@article{96f60495d6bd4ca5835387e9fc3fdadb,
title = "Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature",
abstract = "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 (IFN) therapies, with recent concern regarding the use of IFN 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 such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center 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 IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation.",
author = "David Kavanagh and Sarah McGlasson and Alexa Jury and Jac Williams and Neil Scolding and Chris Bellamy and Claudia Gunther and Diane Ritchie and Gale, {Daniel P.} and Kanwar, {Yashpal S.} and Rachel Challis and Holly Buist and James Overell and Belinda Weller and Oliver Flossmann and Mark Blunden and Meyer, {Eric P.} and Thomas Krucker and Evans, {Stephen J.W.} and Campbell, {Iain L.} and Jackson, {Andrew P.} and Siddharthan Chandran and Hunt, {David P.J.}",
note = "Funding Information: The authors thank neurology consultants and nurses in all major Scottish multiple sclerosis centers and the MHRA for providing data as part of safety audit. The authors also thank James Ironside for advice on neuropathology and Tim Goodship and Martin Reijns for discussions on the manuscript. D.P.J.H. and D.K. were supported by the Wellcome Trust (WT101153MA) (D.P.J.H.) and the Academy of Medical Sciences. C.G. was supported by a grant from the Deutsche Forschungsgemeinschaft (KFO 249/GU1212/1-1 and GU1212/1-2). A.P.J. was supported by the Medical Research Council. I.L.C. was supported by the National Health Medical Research Council (project grant 512407) and the National Institutes of Health, National Institute of Mental Health (grant MH47680). D.K. and D.P.J.H. are supported by the Wellcome Trust. B.W. is a principal investigator in clinical trials supported by Novartis, Sanofi-Aventis, and Biogen Idec and receives honoraria for advisory work from Merck, Biogen Idec, Novartis, and Bayer. D.K. received honoraria for consultancy work from Alexion Pharmaceuticals. D.P.G. received honoraria for consultancy from Alexion, Novartis, and Otsuka. T.K. is currently employed by Novartis (experimental work here performed prior to this). J.O. received honoraria for consultancy work and travel grants from Novartis, Teva UK Ltd., Biogen Idec, and Merck . N.S. received honoraria and/or research and/or educational support from Merck Serono, Biogen Idec, Teva, GSK, and Novartis. S.C. received honoraria for consultancy work from Merck Serono, Biogen Idec, and Novartis and research and/or educational support from Merck, Novartis, and Biogen Idec. The remaining authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2016 by The American Society of Hematology.",
year = "2016",
month = dec,
day = "15",
doi = "10.1182/blood-2016-05-715987",
language = "English (US)",
volume = "128",
pages = "2824--2833",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "24",
}