Effect of PF-00547659 on Central Nervous System Immune Surveillance and Circulating beta 7+T Cells in Crohn's Disease: Report of the TOSCA Study

Autor: Richard M. Ransohoff, Olaf Stüve, Harald Vogelsang, Sunday Rivers, Clare Robert A, Kenneth J. Gorelick, Fabio Cataldi, Mina Hassan-Zahraee, Pierre Desreumaux, Geert R. D'Haens, John B. Cheng, Annamarie Kaminski, Yanhua Zhang, Alaa Ahmad, William J. Sandborn, Vivek Pradhan, Severine Vermeire, Matthieu Allez, André Van Gossum, Daniel C. Baumgart, Matthew O Sikpi, Gail M. Comer, Walter Reinisch
Přispěvatelé: AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Adult
Central Nervous System
Male
Crohn’s disease
Integrin beta Chains
Adolescent
Lymphocyte
medicine.medical_treatment
T cell
T-Lymphocytes
Antibodies
Monoclonal
Humanized
Inflammatory bowel disease
03 medical and health sciences
Young Adult
Natalizumab
Crohn Disease
T-Lymphocyte Subsets
inflammatory bowel disease
medicine
Humans
Gastro-entérologie
MAdCAM-1
Lymphocyte Count
Immunologic Surveillance
Crohn's disease
business.industry
Progressive multifocal leukoencephalopathy
Multiple sclerosis
immune surveillance
PF-00547659
Gastroenterology
Leukoencephalopathy
Progressive Multifocal
Immunosuppression
General Medicine
Original Articles
Middle Aged
medicine.disease
3. Good health
Immune surveillance
030104 developmental biology
medicine.anatomical_structure
Immunology
Female
business
Immunosuppressive Agents
medicine.drug
Zdroj: Journal of Crohn's and Colitis, 12 (2
Journal of Crohn's & Colitis
Journal of Crohn s & colitis, 12(2), 188-196. Elsevier
ISSN: 1873-9946
DOI: 10.1093/ecco-jcc/jjx128
Popis: Background and Aims: Progressive multifocal leukoencephalopathy [PML], a brain infection associated with anti-integrin drugs that inhibit lymphocyte translocation from bloodstream to tissue, can be fatal. Decreased central nervous system [CNS] immune surveillance leading to this infection has been reported in patients with multiple sclerosis or Crohn's disease treated with antiintegrin antibody natalizumab. PF-00547659 is an investigational human monoclonal antibody for inflammatory bowel disease, targeted against α4β7-mucosal addressin cell-adhesion molecule-1 [the integrin ligand selectively expressed in the gut]. We hypothesised that this selective agent would not affect central nervous system immune surveillance. Methods: Cerebrospinal fluid from five healthy volunteers, and from 10 patients with Crohn's disease previously treated with immunosuppressants, was evaluated to assess the feasibility of the study. Subsequently, 39 patients with active Crohn's disease and previous immunosuppression were evaluated over 12 weeks of PF-00547659-induction therapy. We measured total lymphocytes, T cell subsets in cerebrospinal fluid, and circulating β7+ memory cells. Disease activity was assessed using the Harvey-Bradshaw Index. Results: Patients treated with PF-00547659 had no reduction of cerebrospinal fluid lymphocytes, T-lymphocyte subsets, or CD4:CD8 ratio, whereas circulating β7+ memory cells increased significantly. A total of 28/35 [80%] patients had a clinical response and 27/34 [79%] had disease remission. Treatment-related adverse events, none serious, were reported in 23/49 [47%] patients. Conclusions: In patients with active Crohn's disease, natalizumab therapy increases the risk for PML, and the increased risk is thought to be associated with iatrogenic leukopenia within the CNS. PML under PF-00547659 may be a lesser concern, as this agent did not reduce lymphocytes or T cell subsets in the cerebrospinal fluid.
SCOPUS: ar.j
info:eu-repo/semantics/published
Databáze: OpenAIRE
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