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

BACKGROUND: A 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
SUMMARY: We 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.
CONCLUSION: Given 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.

Core tip: A 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. We report the first case of metastatic renal cell cancer treated with the anti-CTLA-4 monoclonal antibody Ipilimumab and the immune checkpoint inhibitor Nivolumab to develop severe steroid-refractory colitis, and describe its resolution after treatment with Infliximab.

INTRODUCTION

A 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 (IMAE), including gastrointestinal symptoms such as diarrhea, nausea and vomiting. We report a case of severe steroid-refractory colitis induced by the anti-CTLA-4 monoclonal antibody Ipilimumab and the immune checkpoint inhibitor Nivolumab in a patient with metastatic renal cell carcinoma, and its resolution after treatment with Infliximab.

CASE PRESENTATION

Chief complaints

A 63 year male diagnosed with metastatic renal cell carcinoma presents to the hospital with a several day history of diarrhea and fatigue.

History of present illness

The patient had received his third combination infusion of Ipilimumab and Nivolumab and developed severe watery non-bloody diarrhea the same day. He continued to have upwards of 10 watery bowel movements over the next week and ultimately presented to the hospital.

History of past illness

Past medical history included metastatic renal cell carcinoma, deep vein thrombosis of the lower extremity and hypertension.

Personal and family history

He had no significant family history of cancer or inflammatory bowel disease, and did not have a personal history of alcohol, tobacco, drug use or foreign travel.

Examinations

Physical examination revealed an ill-appearing man, with mild generalized abdominal tenderness and tachycardia. He was found to be severely dehydrated, in acute renal failure (Creatinine 5.5 mg/dL) with a significant leukocytosis (WBC 20.4 103/μL) (Table 1). An extensive infectious workup for diarrhea was performed which was ultimately negative (Table 2). A computed tomography (CT) scan of the abdomen/pelvis was performed which revealed a moderate amount of liquid stool throughout the colon, greatest within the rectosigmoid colon.

Table 1

Labs at admission

Items	Data
WBC	20.39 × 109/L
Neutrophil	61%
Lymphocytes	6%
Monocytes	6%
Eosinophil	0%
Hemoglobin	9.9 mmol/L
Platelets	335 × 109/L
RDW	20%
Sodium	132 mmol/L
Potassium	2.8 mmol/L
Chloride	92 mmol/L
CO2	7 mmol/L
Creatinine	486.2 µmol/L
Calcium	2.3 mmol/L
Anion gap	33 mmol/L
Albumin	0.57 mmol/L
Phosphorous	3 mmol/L
AST	15 IU/L
ALT	26 IU/L
Total bilirubin	6.8 µmol/L
Alkaline phosphatase	110 IU/L
Magnesium	1.1 mmol/L

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; CO2: Serum carbon dioxide; RDW: Red blood cell distribution width; WBC: White blood cell count.

Table 2

Infectious workup

Infectious workup
Clostridium difficile toxin B gene DNA PCR
Salmonella, shigella/enteroinvasive E coli, campylobacter, shiga toxin 1/2 NAAT
Cryptosporidium stool antigen, giardia stool antigen
Ova and parasite
Yersinia enterocolitica culture
Vibrio stool culture
Stool cultures
Influenza/respiratory synctial virus /rhinovirus/adenovirus/metapneumovirus
Blood and urine cultures
Cytomegalovirus colon biopsy DNA PCR
Herpes simplex virus 1/2 colon biopsy DNA PCR

NAAT: Nucleic acid amplification test; PCR: Polymerase chain reaction.

A colonoscopy was obtained and revealed copious amounts of fluid and liquid stool, with over 2 liters of fluid suctioned out, but no endoscopic evidence of inflammation (Figure 1). Random biopsies for histology were obtained, as well as biopsies for cytomegalovirus and herpes simplex virus polymerase chain reaction (PCR) testing. His biopsies came back for mild colitis (Figure 2). His cytomegalovirus and herpes simplex virus PCR were also negative, as was testing for C. difficile, tuberculosis and hepatitis B.

Figure 1

Colonoscopy revealing copious amounts of fluids and liquid stools in colon without endoscopic evidence of disease after removal.

Figure 2

Mild active colitis with increased apoptotic bodies in crypts (arrowhead) and increased plasma cells in lamina propria (HE stain, × 100).

