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Fulminant Diabetes in a Patient with Advanced Melanoma on Nivolumab

Fulminant Diabetes in a Patient with Advanced Melanoma on Nivolumab Hindawi Case Reports in Oncological Medicine Volume 2018, Article ID 8981375, 4 pages https://doi.org/10.1155/2018/8981375 Case Report Fulminant Diabetes in a Patient with Advanced Melanoma on Nivolumab 1,2 1,2 1,2 Nora Chokr , Hafsa Farooq, and Elizabeth Guadalupe Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA Waterbury Hospital, Waterbury, CT, USA Correspondence should be addressed to Nora Chokr; nora.chokr@yale.edu Received 19 September 2017; Revised 19 December 2017; Accepted 2 January 2018; Published 28 January 2018 Academic Editor: Constantine Gennatas Copyright © 2018 Nora Chokr et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Anti-PD-1 agents were approved for advanced melanoma after the landmark trial Checkmate-037. Anti-PD-1 agents can breach immunologic tolerance. Fulminant diabetes is an immune endocrinopathy that results from a violent immune attack leading to complete destruction of pancreatic beta cells in genetically predisposed people. We present a rare case of fulminant diabetes precipitated by anti-PD-1 immunotherapy. Case. A 61-year-old male with advanced melanoma presented with a three- day history of nausea, vomiting, and malaise. He was started on nivolumab and ipilimumab. After the third dose, he developed a generalized rash and was prescribed high-dose prednisone. Labs revealed potassium 9.5mmol/L, sodium 127mmol/L, bicarbonate <10mmol/L, blood glucose 1211mg/dL, anion gap >31mmol, arterial blood pH 7.14, and beta-hydroxybutyrate 13.7mmol/L. He was diagnosed with diabetic ketoacidosis. Hemoglobin A1C was 6.9%. C-peptide was undetectable (<0.1ng/ml). Glutamic acid decarboxylase autoantibodies, zinc transporter 8 autoantibodies, insulin autoantibodies, islet antigen 2 auto- antibodies, and islet cell antibodies were all negative. Conclusion. Anti-PD-1 immunotherapy is effective in cancers refractory to standard chemotherapy. )ese agents can precipitate autoimmune disorders. As the use of anti-PD-1 agents is expected to rise, physicians should be educated about the potential side effects. We recommend conducting routine blood glucose checks in patients on these agents. )e first human trial was conducted in 39 patients with 1. Background different types of solid cancers who received the fully human Programmed cell death receptor (PD-1) and programmed IgG4 anti-PD-1 antibody nivolumab (Opdivo , Bristol- cell death ligand (PD-L1) were discovered in the 1990s. Myers Squibb). Durable responses were observed espe- PD-1/PD-1L checkpoint is involved in immunologic tol- cially in melanoma, nonsmall cell lung cancer, and renal cell erance by regulating T cells at the level of the peripheral carcinoma [1, 3]. More patients were later enrolled in several tissues. Tumors can express PD-L1 and use these ligands to clinical trials, some of which are still ongoing. Pem- evade the host’s immune system, making this checkpoint brolizumab (Keytruda , Merck) was the first anti-PD-1 a potential target for cancer therapy [1]. )is pathway was inhibitor that was approved by the US Food and Drug used to develop monoclonal antibodies that block the in- Administration (FDA) in September 2014 for treating pa- teraction between PD-1 receptor and PD-L1 ligand to help tients with advanced melanoma who had responded poorly restore anticancer immune responses. In 2005, the PD-1/PD- to BRAF inhibitors and ipilimumab (Yervoy , Bristol-Myers L1 interaction was used to treat animal tumors. Many clinical Squibb), a monoclonal antibody that upregulates and acti- trials were launched in humans after that. )e efficiency of vates the immune system by targeting CTLA-4 protein. those agents has been shown in tumors belonging to 9 organ Nivolumab was approved by the FDA on December 22,2014, systems [2]. )ey have proven to be very effective in tumors for unresectable or metastatic melanoma that progressed refractory to standard chemotherapy regimens. after ipilimumab therapy and for patients with positive 2 Case Reports in Oncological Medicine BRAF V600 mutation who failed treatment with BRAF 2. Case Presentation inhibitors. )e approval came after the landmark clinical A 61-year-old male with a history of melanoma metastatic to trial