster, Germany.
⁷ Inserm U1256 NGERE, 8 Lorraine University, Vandoeuvre-les-Nancy, France.
⁸ Department of Gastroenterology, Nancy University Hospital Center, Vandoeuvre-les-Nancy, France.
⁹ Stead Family Department of Pediatrics, University of Iowa, Iowa, USA.
¹⁰ Department of Pharmacology, University of Oxford, Oxford, UK.
¹¹ College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
¹² Department of Paediatrics, Dr. von Hauner Children's Hospital, Munich, Germany.
¹³ Department of Paediatrics, University of Oxford, Oxford, UK.
¹⁴ Biomedical research centre, University of Oxford, Oxford, UK.

Abstract

Background: Blockade of tumour necrosis factor (anti-TNF) is effective in patients with Crohn's Disease but has been associated with infection risk and neurological complications such as demyelination. Niemann-Pick disease Type C1 (NPC1) is a lysosomal storage disorder presenting in childhood with neurological deterioration, liver damage and respiratory infections. Some NPC1 patients develop severe Crohn's disease. Our objective was to investigate the safety and effectiveness of anti-TNF in NPC1 patients with Crohn's disease. Methods: Retrospective data on phenotype and therapy response were collected in 2019-2020 for the time period 2014 to 2020 from patients in the UK, France, Germany and Canada with genetically confirmed NPC1 defects and intestinal inflammation. We investigated TNF secretion in peripheral blood mononuclear cells treated with NPC1 inhibitor in response to bacterial stimuli . Results: NPC1 inhibitor treated peripheral blood mononuclear cells (PBMCs) show significantly increased TNF production after lipopolysaccharide or bacterial challenge providing a rationale for anti-TNF therapy. We identified 4 NPC1 patients with Crohn's disease (CD)-like intestinal inflammation treated using anti-TNF therapy (mean age of onset 8.1 years, mean treatment length 27.75 months, overall treatment period 9.25 patient years). Anti-TNF therapy was associated with reduced gastrointestinal symptoms with no apparent adverse neurological events. Therapy improved intestinal inflammation in 4 patients. Conclusions: Anti-TNF therapy appears safe in patients with NPC1 and is an effective treatment strategy for the management of intestinal inflammation in these patients.

Keywords: Niemann-Pick disease Type C1.

Grants and funding

202834/Z/16/Z/WT_/Wellcome Trust/United Kingdom