Dig Dis Sci (2014) 59:1112–1114 DOI 10.1007/s10620-014-3147-x
UNM CLINICAL CASE CONFERENCES
Colitis Associated with Biological Agents K. Khirfan • M. Kistin
Published online: 23 April 2014 Springer Science+Business Media New York 2014
Case Presentation A 63-year-old man with a history of malignant melanoma was admitted with a 4-day history of severe watery diarrhea, tenesmus, and abdominal pain. Prior to this hospitalization, he had undergone a surgical resection of a stage IIIB melanoma of the anterior abdominal wall followed by treatment with two doses of ipilimumab, a monoclonal antibody directed against cytotoxic T lymphocytes, for his melanoma, with the last dose 7 weeks prior to the current hospitalization. He had had a recent admission for bacterial multi-lobar pneumonia complicated by severe Clostridium difficile infection that was still in treatment with a tapering course of oral vancomycin after completing the antibiotic treatment for pneumonia. Physical examination revealed heart rate of 101, blood pressure of 72/46 mmHg, temperature 38.2 C, respiratory rate of 18/min, dry mucous membranes, and diffuse abdominal tenderness and some guarding without rebound tenderness. Complete blood count, liver function tests, serum amylase, and serum lipase were all normal. Kidney function tests and fractional urinary excretion of sodium suggested the presence of prerenal azotemia. After admission, he was intravenously hydrated while the etiology of his diarrhea was investigated with stool microscopic examination, culture, and polymerase chain reaction for C. difficile, which were all negative, diminishing the likelihood of an infectious etiology. An abdominal computed tomography (CT) scan was reported as showing diffuse colonic wall thickening and a
K. Khirfan (&) M. Kistin Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, 1 University of New Mexico, MSC10-5550, Albuquerque, NM 87131, USA e-mail: [email protected]
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number of colonic microperforations consistent with severe colitis (Fig. 1). Due to the severity of these findings, colonoscopy was not performed. The patient was initially diagnosed with an immune-related colitis, possibly due to ipilimumab. Accordingly, ipilimumab was discontinued in favor of IV steroid treatment, which partially improved his symptoms after a week of therapy. Infliximab was then added, with which complete symptom resolution. He was discharged home 2 weeks after admission.
Discussion The use of biological agents for the treatment of autoimmune and malignant conditions has increasingly been complicated by immune-mediated colitis. Ipilimumab, a monoclonal antibody approved by the US FDA for the treatment of malignant melanoma, is particularly associated with colitis. Ipilimumab augments the immune-mediated blockage of cytotoxic T lymphocyte antigen 4 (CTLA-4), a key inhibitor of regulatory T cell-mediated immune tolerance to tumor cell growth. This dysregulation of immune tolerance is also reflected in the occurrence of a unique set of immune-related adverse effects, with colitis being one of the most common [1]. Other biologic agents, including rituximab (an antiCD20 monoclonal antibody) and bevacizumab (a monoclonal antibody against the vascular endothelial growth factor), have also been reported to cause colitis [2]. Furthermore, emerging evidence indicates the paradoxical occurrence of new-onset colitis and exacerbation of previously documented inflammatory bowel disease-related colitis due to anti-tumor necrosis factor (TNF)-a agents used in the treatment of inflammatory bowel disease (IBD) including infliximab, adalimumab, and etanercept [2, 3].
