- Email: [email protected]
Association Between Ipilimumab and Celiac Disease
CASE REPORT
Association Between Ipilimumab and Celiac Disease Nicole M. Gentile, MD; Anita D’Souza, MBBS; Larissa L. Fujii, MD; Tsung-Teh Wu, MD, PhD; and Joseph A. Murray, MD Abstract A 62-year-old man with chemotherapy-naive, castration-resistant metastatic prostate cancer presented with refractory diarrhea despite prolonged high-dose corticosteroid treatment after receiving 3 doses of ipilimumab as part of a phase 3 clinical trial. The investigative work-up and response to a gluten-free diet essentially confirm celiac disease. Although ipilimumab-induced enterocolitis is a well-reported complication, there have been no reported cases of celiac disease with ipilimumab therapy, to our knowledge. We suspect that ipilimumab may have amplified the symptomatic presentation of previously unrecognized celiac disease or perhaps even triggered the disease itself. With ipilimumab being used more commonly in the treatment of melanoma and prostate cancer, we believe that physicians should be aware of this potential adverse outcome when evaluating a patient who experiences persistent diarrhea during or after ipilimumab treatment. ª 2013 Mayo Foundation for Medical Education and Research From the Department of Internal Medicine (N.M.G.), Department of Oncology (A.D.), Division of Gastroenterology (L.L.F., J.A.M.), Department of Laboratory Medicine and Pathology (T.-T.W.), Mayo Clinic, Rochester, MN.
I
pilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), is commonly used in metastatic melanoma. It is currently being investigated in clinical trials in other cancers.1 Gastrointestinal adverse effects, such as diarrhea, may be seen in up to 44% of patients taking ipilimumab.1 We report the first case of ipilimumab-associated celiac disease. REPORT OF A CASE A 62-year-old man presented to Mayo Clinic in Rochester, Minnesota, with persistent diarrhea. His medical history was significant for Gleason grade 4þ5 prostatic adenocarcinoma diagnosed in 2006, for which he underwent robotic nerve-sparing prostatectomy and adjuvant radiotherapy. Two years later, his prostatespecific antigen (PSA) level increased, and leuprolide and bicalutamide were administered. In 2011, his PSA level continued to increase, and he had evidence of recurrence in the prostatectomy bed and bladder neck. He underwent a radical cystectomy with an ileal conduit urinary diversion, extended pelvic lymphadenectomy, retroperitoneal lymph node dissection, and bilateral orchiectomy. Six months later, his PSA level continued to rise, and he was enrolled in a randomized, double-blind, phase 3 trial to compare the
414
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Mayo Clin Proc. 2013;88(4):414-417
efficacy of ipilimumab vs placebo in asymptomatic or minimally symptomatic patients with chemotherapy-naive, castration-resistant metastatic prostate cancer involving 3 doses of ipilimumab at 10 mg/kg given every 3 weeks. He tolerated the first ipilimumab infusion without any untoward effect. After the second infusion, he experienced watery diarrhea, which resolved with the use of prednisone, 10 mg twice daily for 1 week. At the time of his third infusion, he was undergoing a corticosteroid taper of 5 mg twice daily. A week later, he experienced profuse nonbloody watery diarrhea, leading to multiple emergency department visits and a subsequent increase in his prednisone dose to 50 mg/d. His diarrhea continued to worsen, with up to 20 bowel movements per day, requiring hospitalization locally. At baseline, he had 3 to 4 bowel movements per day after ileal conduit urinary diversion. He was treated with 3 days of intravenous methylprednisone, 250 mg/d, and he was discharged from the hospital taking prednisone, 150 mg/d. Despite a month of high-dose corticosteroid treatment, his diarrhea persisted with no improvement. The patient was subsequently admitted to the hospital for fluid resuscitation and possible infliximab administration for ipilimumabinduced colitis. He did not have abdominal pain, nausea, or fever. His diarrhea improved
Mayo Clin Proc. n April 2013;88(4):414-417 n http://dx.doi.org/10.1016/j.mayocp.2013.01.015 www.mayoclinicproceedings.org n ª 2013 Mayo Foundation for Medical Education and Research
IPILIMUMAB-ASSOCIATED CELIAC DISEASE
FIGURE 1. Biopsy specimen of the colon showing fragments of colonic mucosa with increased crypt apoptosis (arrows) and mild crypt distortion (hematoxylin-eosin, 200).