Checkmate-037 in which 370 patients with advanced the chest wall and lungs presents to the emergency de- melanoma carrying the BRAF mutation and who failed partment with a three-day history of malaise, nausea, therapy with ipilimumab and BRAF inhibitors were en- vomiting, polyuria, decreased PO intake, and dizziness. He rolled and randomized to receive either nivolumab or has no other history of chronic diseases. He was recently investigator choice of chemotherapy (dacarbazine or car- started on nivolumab and ipilimumab, a combination of boplatin plus paclitaxel). )e effect of nivolumab was anti-PD-1 and anti-CTLA-4 immunotherapy. After the third evaluated in the first 120 patients who received the drug and dose, he developed a generalized maculopapular rash, in those who were followed for a minimum duration of a known side effect of his immunotherapy regimen, for 6 months. )e overall response rate was 32%, with 4 pa- which he was started on high-dose prednisone three days tients achieving complete response and the rest achieving prior to presentation. )e patient reports antecedent fatigue partial responses. )e most common adverse reactions and nausea that profoundly worsened after starting high- described in the Checkmate-037 trial occurring in more dose prednisone. On presentation, he appeared in distress. than 10% of the patients were rash, pruritus, cough, upper He was tachycardic with a heart rate of 126 beats per minute, respiratory infections, and peripheral edema [4]. Other tachypneic with a respiratory rate of 24 breaths per minute, clinical trials followed evaluating the efficacy of anti-PD-1 and hypotensive with a blood pressure of 90/50mmHg. His agents in other types of solid tumors. In March 2015, oral mucosa was dry. His labs revealed potassium nivolumab was approved for the treatment of metastatic 9.5mmol/L, sodium 127mmol/L, bicarbonate <10mmol/L, nonsmall cell lung cancer. In November 2015, nivolumab blood glucose 1211mg/dL, anion gap >31mmol, arterial was approved for metastatic renal cell carcinoma. In blood pH 7.14, beta-hydroxybutyrate 13.7mmol/L, lactic May 2016, approval was extended for refractory Hodgkin’s acid 2.4mmol/L, serum creatinine 4.55, positive urine ke- lymphoma. In February 2017, nivolumab was approved for tones, urine glucose >1000mg/dL, and serum lipase locally advanced and metastatic urothelial cancers. )ese 414IU/L. )e patient was admitted to the intensive care unit agents have gained popularity since 2014, and over 1 year, for management of diabetic ketoacidosis (DKA). He has no FDA has expanded the approval of anti-PD-1 agents across prior history of diabetes. He was managed with IV hydration variable cancer types. Currently, clinical trials are studying and insulin drip and later transitioned to subcutaneous the role of PD-1 blockage in myelodysplastic syndromes insulin after the anion gap closed. He required daily insulin and other hematologic malignancies. )e use of checkpoint adjustments, and it was hard to achieve optimal glycemic inhibitors is expected to rise dramatically as we learn more control. During his hospitalization, workup revealed a hemo- about their efficacy across other types of malignancies. globin A1C of 6.9%. His serum C-peptide was undetectable While these medications have proven to be very efficacious <0.1ng/ml. Glutamic acid decarboxylase autoantibodies in fighting refractory cancers, they are not harmless. Some (GADA) and zinc transporter 8 autoantibodies (ZnT8A) an- of the adverse effects are mild and easily controlled; alyzed by ELISA, insulin autoantibodies (IAA) analyzed by however, some can be very serious and fatal. It is imperative radioimmunoassay, islet antigen 2 autoantibodies (IA-2A) for physicians to be educated about the potential adverse analyzed by radiobinding assay, and islet cell antibodies effects of anti-PD-1 immunotherapy. In their attempt (ICA)analyzedbyimmunofluorescenceassaywereallnegative. to augment the immune response, anti-PD-1 agents can To date, the patient is on subcutaneous basal-bolus insulin breach immunologic tolerance by upregulating autoreactive regimen with glargine and lispro, respectively. Our patient did Tcells. Some of the side effects described in the literature are not carry the high-risk HLA haplotype of FD identified in immune-mediated rash, pneumonitis, colitis, thyroiditis, Japanese