Dig Dis Sci (2014) 59:1112–1114
Fig. 1 Abdominal computed tomographic scan, showing intestinal mucosal thickening and a small amount of free air in the peritoneal cavity
Unmasking of underlying disease, colonic ischemia, or superimposed infection have been suggested as possible factors involved in the development of the colitis [2]. This case demonstrates severe colitis, the most commonly reported serious toxicity due to ipilimumab, that if left untreated may lead to intestinal perforation [4]. Ideally, patients with moderate-to-severe disease should undergo colonoscopy or flexible sigmoidoscopy to confirm the diagnosis or to determine the cause of colitis [1], although this option is not always possible. Histologic examination typically shows neutrophilic infiltration (46 % of cases) or less commonly mixed neutrophilic–lymphocytic (38 % of cases) or lymphocytic infiltration (15 % of cases) [1]. Abdominal radiologic imaging can be helpful in excluding complications such as perforation or obstruction [1]. It is recommended to consider of simultaneous pituitary insufficiency from autoimmune hypophysitis as a cause of diarrhea [5]. Treatment depends on the severity of the diarrhea according to the following: grade 1 is defined as an increase of \4; grade 2, an increase of 4–6; grade 3 an increase of C7 stools per day over baseline and incontinence or hospitalization; and grade 4 is defined by lifethreatening consequences or when urgent intervention indicated [6]. The endoscopic extent and severity of colitis help to determine the therapeutic approach. Patients who present with grade 3 or 4 gastrointestinal toxicity due to ipilimumab and patients with endoscopic findings consistent with colitis should be treated with systemic steroids [7], usually oral prednisone 1–2 mg/kg once per day or oral dexamethasone 4 mg every 4 h with methylprednisolone 125 mg IV/day reserved for severe cases [1] followed by a 4 week taper. Infliximab, a monoclonal antibody and TNF-a inhibitor, used to treat autoimmune diseases, is
1113
reserved for the treatment of patients who respond poorly to steroids or relapse after a few days of steroid treatment [1, 7–9]. Johnston et al. [10] reported a case series of five patients who developed colitis in response to ipilimumab after poor response to systemic steroids requiring treatment with infliximab in all the five patients. There is little data to predict who will respond to oral steroids and who will need infliximab in addition to steroids. Guidelines suggested by Weber et al. [1] recommend the addition of infliximab if steroids do not resolve symptoms within 48–72 h. Minor et al. [8] reported 3 patients with grade 2 diarrhea who responded quickly to infliximab, mesalamine, and hydrocortisone enemas, allowing continued administration of immunotherapy with ipilimumab. Using infliximab for grade 1 or grade 2, diarrhea is not recommended unless associated with endoscopic findings of extensive colitis or if the colitis was steroid resistant. Infliximab is recommended for patients with grade 4 diarrhea, for patients who relapse with tapering of steroids, for patients with symptoms lingering 72 h after treatment with steroids, and for patients with severe or extensive colitis. Ipilimumab should be stopped in patients with severe colitis [1]. Colectomy is indicated in cases with perforation [4]. As yet there are no published guidelines for treating colitis related to other biologic agents. Early identification and treatment of this common and serious complication is crucial to improving the outcome. Provider awareness of such potentially fatal adverse events is also important if the complication is to be promptly recognized and treated.
Learning Points • •
Biological agents can cause colitis. Ipilimumab-induced colitis is very common and potentially fatal if not promptly recognized and treated. Ipilimumab-induced colitis is treated with steroids and with infliximab.
References 1. Weber JS, Ka¨hler KC, Hauschild A. Management of immunerelated adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–2697. 2. Freeman HJ. Colitis associated with biological agents. World J Gastroenterol. 2012;18:1871–1874. 3. Fouache D, Goe¨b V, Massy-Guillemant N, Avenet G, et al. Paradoxical adverse events of anti-tumor necrosis factor therapy for spondylo-arthropathies: a retrospective study. Rheumatology. 2009;48:761–764. 4. Mitchell KA, Kluger H, Sznol M, Hartman DJ. Ipilimumabinduced perforating colitis. J Clin Gastroenterol. 2013;47: 781–785.
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1114 5. Blansfield JA, Beck KE, Tran K, Yang JC, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28:593–598. 6. National Cancer Institute. Common terminology criteria for adverse events (CTCAE), version 4.0. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_ 2010-06-14_QuickReference_8.5x11.pdf. 7. Beck KE, Blansfield JA, Tran KQ, Feldman AL, et al. Enterocolitis in patients with cancer after antibody blockade of
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Dig Dis Sci (2014) 59:1112–1114 cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24:2283–2289. 8. Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm. 2009;24:321–325. 9. Page`s C, Gornet JM, Monsel G, Allez M, et al. Ipilimumabinduced acute severe colitis treated by infliximab. Melanoma Res. 2013;23:227–230. 10. Johnston RL, Lutzky J, Chodhry A, Barkin JS. Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. Dig Dis Sci. 2009;54:2538–2540.