when he restricted himself to a diet of clear liquids. Laboratory evaluation revealed mild normocytic anemia. Stool examination revealed no leukocytes, Clostridium difficile, Giardia lamblia, or enteric pathogens on culture. Findings from a serum cytomegalovirus polymerase chain reaction were negative. Results of a colonoscopy were unremarkable on gross visualization. Biopsy specimens of the colon showed fragments of colonic mucosa with increased crypt apoptoses and mild crypt distortion (Figure 1). Goblet cells were present. No cytomegalovirus was identified by immunostain. There was no evidence of collagenous or lymphocytic colitis.
FIGURE 2. Biopsy specimen of the duodenum showing a malabsorptive pattern with partial to near-total villous atrophy, crypt hyperplasia, and chronic inflammation, with a decreased number of Paneth cells (hematoxylin-eosin, 200). Mayo Clin Proc. n April 2013;88(4):414-417 www.mayoclinicproceedings.org
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Further gastroenterology-directed testing revealed elevated levels of serum antietissue transglutaminase IgA at 79.1 U/mL (reference value, <4.0 U/mL), antietissue transglutaminase IgG at 6.3 U/mL (reference value, <6.0 U/mL), antiedeamidated gliadin peptide IgA at 129.0 (reference value, <20.0), and antiedeamidated gliadin peptide IgG at 91.5 (reference value, <20.0). Antieendomysial antibodies were absent. He had an HLA-DQ2 haplotype permissive for celiac disease. Antienterocyte antibody was absent. Upper gastrointestinal endoscopy was performed; a duodenal biopsy specimen showed a malabsorptive pattern with partial to near-total villous atrophy, crypt hyperplasia, and chronic inflammation, with a decreased number of Paneth cells (Figure 2). Intraepithelial lymphocytosis (60 lymphocytes per 100 epithelial cells by CD3 immunostain) was present (Figure 3). No notable thickening of the subepithelial collagen band was identified by trichrome stain. Small-bowel aspirate was negative for bacterial overgrowth. These results confirmed celiac disease that appeared after the initiation of treatment with ipilimumab. Because of the severity of the enteropathy and his symptoms, the patient was given budesonide, 3 mg 3 times a day. He was also started on a gluten-free diet, and his prednisone dose was tapered. However, once the laboratory analysis was complete, particularly the absence of antienterocyte antibody and his response to a gluten-free diet, systemic and mucosally directed corticosteroid doses were tapered as the patient was believed to not have autoimmune enteropathy. Follow-up was conducted at 2, 8, and 20 weeks. At 2 weeks, the patient was
FIGURE 3. CD3 immunostain of the duodenal biopsy specimen showing intraepithelial lymphocytosis (200).
http://dx.doi.org/10.1016/j.mayocp.2013.01.015
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MAYO CLINIC PROCEEDINGS
undergoing a prednisone and budesonide taper while adhering to a gluten-free diet. He noted that his bowel movements were decreasing to 5 per day, and he noted weight gain. At 8 weeks, he had completed the prednisone and budesonide taper 3 weeks before follow-up. He continued to gain weight and described having 3 to 4 bowel movements a day, consistent with his baseline after ileal conduit urinary diversion, and overall reported feeling well. At 20 weeks of follow-up, while remaining compliant with a gluten-free diet, he reported 3 bowel movements a day, was at his original weight, and felt well. In addition, laboratory testing was performed at follow-up to assess his disease activity. The antietissue transglutaminase IgA level had decreased from 79.1 U/mL to less than 1.2 U/mL at 20 weeks of follow-up. The antie deamidated gliadin peptide IgA level had decreased from 129 to 25 at 20 weeks of followup. He has remained well on a gluten-free diet without taking prednisone or corticosteroids. DISCUSSION Ipilimumab is a humanized IgG1 monoclonal antibody with activity against CTLA-4, leading to up-regulation of the T-cell response.1 It is currently Food and Drug Administrationeapproved for metastatic melanoma,1 and it is being tested for prostate cancer. It is proposed that adverse effects are a result of an increase in cytokine release.1 Known gastrointestinal adverse effects range from diarrhea to ipilimumab-induced enterocolitis, hepatotoxicity, and pancreatitis.1 General guidelines for the management of gastrointestinal adverse effects include symptomatic management with antidiarrheal agents and hydration for grade 1 diarrhea,1 defined as fewer than 4 stools over baseline in 24 hours.2 With grade 2 diarrhea (defined as 4 to 6 bowel movements over baseline in 24 hours),2 or greater, an investigative evaluation with fecal leukocyte, stool cultures, and C difficile testing and treatment with budesonide, 9 mg/d, should be considered.1 For persistent diarrhea despite treatment, evaluation with colonoscopy is recommended.1 For those who experience grade 3 (defined as an increase of 7 diarrheal bowel movements above baseline in 24 hours2) or grade 4 (defined as diarrhea associated with life-threatening consequences2), it is recommended to discontinue ipilimumab treatment and to initiate high-dose corticosteroid therapy with methylprednisolone 416
Mayo Clin Proc.
