Cindy Franklin1, Isabelle Rooms2, Melanie Fiedler3, Henning Reis4, Laura Milsch2, Saskia Herz2, Elisabeth Livingstone2, Lisa Zimmer2, Kurt Werner Schmid4, Ulf Dittmer3, Dirk Schadendorf2, Bastian Schilling5. 1. Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Dermatology, Inselspital Bern, Bern University Hospital, University of Bern, Switzerland. 2. Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. 3. Department of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 4. German Cancer Consortium (DKTK), Heidelberg, Germany; Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany. 5. Department of Dermatology, Venereology and Allergology, University Hospital Essen, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany. Electronic address: schilling_b@ukw.de.
Abstract
OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected. RESULTS: We identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis.
OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected. RESULTS: We identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis.
Authors: Julian Burla; Sena Bluemel; Luc Biedermann; Marjam J Barysch; Reinhard Dummer; Mitchell P Levesque; Christoph Gubler; Bernhard Morell; Gerhard Rogler; Michael Scharl Journal: Inflamm Intest Dis Date: 2020-05-26
Authors: James A Hutchinson; Katharina Kronenberg; Paloma Riquelme; Jürgen J Wenzel; Gunther Glehr; Hannah-Lou Schilling; Florian Zeman; Katja Evert; Martin Schmiedel; Marion Mickler; Konstantin Drexler; Florian Bitterer; Laura Cordero; Lukas Beyer; Christian Bach; Josef Koestler; Ralph Burkhardt; Hans J Schlitt; Dirk Hellwig; Jens M Werner; Rainer Spang; Barbara Schmidt; Edward K Geissler; Sebastian Haferkamp Journal: Nat Commun Date: 2021-03-04 Impact factor: 14.919