populations. hepatitis, nephritis, uveitis, adrenalitis, facial nerve paresis, hypophysitis, aseptic meningitis, and fulminant diabetes (FD). FD was first described by Imagawa in Japan. It is 3. Discussion a subtype of autoimmune type 1 diabetes that results from a violent and abrupt immune attack leading to a complete Our patient is one of a handful of cases described in the destruction of pancreatic beta cells in genetically predis- literature of FD caused by anti-PD-1 cancer therapy. In FD, posed people. FD is characterized by an abrupt ketoacidosis patients present with severe hyperglycemia or diabetic that presents with severe hyperglycemia but rather low ketoacidosis; however, they have unexpectedly low hemo- hemoglobin A1C, low or undetectable C-peptide levels, flu- globin A1C levels which are probably due to the abrupt onset like symptoms, and elevated pancreatic enzymes [5]. FD has of this endocrinopathy. C-peptide levels, like in our patient, ∗ ∗ been associated with HLA DRB1 04:05-DQB1 04:01 [6]. It are low or undetectable. Islet cell autoantibodies are un- is prevalent in East Asian populations and accounts for detectable which suggest that beta cells are completely a significant proportion of acute onset autoimmune di- destroyed via a process that is not entirely similar to the abetes. After the introduction of anti-PD-1 immunother- pathophysiology of the classically known autoimmune type 1 apy, FD has become a more commonly encountered diabetes. In FD, the islet cells are attacked by autoreactive phenomenon in the Western world. In this paper, we T cells. FD was initially thought to be an entirely cell- present a case of FD in a patient with advanced melanoma mediated phenomenon; however, some patients described who was started on the anti-PD-1 agent nivolumab. in the literature tested positive for 1 or more islet cell Case Reports in Oncological Medicine 3 Table 1: Characteristics of patients reported in the literature so far with fulminant diabetes from anti-PD-1 immunotherapy. Age Anti-PD-1 HbA1C Antibody Study Cancer diagnosis Presentation C-peptide (years)/sex agent (%) positivity 55/F Melanoma Nivolumab DKA 6.9 Undetectable No 83/F NSCLC Nivolumab DKA 7.7 Undetectable GADA GADA, IAA, Hughes et al. [7] 63/M RCC Nivolumab Hyperglycemia 8.2 Low ICA 58/M SCLC Nivolumab DKA 9.7 Undetectable GADA 64/F Melanoma Pembrolizumab Hyperglycemia 7.4 Low No Martin-Liberal 54/F Melanoma Pembrolizumab DKA NA NA GADA et al. [8] 70/M NSCLC Nivolumab DKA 9.8 Low NA Mellati et al. [9] Jaw sarcomatoid squamous 66/F NA DKA 9.4 Undetectable GADA cell carcinoma Gaudy et al. [10] 44/F Melanoma Pembrolizumab DKA 6.85 Undetectable GADA Okamoto et al. 55/F Melanoma Nivolumab Hyperglycemia 7 Undetectable No [11] Miyoshi et al. [5] 66/F Melanoma Nivolumab DKA 7.3 Undetectable No Lowe et al. [12] 54/F Melanoma Nivolumab DKA NA Undetectable GADA Munakata et al. 71/M Hodgkin lymphoma Nivolumab Hyperglycemia 7.3 Undetectable No [13] Ishikawa et al. 54/F Melanoma Nivolumab DKA 7 Low No [14] Li et al. [15] 63/F NSCLC Nivolumab DKA <6.4% NA GADA Araujo ´ et al. [16] 73/F NSCLC Nivolumab DKA 7.2 Undetectable GADA Alzenaidi et al. 47/M Melanoma Nivolumab DKA 8 Undetectable GADA 2017 [17] GADA, IA-2, Godwin et al. [18] 34/F NSCLC Nivolumab DKA 7.1 Undetectable IAA )is study 61/M Melanoma Nivolumab DKA 6.9 Undetectable No DKA: diabetic ketoacidosis; F: female; NSCLC: nonsmall cell lung cancer; SCLC: small cell lung cancer; RCC: renal cell carcinoma; GADA: glutamic acid decarboxylase autoantibodies; IAA: insulin autoantibodies; ICA: islet cell antibodies; NA: not available; IA-2: islet 2 autoantibody. presented with diabetic ketoacidosis, and four with new autoantibodies either at disease onset or later, which sug- gests that a humoral immune response is also implicated in onset hyperglycemia, with or without ketonuria, within the pathophysiology of FD (Table 1). FD was first described weeks to months following treatment onset. )e mean in the literature in the setting of anti-PD-1 immunotherapy hemoglobin A1C was 7.7%. C-peptide levels in all cases were in early 2015, shortly after the drugs were approved by the either undetectable or in the low normal range on pre- FDA. Patients who develop FD become insulin dependent sentation but eventually became undetectable. Two patients for life. It can manifest 1 week to a few months after starting