FINAL DIAGNOSIS

The patient was diagnosed with immune-mediated colitis secondary to Ipilimumab and Nivolumab.

TREATMENT

On admission, the patient was started on broad spectrum antibiotics, intravenous (IV) fluids and electrolyte replenishment for his metabolic derangements. However given the temporal relationship between the onset of his symptoms and his immune treatment and the negative infectious workup, an immune-mediated colitis was suspected. His antibiotics were discontinued and the patient was started on high dose IV steroids. His renal function and leukocytosis improved but the diarrhea persisted. Ten days after receiving his treatment the gastroenterology service was consulted.

The patient had already been on high-dose steroids, diphenoxylate-atropine (Lomotil®), and loperamide without relief or resolution. He continued to have 5-10 large volume watery bowel movements a day, and was on continuous IV fluids, a bicarbonate drip as well as aggressive electrolyte replenishment. The patient was also initiated on a trial of mesalamine and subcutaneous octreotide injections with no improvement. After the colonoscopy was performed the patient was initiated on Infliximab 5 mg/kg.

OUTCOME AND FOLLOW-UP

After initiation of Infliximab, the patient noted improvement later the same day. The following day the patient had complete resolution of his diarrhea without any bowel movements. Over the next few days his renal function normalized and all medications were gradually discontinued. He was discharged with a steroid taper and instructed to follow up as an outpatient. On follow up in clinic his colitis had resolved, and he remained symptom free at 3 mo follow up.

DISCUSSION

Immune checkpoint inhibitors such as Ipilimumab, the CTLA-4 antibody, and Nivolumab, an anti-PD-1 antibody, have been increasingly used in cancers such as metastatic melanoma and renal cell carcinoma but have been associated with several IMAE, including a high incidence of diarrhea and colitis[1]. Although more common in Ipilimumab than Nivolumab, the incidence of colitis is highest when these two drugs are used in combination[2] . These side effects can be severe, and some patients may require the initiation of high dose intravenous steroids such as Methylprednisolone 2 mg/kg per day[3]. However, up to 40% may not respond[4], and many have used Infliximab for treatment of immune-mediated colitis in patients unresponsive to steroid therapy[1-3,5-7]. Infliximab is thought to work in these cases by several mechanisms including opposing the activation of T cells by CTLA-4 antibodies by suppressing the pro-inflammatory cytokines IL-1 and IL-6[8] , enhancing FOXp3+ regulatory T cells[9], as well as preventing tumor necrosis factor (TNF)-alpha from binding to its receptor, thereby preventing it from recruiting neutrophils to the site of inflammation in the colon[10]. Abdominal CT imaging usually shows mesenteric vessel engorgement, bowel wall thickening, and fluid-filled colonic distention[11]. In one study, endoscopy of patients who ultimately required Infliximab revealed ulceration in 59%, inflammation in 36% and no endoscopic evidence in 5%. Histological findings included chronic inflammation in 68% and acute inflammation in 27%[4]. The grade of diarrhea has not been found to be associated with endoscopic or histologic findings[4,6], and on follow up over a third of patients develop recurrent diarrhea[4]. The median time of response to Infliximab is 2 d, and some patients may need more than one treatment[6]. Caucasians and patients with melanoma seem to have a higher incidence of diarrhea and colitis[5] . Studies have suggested better overall outcomes and survival in patients who develop IMAE[5,12], and in the case of colitis this is thought to be in part secondary to distinct baseline gut microbiota[13]. Although the use of Infliximab has become part of the treatment algorithm for immune-mediated colitis, the influence of a TNF-alpha on the progression of metastatic cancer is unclear, and further studies evaluating long-term effects are needed. To our knowledge this is the first case of renal cell carcinoma treated with both Ipilimumab and Nivolumab with resultant steroid refractory colitis that resolved with Infliximab. Given 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 management.

CONCLUSION

The incidence of immune-mediated colitis is higher when Nivolumab is used with Ipilimumab, and many patients may require high dose intravenous steroids for therapy. However, up to 40% of patients will not respond and will need to be initiated on infliximab. Gastroenterologists should be able to recognize adverse events related to novel immune therapy agents and be comfortable managing them, including prescribing anti-TNF-alpha inhibitors for immune-mediated colitis. Future studies are needed to evaluate the response to alternate biological agents, long term management of recurrent immune mediated colitis, and the role of TNF-alpha administration on the progression of metastatic cancer.