n
followed by treatment with prednisone, 1 to 2 mg/kg daily, tapered over 4 weeks.1 Symptom improvement is generally noted at 1 to 2 weeks.1 Infliximab is recommended for those who do not respond to corticosteroid treatment within 72 hours.1 The present patient did not respond to prolonged high-dose corticosteroid therapy and presented to us for further opinion regarding the potential use of infliximab. Although ipilimumab-induced enterocolitis is a wellreported complication, there have been no reported cases of celiac disease with ipilimumab therapy, to our knowledge. Celiac disease is an autoimmune condition in which genetically predisposed (HLA-DQ2 or HLA-DQ8 haplotype) individuals experience symptoms from gluten (barley, rye, wheat) consumption, with resultant gliadin recognition by T lymphocytes triggering an immune cascade that results in the destruction of intestinal villi.3 Symptom presentation varies and includes diarrhea, fatigue, and malabsorption, leading to weight loss, anemia, and osteoporosis.3 Celiac disease is often not considered, and there may be great delays in diagnosis. Celiac disease can also be associated with microscopic colitis. Consideration of the possible contribution of celiac disease to persistent diarrhea that occurs in patients being treated with ipilimumab should be explored. Serologic tests helpful in screening include antietissue transglutaminase IgA (93% sensitivity, >98% specificity) and antiendomysial antibody IgA (93% sensitivity, >99% specificity).4 In addition, antiedeamidated gliadin peptide IgA plus IgG have a sensitivity of 75%, a specificity of 94%, and an accuracy of 86% in histologically proved celiac disease.4 Histologic changes in the duodenal mucosa are the criterion standard for diagnosis and include intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy.3 Symptomatic resolution is often achieved with a gluten-free diet.3 The CTLA4 gene is associated with autoimmunity and T-cell response.5 A native soluble CTLA-4 has been found in those with autoimmune thyroid diseases.5 Simone et al5 found that untreated patients with celiac disease had high serum concentrations of CTLA-4 and, thus, correlated with gluten intake and degree of mucosal damage, and they ultimately suggested that soluble CTLA-4 may have an immunomodulatory effect on T cells. Ipilimumab is
April 2013;88(4):414-417
n
http://dx.doi.org/10.1016/j.mayocp.2013.01.015 www.mayoclinicproceedings.org
IPILIMUMAB-ASSOCIATED CELIAC DISEASE
a monoclonal antibody against CTLA-4 that causes up-regulation of the T-cell response1; therefore, the potential effect of drug-induced T-cell up-regulation in an individual with potential or even unrecognized celiac disease is not known. There is a precedent for celiac disease by interferon alfa treatment for hepatitis C, which is known to trigger autoimmune phenomena.6 This case differs from drug-associated villous injury that mimics celiac disease recently reported for olmesartan and mycophenolate mofetil in that the present case was celiac disease, not a mimic of celiac disease.7,8 CONCLUSION In this patient, the presence of intraepithelial lymphocytosis and villous atrophy, the presence of anti-tissue transglutaminase antibodies and HLA haplotype, and response to a glutenfree diet essentially confirm celiac disease. We suspect that ipilimumab therapy may have precipitated or amplified the symptomatic presentation of this patient’s celiac disease or perhaps even the disease itself. This case report exemplifies that not all diarrhea seen after ipilimumab therapy is ipilimumab-induced colitis and, therefore, that patients with refractory diarrhea despite high-dose corticosteroid treatment should have additional testing to look for celiac disease or autoimmune enteropathy before a trial of infliximab is given. Perhaps celiac disease should be sought systematically in such patients, especially those
Mayo Clin Proc. n April 2013;88(4):414-417 www.mayoclinicproceedings.org
n
who are at risk for the disease owing to a personal or family history of autoimmune disease. Abbreviations and Acronyms: CTLA-4 = cytotoxic T-lymphocyte antigen 4; PSA = prostate-specific antigen Potential Competing Interests: Dr Murray has received grant support from the National Institutes of Health and Alba Therapeutics and consulting fees or honoraria from Ironwood Inc, Flamenteras, Actogenix, Bayer Healthcare, Vysera Biomedical, 2G Pharma Inc, ImmunosanT Inc, and Shire US Inc. Correspondence: Address to Joseph A. Murray, MD, Division of Gastroenterology and Hepatology, 200 First St SW, Rochester, MN 55905 ([email protected]).