tested positive for 3 out of 4 islet antibodies, nine patients the therapy. Diagnosis should be prompt because of the tested positive for GADA only, and the rest had negative increased risk of death within the first 24 hours. It is worth antibody titers. Few of these patients had HLA haplotypes mentioning that these drugs can upset the gastrointestinal associated with the development of autoimmune type 1 tract and cause nausea, vomiting, and abdominal pain that diabetes. )ese cases illustrate that anti-PD-1 agents affect the Tcells regulatory pathways triggering both humoral and can all be managed symptomatically. It is important to distinguish these drug adverse effects from DKA symptoms cell-mediated autoimmunity [7] (Table 1). [5]. Our patient must have had high blood glucose levels days to weeks prior to presentation. )e high-dose pred- 4. Conclusion nisone that he was started on for the rash definitely played a major role in exacerbating his condition. Anti-PD-1 immunotherapy has shown great efficacy in )ere are around 19 cases described to date of fulminant refractory cancers. PD-1/PD-1L is a complex pathway in- diabetes in 6 male and 13 female patients after receiving anti- volved in autoimmunity, and many of the details of its PD-1 agents with either nivolumab or pembrolizumab, with molecular signaling remain unclear to date. )is complexity or without other chemotherapeutic drugs, for different types accounts for the selective emergence of autoimmune dis- of advanced cancers like melanoma, small and nonsmall cell eases in some patients but not others [3]. Although there are lung cancer, renal cell carcinoma, and Hodgkin’s lymphoma. no formal guidelines for managing the adverse effects of )e mean age is 59.7 years. Fifteen of these patients anti-PD-1 immunotherapy, most of these are managed with 4 Case Reports in Oncological Medicine diabetes,” ,e Tohoku Journal of Experimental Medicine, high-dose steroids. )is can be critical in autoimmune di- vol. 239, no. 2, pp. 155–158, 2016. abetes. Hyperglycemia with no ketoacidosis can be a “silent” [6] A. Imagawa and T. Hanafusa, “Fulminant type 1 diabetes—an adverse drug reaction, because it is not felt or seen like, for important subtype in East Asia,” Diabetes Metabolism Research example, colitis and rash, respectively. We recommend and Reviews, vol. 27, no. 8, pp. 959–964, 2011. obtaining baseline hemoglobin A1C levels and conducting [7] J. Hughes, N. Vudattu, M. Sznol et al., “Precipitation of au- routine blood glucose checks in patients on anti-PD-1 toimmune diabetes with anti-PD-1 immunotherapy,” Tohoku agents, especially in those presenting with other drug re- Journal of Experimental Medicine, vol. 38, no. 4, pp. e55–e57, actions that require high-dose steroids. )is can help detect early hyperglycemia and prevent fulminant diabetes, which [8] J. Martin-Liberal, A. J. Furness, K. Joshi, K. S. Peggs, can be fatal, if not managed promptly. S. A. Quezada, and J. Larkin, “Anti-programmed cell death-1 therapyand insulin-dependent diabetes: acase report,” Cancer Immunology, Immunotherapy, vol. 64, no. 6, pp. 765–767, Abbreviations [9] M. Mellati, K. D. Eaton, B. M. Brooks-Worrell et al., DKA: Diabetic ketoacidosis “Anti–PD-1 and anti–PDL-1 monoclonal antibodies causing ICU: Intensive care unit type 1 diabetes,” Diabetes Care, vol. 38, no. 9, pp. e137–e138, PD-1: Antiprogrammed death 1 receptor PD-1L: Programmed death ligand [10] C. Gaudy, C. Clevy, ´ S. Monestier et al., “Anti-PD1 pem- GADA: Glutamic acid decarboxylase autoantibodies brolizumab can induce exceptional fulminant type 1 diabetes,” IAA: Insulin autoantibodies Diabetes Care, vol. 38, no. 11, pp. e182–e183, 2015. IA-2A: Islet antigen 2 autoantibodies [11] M. Okamoto, M. Okamoto, K. Gotoh et al., “Fulminant type 1 ICA: Islet cell antibodies diabetes mellitus with anti-programmed cell death-1 therapy,” ZnT8A: Zinc transporter 8 autoantibodies. Journal of Diabetes Investigation, vol. 7, no. 6, pp. 915–918, [12] J. R. Lowe, D. J. Perry, A. K. Salama, C. E. Mathews, Consent L. G. Moss, and B. A. Hanks, “Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus sec- Consent to publish was obtained from the patient. ondary to combination ipilimumab and nivolumab immu- notherapy,” Journal for Immuno,erapy of Cancer, vol. 4, Conflicts of Interest no. 1, p. 89, 2016. [13] W. Munakata, K. Ohashi, N. Yamauchi, and