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Lookup NU author(s): Professor David KavanaghORCiD, Rachel Challis
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular TMA has been reported in association with recombinant type I interferon therapies, with recent concern regarding the use of interferon in multiple sclerosis patients. However a causal association has yet to be demonstrated. Here we adopt a combined clinical and experimental approach to provide evidence of a such an association between type I interferon and TMA. We show the clinical phenotype of cases referred to a national centre is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of interferon toxicity. This includes specific microvascular pathological changes seen in patient biopsies, and is dependent on transcriptional activation of the interferon response through the type I interferon receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I interferon and thrombotic microangiopathy. As such, recombinant type I interferon therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation.
Author(s): Kavanagh D, McGlasson S, Jury A, Williams J, Scolding N, Bellamy C, Gunther C, Ritchie D, Gale DP, Kanwar YS, Challis R, Buist H, Overell J, Weller B, Flossmann O, Blunden M, Meyer EP, Krucker T, Evans SJ, Campbell IL, Jackson AP, Chandran S, Hunt DP
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2016
Volume: 128
Issue: 24
Pages: 2824-2833
Print publication date: 15/12/2016
Online publication date: 15/12/2016
Acceptance date: 30/08/2016
Date deposited: 11/10/2016
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: American Society of Hematology
URL: http://dx.doi.org/10.1182/blood-2016-05-715987
DOI: 10.1182/blood-2016-05-715987
PubMed id: 27663672
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