title: Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis.
abstract: Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics.
authors.affiliation: Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Lankes
authors.affiliation: Department of Gastroenterology, Pneumology and Endocrinology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany.
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Hundorfean
authors.affiliation: Department of Medicine 3, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrer
authors.affiliation: Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany.
authors.forename: Ansgar J
authors.initials: AJ
authors.lastname: Pommer
authors.affiliation: Institute of Pathology, University Hospital Erlangen , Krankenhausstraße 8-10 , Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.affiliation: Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany.
authors.forename: Irena
authors.initials: I
authors.lastname: Angelovska
authors.affiliation: Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Tajmir-Riahi
authors.affiliation: Department of Surgery, University Hospital Erlangen , Krankenhausstraße 12 , Erlangen, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Göhl
authors.affiliation: Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany.
authors.forename: Gerold
authors.initials: G
authors.lastname: Schuler
authors.affiliation: Department of Gastroenterology, Pneumology and Endocrinology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.affiliation: Department of Surgery, University Hospital Erlangen , Krankenhausstraße 12 , Erlangen, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Hohenberger
authors.affiliation: Department of Dermatology, University Hospital Erlangen , Ulmenweg 18 , Erlangen, Germany.
authors.forename: Lucie
authors.initials: L
authors.lastname: Heinzerling
keywords: Autoimmune colitis; CMV; immune-related adverse event irAE; immunotherapy; ipilimumab; multi epitope ligand cartography MELC; nivolumab; side effect management; virus reactivation