K. Tobinai, )e authors declare that there are no conflicts of interest “Fulminant type I diabetes mellitus associated with nivolumab regarding the publication of this article. in a patient with relapsed classical Hodgkin lymphoma,” International Journal of Hematology, vol. 105, no. 3, Authors’ Contributions pp. 383–386, 2016. [14] K. Ishikawa, T. Shono-Saito, T. Yamate et al., “A case of Nora Chokr identified the case, came up with the idea of the fulminant type 1 diabetes mellitus, with a precipitous decrease article, performed literature search, and wrote and edited the in pancreatic volume, induced by nivolumab for malignant article. Elizabeth Guadalupe and Hafsa Farooq performed melanoma: analysis of HLA and CTLA-4 polymorphisms,” the literature search and edited and reviewed the article. All European Journal of Dermatology, vol. 27, no. 2, pp. 184-185, authors read and approved the final manuscript. 2017. [15] L. Li, A. Masood, S. Bari, S. Yavuz, and A. B. Grosbach, “Autoimmune diabetes and thyroiditis complicating treat- Acknowledgments ment with nivolumab,” Case Reports in Oncology, vol.10, no.1, pp. 230–234, 2017. )e authors thank Dr. Shoshana Streiter, Dr. Pia Dogbey, [16] M. Araujo, ´ D. Ligeiro, L. Costa et al., “A case of fulminant type and Dr. Jadwiga Stepczynski for reviewing the article and 1 diabetes following anti-PD1 immunotherapy in a genetically providing feedback and mentorship. susceptible patient,” Immunotherapy, vol. 9, no. 7, pp. 531– 535, 2017. References [17] A. A. Alzenaidi, J. Dendy, and L. Rejjal, “Autoimmune di- abetes presented with diabetic ketoacidosis induced by im- [1] J. Sunshine and J. M. Taube, “PD-1/PD-L1 inhibitors,” Current munotherapy in an adult with melanoma,” Journal of the Opinion in Pharmacology, vol. 23, pp. 32–38, 2015. Louisiana State Medical Society, vol. 169, no. 2, p. 49, 2017. [2] J. D. Wolchok, “PD-1 blockers,” Cell, vol. 162, no. 5, p. 937, [18] J. L. Godwin, S. Jaggi, I. Sirisena et al., “Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoa- [3] S. Dai, R. Jia, X. Zhang, Q. Fang, and L. Huang, “)e cidosis in a patient with metastatic lung cancer,” Journal for PD-1/PD-Ls pathway and autoimmune diseases,” Cellular Immuno,erapy of Cancer, vol. 5, no. 1, 2017. Immunology, vol. 290, no. 1, pp. 72–79, 2014. [4] L. A. Raedler, “Opdivo (nivolumab): second pd-1 inhibitor receives FDA approval for unresectable or metastatic mela- noma,” American Health and Drug Benefits, vol. 8, pp. 180–183, [5] Y. Miyoshi, O. Ogawa, and Y. Oyama, “Nivolumab, an anti- programmed cell death-1 antibody, induces fulminant type 1 MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Hindawi Publishing Corporation Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 http://www www.hindawi.com .hindawi.com V Volume 2018 olume 2013 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 International Journal of Journal of Immunology Research Endocrinology Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 Submit your manuscripts at www.hindawi.com BioMed PPAR Research Research International Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2013 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Neurology Research and Treatment Cellular Longevity Hindawi Hindawi Hindawi Hindawi Hindawi www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 www.hindawi.com Volume 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

Fulminant Diabetes in a Patient with Advanced Melanoma on Nivolumab

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Hindawi Publishing Corporation
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Copyright © 2018 Nora Chokr et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2018/8981375
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2018, Article ID 8981375, 4 pages https://doi.org/10.1155/2018/8981375 Case Report Fulminant Diabetes in a Patient with Advanced Melanoma on Nivolumab 1,2 1,2 1,2 Nora Chokr , Hafsa Farooq, and Elizabeth Guadalupe Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA Waterbury Hospital, Waterbury, CT, USA Correspondence should be addressed to Nora Chokr; nora.chokr@yale.edu Received 19 September 2017; Revised 19 December 2017; Accepted 2 January 2018; Published 28 January 2018 Academic Editor: Constantine Gennatas Copyright © 2018 Nora Chokr et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Anti-PD-1 agents