REFERENCES 1. Weber JS, Kahler KC, Hauschild A. Management of immunerelated adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697. 2. Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol. 2010;2(1):51-63. 3. Rashtak S, Murray JA. Review article: coeliac disease, new approaches to therapy. Aliment Pharmacol Ther. 2012;35(7):768-781. 4. Scanlon SA, Murray JA. Update on celiac disease: etiology, differential diagnosis, drug targets, and management advances. Clin Exp Gastroenterol. 2011;4:297-311. 5. Simone R, Brizzolara R, Chiappori A, et al. A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury. Int Immunol. 2009;21(9): 1037-1045. 6. Bardella MT, Marino R, Meroni PL. Celiac disease during interferon treatment. Ann Intern Med. 1999;131(2):157-158. 7. Weclawiak H, Ould-Mohamed A, Bournet B, et al. Duodenal villous atrophy: a cause of chronic diarrhea after solid-organ transplantation. Am J Transplant. 2011;11(3):575-582. 8. Rubio-Tapia A, Herman ML, Ludvigsson JF, et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc. 2012; 87(8):732-738.
http://dx.doi.org/10.1016/j.mayocp.2013.01.015
417
Association Between Ipilimumab and Celiac Disease Nicole M. Gentile, MD; Anita D’Souza, MBBS; Larissa L. Fujii, MD; Tsung-Teh Wu, MD, PhD; and Joseph A. Murray, MD Abstract A 62-year-old man with chemotherapy-naive, castration-resistant metastatic prostate cancer presented with refractory diarrhea despite prolonged high-dose corticosteroid treatment after receiving 3 doses of ipilimumab as part of a phase 3 clinical trial. The investigative work-up and response to a gluten-free diet essentially confirm celiac disease. Although ipilimumab-induced enterocolitis is a well-reported complication, there have been no reported cases of celiac disease with ipilimumab therapy, to our knowledge. We suspect that ipilimumab may have amplified the symptomatic presentation of previously unrecognized celiac disease or perhaps even triggered the disease itself. With ipilimumab being used more commonly in the treatment of melanoma and prostate cancer, we believe that physicians should be aware of this potential adverse outcome when evaluating a patient who experiences persistent diarrhea during or after ipilimumab treatment. ª 2013 Mayo Foundation for Medical Education and Research From the Department of Internal Medicine (N.M.G.), Department of Oncology (A.D.), Division of Gastroenterology (L.L.F., J.A.M.), Department of Laboratory Medicine and Pathology (T.-T.W.), Mayo Clinic, Rochester, MN.
