Budesonide treatment for microscopic colitis from immune checkpoint inhibitors

Abstract

BackgroundImmune checkpoint inhibitors (CPIs) are effective against a variety of malignancies but can be limited by inflammatory toxicities such as enterocolitis. Enterocolitis is typically treated with systemically active glucocorticoids. Endoscopy can stratify patients by the severity of mucosal inflammation, including identifying patients with colitis in the absence of visible mucosal changes: microscopic colitis. Whether patients with CPI microscopic colitis could be managed differently from colitis with more severe mucosal involvement is unclear. The objective of this study was to describe outcomes in CPI microscopic colitis focusing on the response to first line treatment with budesonide.MethodsWe evaluated data from a retrospective cohort from a single-center large academic hospital. The participants were all adult patients evaluated by endoscopy for suspected CPI enterocolitis between 3/2017 and 3/2019. The exposures were: Mayo Endoscopic Score (range 0–3). The subset was: oral budesonide, maximum dose 12 mg daily, administered minimum of 5 weeks. The main outcomes and measures were: Primary: time from first CPI exposure to first glucocorticoid use; use of systemic glucocorticoids; time from symptom onset to resolution; continuation of CPI therapy; number of additional CPI infusions received. Secondary: admissions for symptom control; novel irAE development; need for second-line immunosuppression; oncologic outcomes.ResultsWe identified 38 patients with biopsy confirmed CPI enterocolitis, 13 in the microscopic colitis cohort, and 25 in the non-microscopic colitis cohort. Budesonide use was higher in the microscopic colitis cohort (12/13 vs 3/25, p < 0.001), and systemic glucocorticoid use was higher in non-microscopic colitis (22/25 vs. 3/13, p < 0.001). Time from symptom onset to resolution did not differ. Microscopic colitis patients more frequently remained on CPI after developing (entero)colitis (76.9% vs 16.0%, p < 0.001). Microscopic colitis patients tolerating further CPI received, on average, 4.2 CPI infusions more than non-microscopic colitis patients tolerating CPI (5.8 vs 1.6, p = 0.03). Microscopic colitis was associated with increased time-to-treatment-failure (HR 0.30, 95% CI 0.14–0.66) and progression-free survival (HR 0.22, 95% CI 0.07–0.70).ConclusionsGastrointestinal mucosal inflammation without visible mucosal injury is a distinct, prevalent CPI enterocolitis subset that can be diagnosed by endoscopy. First-line budesonide appears effective in controlling “microscopic colitis” symptoms and prolonging immunotherapy duration. These findings present a compelling rationale for routine endoscopic evaluation of suspected CPI enterocolitis and suggest an alternative glucocorticoid-sparing treatment strategy for a subset of such patients.

Autoimmune complications of immunotherapy: pathophysiology and management

“…In a single center study of 117 patients treated with ICIs who had diarrhea, about one third required no treatment, corticosteroids, or corticosteroids plus infliximab (a tumor necrosis factor (TNF) inhibitor) 59. A randomized controlled trial showed that prophylactic budesonide was not effective against anti-CTLA-4 induced colitis,60 but it is commonly used to treat ICI-associated microscopic colitis 61. Infliximab has been associated with a shorter time to symptom resolution than corticosteroids alone,62 and vedolizumab (an antibody to α 4 β 7 integrin), has also been used as a steroid sparing agent 63.…”

Systematic review with meta‐analysis: effectiveness of anti‐inflammatory therapy in immune checkpoint inhibitor‐induced enterocolitis

“…Although prophylactic budesonide, was not effective in preventing ipilimumab-induced diarrhoea in a phase 2 randomised placebo-controlled trial, 49 our study highlights the potential for budesonide as a primary therapeutic strategy in checkpoint inhibitor induced-enterocolitis. Eight studies report the use of budesonide, 10,14,16,27,29,30,33,37 although few describe the clinical outcomes related to its ad- Other studies report a few cases where budesonide was successfully used as the primary corticosteroid. 27,29 In line with this, a small case series (n = 2) also demonstrated that Infliximab has an established role as second-line therapy in corticosteroid refractory cases, or some instances of corticosteroid relapse.…”

“…Notably, we observed a significant degree of heterogeneity between studies, which may be partly explained by differences in their inclusion criteria. For example, many studies included patients with any gastrointestinal symptom, 14,22,25,27,35,37,41,[60][61][62] while others were more stringent and only included patients exhibiting at least CTCAE grade 2 40,63,64 or 3 23,34 diarrhoea, endoscopic and/or histological evidence of inflammation, 16,33,42,44,[65][66][67] patients requiring corticosteroids 24,30 or having some response to immunosuppressive therapy. 68 Moreover, there was marked variation between studies Finally, in the subgroup analysis we included some studies where not all the study group belonged to the covariate being analysed.…”

“…Overall, the pooled response to corticosteroids was 59% (95% CI 54-65), which was associated with a high degree of statistically significant heterogeneity between studies (I 2 = 61%, P < 0.001) ( Figure 2A). The median time to response was defined in seven studies, [27][28][29][30][31][32][33] varying between 1 day 27 and 95 29…”

Management of immunotherapy colitis: Special considerations in the COVID‐19 era

“…Although budesonide has not been proven effective for the prevention of enterocolitis from treatment with ipilimumab, limited data have suggested that it can control symptoms and prolong the duration of immunotherapy. 13,14 Corticosteroid enemas can also alleviate symptoms of urgency and tenesmus in patients with rectosigmoid inflammation. In patients who fail to improve and those with grade 3 colitis, transition to biologic agents (eg, TNF-α inhibitor infliximab or anti-integrin vedolizumab) rather than an initial trial of high-dose glucocorticoids (prednisone at a dose of 1-2 mg/kg) may be considered.…”