Mucosal inflammation predicts response to systemic steroids in immune checkpoint inhibitor colitis

Abstract

BackgroundImmune-related colitis is a common, often serious complication of immune checkpoint inhibition (ICI). Although endoscopy is not strictly recommended for any grade of diarrhea/colitis, emerging evidence suggests that endoscopic evaluation may have important therapeutic implications. In this retrospective study, we sought to comprehensively characterize the clinical and histologic features of ICI-induced colitis with a specific focus on evaluating the prognostic role of endoscopy.MethodsData were collected from the medical records of 130 patients with confirmed ICI-induced colitis. In a subset of patients (n=44) with endoscopic and pathologic data, endoscopic data were scored using the Mayo Endoscopic Score (MES) with scores ranging from 0 (no inflammation) to 3 (colonic ulceration). The impact of infliximab on antitumor outcomes was evaluated using progression-free survival (PFS) and overall survival (OS).ResultsWe identified 130 patients with ICI-induced colitis across two institutions. All patients were treated with corticosteroids. Additional and/or alternative immunosuppression was employed in 59 cases, with 52 patients (42%) requiring at least one infusion of infliximab 5 mg/kg. Endoscopic assessment with biopsy was performed in 123 cases of suspected colitis (95%), with 44 cases available for MES tabulation. Presence of ulceration (MES 3) was associated with use of infliximab (p=0.008) and MES was significantly higher in patients who received infliximab compared with those who did not (p=0.003) with a median score of 2.5; conversely, those with an MES of zero rarely required secondary immunosuppression. Notably, symptoms of colitis based on Common Terminology Criteria for Adverse Events grade had no association with endoscopic findings based on MES classification. After adjustment for baseline patient and disease characteristics, there was no significant difference in steroid duration or cancer-related outcomes in patients treated with infliximab.ConclusionsIn our study, we demonstrate the association of endoscopic features, specifically the MES, with immunosuppressive needs. Importantly, we also show that MES was not related to severity of patient symptoms. The data suggest that endoscopic features can guide clinical decision-making better than patient symptoms, both identifying high-risk patients who will require infliximab and those who are likely to respond to initial corticosteroids.

Clinicopathological characteristics and management of colitis with anti-PD1 immunotherapy alone or in combination with ipilimumab

“…A previous study of 53 patients has also shown no clear association between grades of diarrhea and colitis, 16 while a recent case series showed higher use of infliximab in patients with severe endoscopic findings (by Mayo Endoscopic Score) but dissociation between clinical symptoms and endoscopic severity scores, highlighting the importance of endoscopy when deciding further immunosuppression in steroid-refractory cases. 24 Similar to these studies, we observed that infliximab-treated patients (steroid refractory) tend to have higher grade colitis (46/60, 77%) and ulceration on endoscopy (30%) though this did not reach statistical significance (p=0.07). Compared with previous case series that reported endoscopic and histologic outcomes on immune-mediated colitis, our cohort had greater numbers of combination immunotherapy patients reflecting substantial clinical trial recruitment and a change in clinical practice over time.…”

“… 26 Regardless of the use of non-selective immunosuppressives in our study, OS was similar irrespective of colitis management strategy (steroids, infliximab, or other drugs) and similar to phase 3 clinical trial data, suggesting that immunosuppression in patients with significant immune activation (in the form of colitis) may not impact melanoma outcome. 24 27 28 …”

The significance of histological activity measurements in immune checkpoint inhibitor colitis

“…The poor correlation between symptoms and both endoscopy and histology is an important finding of this study. This finding, particularly the poor correlation between symptoms and endoscopy, has also been confirmed by others 22,25 . These results indicate that symptoms do not reliably capture the severity of colonic inflammation.…”

“…The presence of active inflammation as defined above was not predictive of biological use on multivariate analysis in their cohort. More recently, Mooradian et al evaluated a cohort of 130 patients with ICI colitis, of which 44 had endoscopic data 25 . They found no correlation with clinical colitis grade and Mayo endoscopic score.…”

Diagnostic utility of CT for suspected immune checkpoint inhibitor enterocolitis

“…Endoscopy has the added advantage of the ability to assess the severity of mucosal inflammation, potentially helping to guide enterocolitis therapy, although we show that endoscopy alone cannot substitute for biopsy evaluation. [17][18][19][20] However, endoscopy with biopsy is time-intensive and resource-intensive and may not be a readily available diagnostic tool in all settings. Continued exploration of possible noninvasive biomarkers and previously unidentified radiological signatures will be necessary to advance the care of patients presenting with concern for ICI enterocolitis.…”