I
pilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), is commonly used in metastatic melanoma. It is currently being investigated in clinical trials in other cancers.1 Gastrointestinal adverse effects, such as diarrhea, may be seen in up to 44% of patients taking ipilimumab.1 We report the first case of ipilimumab-associated celiac disease. REPORT OF A CASE A 62-year-old man presented to Mayo Clinic in Rochester, Minnesota, with persistent diarrhea. His medical history was significant for Gleason grade 4þ5 prostatic adenocarcinoma diagnosed in 2006, for which he underwent robotic nerve-sparing prostatectomy and adjuvant radiotherapy. Two years later, his prostatespecific antigen (PSA) level increased, and leuprolide and bicalutamide were administered. In 2011, his PSA level continued to increase, and he had evidence of recurrence in the prostatectomy bed and bladder neck. He underwent a radical cystectomy with an ileal conduit urinary diversion, extended pelvic lymphadenectomy, retroperitoneal lymph node dissection, and bilateral orchiectomy. Six months later, his PSA level continued to rise, and he was enrolled in a randomized, double-blind, phase 3 trial to compare the
414
n
Mayo Clin Proc. 2013;88(4):414-417
efficacy of ipilimumab vs placebo in asymptomatic or minimally symptomatic patients with chemotherapy-naive, castration-resistant metastatic prostate cancer involving 3 doses of ipilimumab at 10 mg/kg given every 3 weeks. He tolerated the first ipilimumab infusion without any untoward effect. After the second infusion, he experienced watery diarrhea, which resolved with the use of prednisone, 10 mg twice daily for 1 week. At the time of his third infusion, he was undergoing a corticosteroid taper of 5 mg twice daily. A week later, he experienced profuse nonbloody watery diarrhea, leading to multiple emergency department visits and a subsequent increase in his prednisone dose to 50 mg/d. His diarrhea continued to worsen, with up to 20 bowel movements per day, requiring hospitalization locally. At baseline, he had 3 to 4 bowel movements per day after ileal conduit urinary diversion. He was treated with 3 days of intravenous methylprednisone, 250 mg/d, and he was discharged from the hospital taking prednisone, 150 mg/d. Despite a month of high-dose corticosteroid treatment, his diarrhea persisted with no improvement. The patient was subsequently admitted to the hospital for fluid resuscitation and possible infliximab administration for ipilimumabinduced colitis. He did not have abdominal pain, nausea, or fever. His diarrhea improved
Mayo Clin Proc. n April 2013;88(4):414-417 n http://dx.doi.org/10.1016/j.mayocp.2013.01.015 www.mayoclinicproceedings.org n ª 2013 Mayo Foundation for Medical Education and Research
IPILIMUMAB-ASSOCIATED CELIAC DISEASE
FIGURE 1. Biopsy specimen of the colon showing fragments of colonic mucosa with increased crypt apoptosis (arrows) and mild crypt distortion (hematoxylin-eosin, 200).
when he restricted himself to a diet of clear liquids. Laboratory evaluation revealed mild normocytic anemia. Stool examination revealed no leukocytes, Clostridium difficile, Giardia lamblia, or enteric pathogens on culture. Findings from a serum cytomegalovirus polymerase chain reaction were negative. Results of a colonoscopy were unremarkable on gross visualization. Biopsy specimens of the colon showed fragments of colonic mucosa with increased crypt apoptoses and mild crypt distortion (Figure 1). Goblet cells were present. No cytomegalovirus was identified by immunostain. There was no evidence of collagenous or lymphocytic colitis.
FIGURE 2. Biopsy specimen of the duodenum showing a malabsorptive pattern with partial to near-total villous atrophy, crypt hyperplasia, and chronic inflammation, with a decreased number of Paneth cells (hematoxylin-eosin, 200). Mayo Clin Proc. n April 2013;88(4):414-417 www.mayoclinicproceedings.org
n
Further gastroenterology-directed testing revealed elevated levels of serum antietissue transglutaminase IgA at 79.1 U/mL (reference value, <4.0 U/mL), antietissue transglutaminase IgG at 6.3 U/mL (reference value, <6.0 U/mL), antiedeamidated gliadin peptide IgA at 129.0 (reference value, <20.0), and antiedeamidated gliadin peptide IgG at 91.5 (reference value, <20.0). Antieendomysial antibodies were absent. He had an HLA-DQ2 haplotype permissive for celiac disease. Antienterocyte antibody was absent. Upper gastrointestinal endoscopy was performed; a duodenal biopsy specimen showed a malabsorptive pattern with partial to near-total villous atrophy, crypt hyperplasia, and chronic inflammation, with a decreased number of Paneth cells (Figure 2). Intraepithelial lymphocytosis (60 lymphocytes per 100 epithelial cells by CD3 immunostain) was present (Figure 3). No notable thickening of the subepithelial collagen band was identified by trichrome stain. Small-bowel aspirate was negative for bacterial overgrowth. These results confirmed celiac disease that appeared after the initiation of treatment with ipilimumab. Because of the severity of the enteropathy and his symptoms, the patient was given budesonide, 3 mg 3 times a day. He was also started on a gluten-free diet, and his prednisone dose was tapered. However, once the laboratory analysis was complete, particularly the absence of antienterocyte antibody and his response to a gluten-free diet, systemic and mucosally directed corticosteroid doses were tapered as the patient was believed to not have autoimmune enteropathy. Follow-up was conducted at 2, 8, and 20 weeks. At 2 weeks, the patient was
FIGURE 3. CD3 immunostain of the duodenal biopsy specimen showing intraepithelial lymphocytosis (200).