UNM CLINICAL CASE CONFERENCES
Colitis Associated with Biological Agents K. Khirfan • M. Kistin
Published online: 23 April 2014 Springer Science+Business Media New York 2014
Case Presentation A 63-year-old man with a history of malignant melanoma was admitted with a 4-day history of severe watery diarrhea, tenesmus, and abdominal pain. Prior to this hospitalization, he had undergone a surgical resection of a stage IIIB melanoma of the anterior abdominal wall followed by treatment with two doses of ipilimumab, a monoclonal antibody directed against cytotoxic T lymphocytes, for his melanoma, with the last dose 7 weeks prior to the current hospitalization. He had had a recent admission for bacterial multi-lobar pneumonia complicated by severe Clostridium difficile infection that was still in treatment with a tapering course of oral vancomycin after completing the antibiotic treatment for pneumonia. Physical examination revealed heart rate of 101, blood pressure of 72/46 mmHg, temperature 38.2 C, respiratory rate of 18/min, dry mucous membranes, and diffuse abdominal tenderness and some guarding without rebound tenderness. Complete blood count, liver function tests, serum amylase, and serum lipase were all normal. Kidney function tests and fractional urinary excretion of sodium suggested the presence of prerenal azotemia. After admission, he was intravenously hydrated while the etiology of his diarrhea was investigated with stool microscopic examination, culture, and polymerase chain reaction for C. difficile, which were all negative, diminishing the likelihood of an infectious etiology. An abdominal computed tomography (CT) scan was reported as showing diffuse colonic wall thickening and a
K. Khirfan (&) M. Kistin Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, 1 University of New Mexico, MSC10-5550, Albuquerque, NM 87131, USA e-mail: [email protected]
123
number of colonic microperforations consistent with severe colitis (Fig. 1). Due to the severity of these findings, colonoscopy was not performed. The patient was initially diagnosed with an immune-related colitis, possibly due to ipilimumab. Accordingly, ipilimumab was discontinued in favor of IV steroid treatment, which partially improved his symptoms after a week of therapy. Infliximab was then added, with which complete symptom resolution. He was discharged home 2 weeks after admission.
Discussion The use of biological agents for the treatment of autoimmune and malignant conditions has increasingly been complicated by immune-mediated colitis. Ipilimumab, a monoclonal antibody approved by the US FDA for the treatment of malignant melanoma, is particularly associated with colitis. Ipilimumab augments the immune-mediated blockage of cytotoxic T lymphocyte antigen 4 (CTLA-4), a key inhibitor of regulatory T cell-mediated immune tolerance to tumor cell growth. This dysregulation of immune tolerance is also reflected in the occurrence of a unique set of immune-related adverse effects, with colitis being one of the most common [1]. Other biologic agents, including rituximab (an antiCD20 monoclonal antibody) and bevacizumab (a monoclonal antibody against the vascular endothelial growth factor), have also been reported to cause colitis [2]. Furthermore, emerging evidence indicates the paradoxical occurrence of new-onset colitis and exacerbation of previously documented inflammatory bowel disease-related colitis due to anti-tumor necrosis factor (TNF)-a agents used in the treatment of inflammatory bowel disease (IBD) including infliximab, adalimumab, and etanercept [2, 3].
