S Meller1, P A Gerber1, A Kislat1, P Hevezi1,2, T Göbel3, U Wiesner1, S Kellermann1, E Bünemann1, A Zlotnik2, D Häussinger3, A Erhardt3, B Homey1. 1. Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany. 2. Physiology and Biophysics, University of California Irvine, Irvine, CA, USA. 3. Clinic of Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.
Abstract
BACKGROUND: The introduction of pegylated interferon (PEG-IFN)-α in the treatment of chronic hepatitis C has led to an increase in sustained virological response. Despite reduced immunogenicity of the pegylated form in comparison with native interferon (IFN)-α, a high frequency of adverse cutaneous reactions has been reported with pegylated IFN-α. Here, we aimed to investigate the immunological mechanisms underlying pegylated IFN-α-induced drug eruptions. METHODS: Hepatitis C patients suffering from drug eruptions in association with administration of pegylated interferons were enrolled in the study (n = 22). Subjects were tested for sensitivity to pegylated IFN-α2a , pegylated IFN-α2b , or ribavirin using intradermal, scratch, and/or patch tests, as well as lymphocyte activation tests (LATs). Skin biopsies obtained from pegylated IFN-α-associated exanthemas, as well as from localized inflammatory skin reactions at pegylated IFN-α injection sites, were analyzed for the expression of relevant chemokines by quantitative real-time PCR and immunohistochemistry. RESULTS: A subset of patients suffering from pegylated IFN-α-associated exanthemas displayed positive intradermal tests to PEG-IFNs but not to conventional IFN (11/22). In selected patients, this observation correlated with the presence of pegylated IFN-specific T cells (3/11). Chemokine profiles of inflammatory skin reactions at the injection sites reflected an IFN-α-signature, whereas lesional skin of exanthemas showed induction of TH2-associated chemokines. CONCLUSIONS: Our results indicate that specific sensitizations are one cause of exanthemas under therapy with PEG-IFNs. Clinical proof-of-concept analyses demonstrate that affected patients may benefit from a switch to conventional, nonpegylated drugs, enabling IFN-α therapy continuation without drug-associated skin eruptions.
BACKGROUND: The introduction of pegylated interferon (PEG-IFN)-α in the treatment of chronic hepatitis C has led to an increase in sustained virological response. Despite reduced immunogenicity of the pegylated form in comparison with native interferon (IFN)-α, a high frequency of adverse cutaneous reactions has been reported with pegylated IFN-α. Here, we aimed to investigate the immunological mechanisms underlying pegylated IFN-α-induced drug eruptions. METHODS: Hepatitis C patients suffering from drug eruptions in association with administration of pegylated interferons were enrolled in the study (n = 22). Subjects were tested for sensitivity to pegylated IFN-α2a , pegylated IFN-α2b , or ribavirin using intradermal, scratch, and/or patch tests, as well as lymphocyte activation tests (LATs). Skin biopsies obtained from pegylated IFN-α-associated exanthemas, as well as from localized inflammatory skin reactions at pegylated IFN-α injection sites, were analyzed for the expression of relevant chemokines by quantitative real-time PCR and immunohistochemistry. RESULTS: A subset of patients suffering from pegylated IFN-α-associated exanthemas displayed positive intradermal tests to PEG-IFNs but not to conventional IFN (11/22). In selected patients, this observation correlated with the presence of pegylated IFN-specific T cells (3/11). Chemokine profiles of inflammatory skin reactions at the injection sites reflected an IFN-α-signature, whereas lesional skin of exanthemas showed induction of TH2-associated chemokines. CONCLUSIONS: Our results indicate that specific sensitizations are one cause of exanthemas under therapy with PEG-IFNs. Clinical proof-of-concept analyses demonstrate that affected patients may benefit from a switch to conventional, nonpegylated drugs, enabling IFN-α therapy continuation without drug-associated skin eruptions.
Authors: Heike C Hawerkamp; Andreas Kislat; Peter A Gerber; Marius Pollet; Katharina M Rolfes; Anatoly A Soshilov; Michael S Denison; Afaque A Momin; Stefan T Arold; Angeliki Datsi; Stephan A Braun; Péter Oláh; Mario E Lacouture; Jean Krutmann; Thomas Haarmann-Stemmann; Bernhard Homey; Stephan Meller Journal: Allergy Date: 2019-09-03 Impact factor: 13.146
Authors: Cosby A Stone; Yiwei Liu; Mary V Relling; Matthew S Krantz; Amanda L Pratt; Andrew Abreo; Jonathan A Hemler; Elizabeth J Phillips Journal: J Allergy Clin Immunol Pract Date: 2018-12-14
Authors: Christopher Michael Warren; Theo Thomas Snow; Alexandra S Lee; Mihir Mukesh Shah; Anja Heider; Andra Blomkalns; Brooke Betts; Anthony S Buzzanco; Joseph Gonzalez; R Sharon Chinthrajah; Evan Do; Iris Chang; Diane Dunham; Grace Lee; Ruth O'Hara; Helen Park; Mohamed H Shamji; Lisa Schilling; Sayantani B Sindher; Deepak Sisodiya; Eric Smith; Mindy Tsai; Stephen J Galli; Cezmi Akdis; Kari C Nadeau Journal: JAMA Netw Open Date: 2021-09-01