http://dx.doi.org/10.1016/j.mayocp.2013.01.015
415
MAYO CLINIC PROCEEDINGS
undergoing a prednisone and budesonide taper while adhering to a gluten-free diet. He noted that his bowel movements were decreasing to 5 per day, and he noted weight gain. At 8 weeks, he had completed the prednisone and budesonide taper 3 weeks before follow-up. He continued to gain weight and described having 3 to 4 bowel movements a day, consistent with his baseline after ileal conduit urinary diversion, and overall reported feeling well. At 20 weeks of follow-up, while remaining compliant with a gluten-free diet, he reported 3 bowel movements a day, was at his original weight, and felt well. In addition, laboratory testing was performed at follow-up to assess his disease activity. The antietissue transglutaminase IgA level had decreased from 79.1 U/mL to less than 1.2 U/mL at 20 weeks of follow-up. The antie deamidated gliadin peptide IgA level had decreased from 129 to 25 at 20 weeks of followup. He has remained well on a gluten-free diet without taking prednisone or corticosteroids. DISCUSSION Ipilimumab is a humanized IgG1 monoclonal antibody with activity against CTLA-4, leading to up-regulation of the T-cell response.1 It is currently Food and Drug Administrationeapproved for metastatic melanoma,1 and it is being tested for prostate cancer. It is proposed that adverse effects are a result of an increase in cytokine release.1 Known gastrointestinal adverse effects range from diarrhea to ipilimumab-induced enterocolitis, hepatotoxicity, and pancreatitis.1 General guidelines for the management of gastrointestinal adverse effects include symptomatic management with antidiarrheal agents and hydration for grade 1 diarrhea,1 defined as fewer than 4 stools over baseline in 24 hours.2 With grade 2 diarrhea (defined as 4 to 6 bowel movements over baseline in 24 hours),2 or greater, an investigative evaluation with fecal leukocyte, stool cultures, and C difficile testing and treatment with budesonide, 9 mg/d, should be considered.1 For persistent diarrhea despite treatment, evaluation with colonoscopy is recommended.1 For those who experience grade 3 (defined as an increase of 7 diarrheal bowel movements above baseline in 24 hours2) or grade 4 (defined as diarrhea associated with life-threatening consequences2), it is recommended to discontinue ipilimumab treatment and to initiate high-dose corticosteroid therapy with methylprednisolone 416
Mayo Clin Proc.
n
followed by treatment with prednisone, 1 to 2 mg/kg daily, tapered over 4 weeks.1 Symptom improvement is generally noted at 1 to 2 weeks.1 Infliximab is recommended for those who do not respond to corticosteroid treatment within 72 hours.1 The present patient did not respond to prolonged high-dose corticosteroid therapy and presented to us for further opinion regarding the potential use of infliximab. Although ipilimumab-induced enterocolitis is a wellreported complication, there have been no reported cases of celiac disease with ipilimumab therapy, to our knowledge. Celiac disease is an autoimmune condition in which genetically predisposed (HLA-DQ2 or HLA-DQ8 haplotype) individuals experience symptoms from gluten (barley, rye, wheat) consumption, with resultant gliadin recognition by T lymphocytes triggering an immune cascade that results in the destruction of intestinal villi.3 Symptom presentation varies and includes diarrhea, fatigue, and malabsorption, leading to weight loss, anemia, and osteoporosis.3 Celiac disease is often not considered, and there may be great delays in diagnosis. Celiac disease can also be associated with microscopic colitis. Consideration of the possible contribution of celiac disease to persistent diarrhea that occurs in patients being treated with ipilimumab should be explored. Serologic tests helpful in screening include antietissue transglutaminase IgA (93% sensitivity, >98% specificity) and antiendomysial antibody IgA (93% sensitivity, >99% specificity).4 In addition, antiedeamidated gliadin peptide IgA plus IgG have a sensitivity of 75%, a specificity of 94%, and an accuracy of 