Dig Dis Sci (2014) 59:1112–1114
Fig. 1 Abdominal computed tomographic scan, showing intestinal mucosal thickening and a small amount of free air in the peritoneal cavity
Unmasking of underlying disease, colonic ischemia, or superimposed infection have been suggested as possible factors involved in the development of the colitis [2]. This case demonstrates severe colitis, the most commonly reported serious toxicity due to ipilimumab, that if left untreated may lead to intestinal perforation [4]. Ideally, patients with moderate-to-severe disease should undergo colonoscopy or flexible sigmoidoscopy to confirm the diagnosis or to determine the cause of colitis [1], although this option is not always possible. Histologic examination typically shows neutrophilic infiltration (46 % of cases) or less commonly mixed neutrophilic–lymphocytic (38 % of cases) or lymphocytic infiltration (15 % of cases) [1]. Abdominal radiologic imaging can be helpful in excluding complications such as perforation or obstruction [1]. It is recommended to consider of simultaneous pituitary insufficiency from autoimmune hypophysitis as a cause of diarrhea [5]. Treatment depends on the severity of the diarrhea according to the following: grade 1 is defined as an increase of \4; grade 2, an increase of 4–6; grade 3 an increase of C7 stools per day over baseline and incontinence or hospitalization; and grade 4 is defined by lifethreatening consequences or when urgent intervention indicated [6]. The endoscopic extent and severity of colitis help to determine the therapeutic approach. Patients who present with grade 3 or 4 gastrointestinal toxicity due to ipilimumab and patients with endoscopic findings consistent with colitis should be treated with systemic steroids [7], usually oral prednisone 1–2 mg/kg once per day or oral dexamethasone 4 mg every 4 h with methylprednisolone 125 mg IV/day reserved for severe cases [1] followed by a 4 week taper. Infliximab, a monoclonal antibody and TNF-a inhibitor, used to treat autoimmune diseases, is
1113
reserved for the treatment of patients who respond poorly to steroids or relapse after a few days of steroid treatment [1, 7–9]. Johnston et al. [10] reported a case series of five patients who developed colitis in response to ipilimumab after poor response to systemic steroids requiring treatment with infliximab in all the five patients. There is little data to predict who will respond to oral steroids and who will need infliximab in addition to steroids. Guidelines suggested by Weber et al. [1] recommend the addition of infliximab if steroids do not resolve symptoms within 48–72 h. Minor et al. [8] reported 3 patients with grade 2 diarrhea who responded quickly to infliximab, mesalamine, and hydrocortisone enemas, allowing continued administration of immunotherapy with ipilimumab. Using infliximab for grade 1 or grade 2, diarrhea is not recommended unless associated with endoscopic findings of extensive colitis or if the colitis was steroid resistant. Infliximab is recommended for patients with grade 4 diarrhea, for patients who relapse with tapering of steroids, for patients with symptoms lingering 72 h after treatment with steroids, and for patients with severe or extensive colitis. Ipilimumab should be stopped in patients with severe colitis [1]. Colectomy is indicated in cases with perforation [4]. As yet there are no published guidelines for treating colitis related to other biologic agents. Early identification and treatment of this common and serious complication is crucial to improving the outcome. Provider awareness of such potentially fatal adverse events is also important if the complication is to be promptly recognized and treated.
Learning Points • •
Biological agents can cause colitis. Ipilimumab-induced colitis is very common and potentially fatal if not promptly recognized and treated. Ipilimumab-induced colitis is treated with steroids and with infliximab.
References 1. Weber JS, Ka¨hler KC, Hauschild A. Management of immunerelated adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–2697. 2. Freeman HJ. Colitis associated with biological agents. World J Gastroenterol. 2012;18:1871–1874. 3. Fouache D, Goe¨b V, Massy-Guillemant N, Avenet G, et al. Paradoxical adverse events of anti-tumor necrosis factor therapy for spondylo-arthropathies: a retrospective study. Rheumatology. 2009;48:761–764. 4. Mitchell KA, Kluger H, Sznol M, Hartman DJ. Ipilimumabinduced perforating colitis. J Clin Gastroenterol. 2013;47: 781–785.
123
1114 5. Blansfield JA, Beck KE, Tran K, Yang JC, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28:593–598. 6. National Cancer Institute. Common terminology criteria for adverse events (CTCAE), version 4.0. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_ 2010-06-14_QuickReference_8.5x11.pdf. 7. Beck KE, Blansfield JA, Tran KQ, Feldman AL, et al. Enterocolitis in patients with cancer after antibody blockade of
123
Dig Dis Sci (2014) 59:1112–1114 cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24:2283–2289. 8. Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm. 2009;24:321–325. 9. Page`s C, Gornet JM, Monsel G, Allez M, et al. Ipilimumabinduced acute severe colitis treated by infliximab. Melanoma Res. 2013;23:227–230. 10. Johnston RL, Lutzky J, Chodhry A, Barkin JS. Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. Dig Dis Sci. 2009;54:2538–2540.
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