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.

Systematic review and case series: flexible sigmoidoscopy identifies most cases of checkpoint inhibitor‐induced colitis

“…Of the 1892 unique studies identified using our search criteria, 61 studies fulfilled our inclusion criteria and were included in the qualitative analysis (38 full text articles, 23 in abstract form) . Results of our search strategy are depicted in Figure .…”

Cytomegalovirus Enterocolitis in a Patient with Refractory Immune-Related Colitis

“…Recently, two reports showed CMV reactivation in patients with refractory irColitis during immunosuppressive therapy. Lankes et al [6] reported a first case of irColitis that was resistant to corticosteroids and infliximab due to CMV reactivation. Franklin et al [7] reported that 5 of 41 patients with irColitis were refractory to immunosuppressive therapy, and all these therapy-refractory cases had detectable CMV.…”

“…However, these treatments may increase the susceptibility to infections. Recently, a few reports showed that cytomegalovirus (CMV) reactivation might be involved in the pathogenesis of refractory gastrointestinal irAEs [6,7].…”

Opportunistic bowel infection after corticosteroid dosage tapering in a stage IV lung cancer patient with tislelizumab‐related colitis

“…During immunotherapy, the cellular components of intestinal bacteria interact with pattern recognition receptors to promote intestinal dendritic cell activation, boost differentiation and activation of Th17 cells; this is a high‐risk factor for severe gastrointestinal infections, such as Clostridium difficile infection (CDI) . Additionally, long‐term systematic corticosteroid treatment (>30 days) and immunosuppression may be associated with an increased risk of gut infection, or virus reactivation . Corticosteroids have an immunosuppressive effect mainly by disrupting T lymphocyte and monocyte functions and blocking the production of inflammatory cytokines; thus, there is a major risk of CDI with long‐term corticosteroid administration .…”