86% in histologically proved celiac disease.4 Histologic changes in the duodenal mucosa are the criterion standard for diagnosis and include intraepithelial lymphocytosis, crypt hyperplasia, and villous atrophy.3 Symptomatic resolution is often achieved with a gluten-free diet.3 The CTLA4 gene is associated with autoimmunity and T-cell response.5 A native soluble CTLA-4 has been found in those with autoimmune thyroid diseases.5 Simone et al5 found that untreated patients with celiac disease had high serum concentrations of CTLA-4 and, thus, correlated with gluten intake and degree of mucosal damage, and they ultimately suggested that soluble CTLA-4 may have an immunomodulatory effect on T cells. Ipilimumab is
April 2013;88(4):414-417
n
http://dx.doi.org/10.1016/j.mayocp.2013.01.015 www.mayoclinicproceedings.org
IPILIMUMAB-ASSOCIATED CELIAC DISEASE
a monoclonal antibody against CTLA-4 that causes up-regulation of the T-cell response1; therefore, the potential effect of drug-induced T-cell up-regulation in an individual with potential or even unrecognized celiac disease is not known. There is a precedent for celiac disease by interferon alfa treatment for hepatitis C, which is known to trigger autoimmune phenomena.6 This case differs from drug-associated villous injury that mimics celiac disease recently reported for olmesartan and mycophenolate mofetil in that the present case was celiac disease, not a mimic of celiac disease.7,8 CONCLUSION In this patient, the presence of intraepithelial lymphocytosis and villous atrophy, the presence of anti-tissue transglutaminase antibodies and HLA haplotype, and response to a glutenfree diet essentially confirm celiac disease. We suspect that ipilimumab therapy may have precipitated or amplified the symptomatic presentation of this patient’s celiac disease or perhaps even the disease itself. This case report exemplifies that not all diarrhea seen after ipilimumab therapy is ipilimumab-induced colitis and, therefore, that patients with refractory diarrhea despite high-dose corticosteroid treatment should have additional testing to look for celiac disease or autoimmune enteropathy before a trial of infliximab is given. Perhaps celiac disease should be sought systematically in such patients, especially those
Mayo Clin Proc. n April 2013;88(4):414-417 www.mayoclinicproceedings.org
n
who are at risk for the disease owing to a personal or family history of autoimmune disease. Abbreviations and Acronyms: CTLA-4 = cytotoxic T-lymphocyte antigen 4; PSA = prostate-specific antigen Potential Competing Interests: Dr Murray has received grant support from the National Institutes of Health and Alba Therapeutics and consulting fees or honoraria from Ironwood Inc, Flamenteras, Actogenix, Bayer Healthcare, Vysera Biomedical, 2G Pharma Inc, ImmunosanT Inc, and Shire US Inc. Correspondence: Address to Joseph A. Murray, MD, Division of Gastroenterology and Hepatology, 200 First St SW, Rochester, MN 55905 ([email protected]).
REFERENCES 1. Weber JS, Kahler KC, Hauschild A. Management of immunerelated adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697. 2. Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol. 2010;2(1):51-63. 3. Rashtak S, Murray JA. Review article: coeliac disease, new approaches to therapy. Aliment Pharmacol Ther. 2012;35(7):768-781. 4. Scanlon SA, Murray JA. Update on celiac disease: etiology, differential diagnosis, drug targets, and management advances. Clin Exp Gastroenterol. 2011;4:297-311. 5. Simone R, Brizzolara R, Chiappori A, et al. A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury. Int Immunol. 2009;21(9): 1037-1045. 6. Bardella MT, Marino R, Meroni PL. Celiac disease during interferon treatment. Ann Intern Med. 1999;131(2):157-158. 7. Weclawiak H, Ould-Mohamed A, Bournet B, et al. Duodenal villous atrophy: a cause of chronic diarrhea after solid-organ transplantation. Am J Transplant. 2011;11(3):575-582. 8. Rubio-Tapia A, Herman ML, Ludvigsson JF, et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc. 2012; 87(8):732-738.
http://dx.doi.org/10.1016/j.mayocp.2013.01.015
417