Ipilimumab and Nivolumab induced steroid-refractory colitis treated with infliximab: A case report

Abstract

BACKGROUNDA variety of immune-modulating drugs are becoming increasingly used for various cancers. Despite increasing indications and improved efficacy, they are often associated with a wide variety of immune mediated adverse events including colitis that may be refractory to conventional therapy. Although these drugs are being more commonly used by Hematologists and Oncologists, there are still many gastroenterologists who are not familiar with the incidence and natural history of gastrointestinal immune-mediated side effects, as well as the role of infliximab in the management of this condition.CASE SUMMARYWe report a case of a 63-year-old male with a history of metastatic renal cell carcinoma who presented to our hospital with severe diarrhea. The patient had received his third combination infusion of the anti-CTLA-4 monoclonal antibody Ipilimumab and the immune checkpoint inhibitor Nivolumab and developed severe watery non-bloody diarrhea the same day. He presented to the hospital where he was found to be severely dehydrated and in acute renal failure. An extensive workup was negative for infectious etiologies and he was initiated on high dose intravenous steroids. However, he continued to worsen. A colonoscopy was performed and revealed no endoscopic evidence of inflammation. Random biopsies for histology were obtained which showed mild colitis, and were negative for Cytomegalovirus and Herpes Simplex Virus. He was diagnosed with severe steroid-refractory colitis induced by Ipilimumab and Nivolumab and was initiated on Infliximab. He responded promptly to it and his diarrhea resolved the next day with progressive resolution of his renal impairment. On follow up his gastrointestinal side symptoms did not recur.CONCLUSIONGiven the increasing use of immune therapy in a variety of cancers, it is important for gastroenterologists to be familiar with their gastrointestinal side effects and comfortable with their management, including prescribing infliximab.

Ipilimumab- and Nivolumab-Induced Colitis Causing Severe Hypokalemia and QTc Prolongation

“…Based on the CTCAE grading scale, our patient would be categorized as grade 2 colitis, due to mucus in the stool, and grade 4 diarrhea, due to severe electrolyte derangement with profound widening of the Q-R-S complex evidenced by QTc prolongation (see Table 1). Previous case reports have described severe colitis secondary to combined ipilimumab and nivolumab therapy refractory to high-dose steroid therapy [3]. While our patient demonstrated a rapid improvement after initiation of steroids, up to 40% of cases may require initiation of infliximab as a second-line therapy (4).…”

A Case of Immune Checkpoint Inhibitor Refractory Colitis Treated with Mycophenolate and High-dose Steroids

“…If no response to high-dose steroids, or if relapse requires an increase in steroid dosing during the tapering period, such cases are considered refractory [4]. In cases of refractory colitis, four different medications were investigated in recent studies, which include: infliximab, mycophenolate, and Entyvio [5][6][7][8].…”

“…Based on the CTCAE grading (severity) scale, the treatment options may vary from the symptomatic treatment of diarrhea with loperamide and electrolyte repletion to the initiation of immunosuppressive agents [4]. In the case of refractory colitis, multiple studies have shown a response to infliximab, mycophenolate, cyclosporine, and Entyvio [5][6][7][8]. We present a case of refractory colitis to both infliximab and Entyvio, treated with a high-dose steroid (methylprednisolone) and mycophenolate.…”

Efficacy and safety of Infliximab for steroid‑resistant immune‑related adverse events: A retrospective study

“…In line with this, steroid therapy with approximately 1 mg/kg/day prednisolone (PSL) equivalent is immediately initiated for grade 3 diarrhea/colitis. However, when symptoms do not improve, infliximab (IFX) treatment, generally at a dose of 5 mg/kg/day according to the Efficacy and safety of Infliximab for steroid-resistant immune-related adverse events: A retrospective study administration for ulcerative colitis (3)(4)(5)(6)(7)(8)(9)(10)(11), has been recommended. Single-dose IFX administration has often been selected as an irAE treatment, with additional doses administered only when no improvements occur after the first dose.…”

“…However, it is imperative to pre-emptively identify symptoms of medium-and long-term adverse reactions such as infectious diseases, demyelinating diseases, aplastic anemia, malignant tumors, autoimmune diseases, and heart failure, among which infectious diseases are of particular concern. Several case reports have described successful treatment of steroid-resistant ICI-induced diarrhea/colitis with IFX in patients receiving ipilimumab (IPI), an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody preparation (3)(4)(5)(6), as well as anti-programmed cell death-1 (PD-1) antibody or anti-programmed cell death-ligand 1 (PD-L1) antibody preparations (7)(8)(9)(10)(11). However, we were unable to identify any report systematically dealing with the required number of IFX doses or the time to switch to after treatment.…”