Inflammatory Bowel Disease

Introduction: Immunotherapy with anti CTLA-4 (Ipilimumab) or anti PD-1 (Pembrolizumab, Nivolumab) antibodies are now the standard of care for metastatic melanoma and other malignancies. These drugs have been associated with various immune related adverse events, including autoimmune colitis with marked similarity to idiopathic inflammatory bowel disease. Current literature regarding immunotherapy related colitis (IRC) are scarce and very little treatment-related data exist. Aims: To describe the clinical spectrum of immunotherapy-related colitis (IRC) and treatment response to systemic steroids alone or a combination of systemic steroids and infliximab therapy. Methods: A retrospective review of case-notes of patients undergoing treatment with Ipilimumab and anti PD-1 therapy from 2009–2015 was conducted across two tertiary referral facilities,Westmead Hospital and the Melanoma Institute Australia. Multiple variables related to the development of colitis, doses of immunotherapy, time from therapy to colitis and treatment of colitis were documented. Patients received treatment with steroid alone or steroids plus infliximab. Symptom resolution was defined no episodes of diarrhea as per patient survey on follow up. Statistical analysis was with SPSS version 23 using t-test analysis. Results: 19 patients (11 male, 8 female) developed IRC. Mean age of onset was 62 years (41–83 yrs). Of these, 16 received treatment with Ipilimumab (15 melanoma, 1 renal cell carcinoma) while three received anti PD-1 therapy alone (2 melanoma, 1 lung cancer). 17 patients had documented endoscopic and histopathological evidence of colitis. All patients received high dose steroid either as intravenous, oral (1–2 mg/kg) or combination. 14/16 patients treated with Ipilimumab were documented to have mild-moderately active disease, with a mean Mayo Endoscopic Score of 1.78 (0–3) with presence of cryptitis, crypt abscesses and lymphocytic infiltration on histopathology. Colitis was predominantly limited to distal colon (proctitis n = 4, left colon n = 7, pancoltis n = 2, R. sided n = 1). Mean onset of colitis from first dose of Ipilimumab was 72 days (8–146 days). 10 patients received high dose steroid therapy only, while 9 patients, with persistent symptoms despite steroid therapy received further treatment with infliximab, as per physician discretion. The mean time to resolution for those treated with corticosteroids only was 61 days whereas those treated with corticosteroids then infliximab was 12 days from the initiation of rescue therapy (p = 0.0873). Of the 16 patient’s treated with Ipilimumab it was noted three patients developed colitis upon being changed rapidly from Ipilimumab to PD-1 therapy (2–26 days). These were though unlikely to be attributable to the addition of PD-1 therapy, given the timing of symptom onset. Three patient’s developed IRC while being treated with anti-PD-1 monotherapy. Anti PD-1 associated IRC, was limited to a L. sided colitis, and were recorded to have Mayo Endoscopy scores of 1,1 and 1 respectively consistent with mild disease. In this group two patients had symptom resolution with steroid therapy alone with one patient requiring rescue therapy with infliximab. The mean time to resolution of symptoms for treatment with steroids only was 36 days, while the mean time to resolution after initiation of rescue therapy was also noted to be 36 days. Conclusions / Discussion: Immunotherapy-related colitis is an important emerging clinical entity and has clinical and histologic similarities to idiopathic inflammatory bowel disease. Infliximab appears to induce earlier resolution of symptoms in patient’s refractory to steroid treatment, and this result trends towards significance. Future research implications include immune-pathogenic analysis of IRC to improve insight into the pathogenesis of idiopathic inflammatory bowel disease.1 page(s