were approved for advanced melanoma after the landmark trial Checkmate-037. Anti-PD-1 agents can breach immunologic tolerance. Fulminant diabetes is an immune endocrinopathy that results from a violent immune attack leading to complete destruction of pancreatic beta cells in genetically predisposed people. We present a rare case of fulminant diabetes precipitated by anti-PD-1 immunotherapy. Case. A 61-year-old male with advanced melanoma presented with a three- day history of nausea, vomiting, and malaise. He was started on nivolumab and ipilimumab. After the third dose, he developed a generalized rash and was prescribed high-dose prednisone. Labs revealed potassium 9.5mmol/L, sodium 127mmol/L, bicarbonate <10mmol/L, blood glucose 1211mg/dL, anion gap >31mmol, arterial blood pH 7.14, and beta-hydroxybutyrate 13.7mmol/L. He was diagnosed with diabetic ketoacidosis. Hemoglobin A1C was 6.9%. C-peptide was undetectable (<0.1ng/ml). Glutamic acid decarboxylase autoantibodies, zinc transporter 8 autoantibodies, insulin autoantibodies, islet antigen 2 auto- antibodies, and islet cell antibodies were all negative. Conclusion. Anti-PD-1 immunotherapy is effective in cancers refractory to standard chemotherapy. )ese agents can precipitate autoimmune disorders. As the use of anti-PD-1 agents is expected to rise, physicians should be educated about the potential side effects. We recommend conducting routine blood glucose checks in patients on these agents. )e first human trial was conducted in 39 patients with 1. Background different types of solid cancers who received the fully human Programmed cell death receptor (PD-1) and programmed IgG4 anti-PD-1 antibody nivolumab (Opdivo , Bristol- cell death ligand (PD-L1) were discovered in the 1990s. Myers Squibb). Durable responses were observed espe- PD-1/PD-1L checkpoint is involved in immunologic tol- cially in melanoma, nonsmall cell lung cancer, and renal cell erance by regulating T cells at the level of the peripheral carcinoma [1, 3]. More patients were later enrolled in several tissues. Tumors can express PD-L1 and use these ligands to clinical trials, some of which are still ongoing. Pem- evade the host’s immune system, making this checkpoint brolizumab (Keytruda , Merck) was the first anti-PD-1 a potential target for cancer therapy [1]. )is pathway was inhibitor that was approved by the US Food and Drug used to develop monoclonal antibodies that block the in- Administration (FDA) in September 2014 for treating pa- teraction between PD-1 receptor and PD-L1 ligand to help tients with advanced melanoma who had responded poorly restore anticancer immune responses. In 2005, the PD-1/PD- to BRAF inhibitors and ipilimumab (Yervoy , Bristol-Myers L1 interaction was used to treat animal tumors. Many clinical Squibb), a monoclonal antibody that upregulates and acti- trials were launched in humans after that. )e efficiency of vates the immune system by targeting CTLA-4 protein. those agents has been shown in tumors belonging to 9 organ Nivolumab was approved by the FDA on December 22,2014, systems [2]. )ey have proven to be very effective in tumors for unresectable or metastatic melanoma that progressed refractory to standard chemotherapy regimens. after ipilimumab therapy and for patients with positive 2 Case Reports in Oncological Medicine BRAF V600 mutation who failed treatment with BRAF 2. Case Presentation inhibitors. )e approval came after the landmark clinical A 61-year-old male with a history of melanoma metastatic to trial Checkmate-037 in which 370 patients with advanced the chest wall and lungs presents to the emergency de- melanoma carrying the BRAF mutation and who failed partment with a three-day history of malaise, nausea, therapy with ipilimumab and BRAF inhibitors were en- vomiting, polyuria, decreased PO intake, and dizziness. He rolled and randomized to receive either nivolumab or has no other history of chronic diseases. He was recently investigator choice of chemotherapy (dacarbazine or car- started on nivolumab and ipilimumab, a combination of boplatin plus paclitaxel). )e effect of nivolumab was anti-PD-1 and anti-CTLA-4 immunotherapy. After the third evaluated in the first 120 patients who received the drug and dose, he developed a generalized maculopapular rash, in those who were followed for a minimum duration of a known side effect of his immunotherapy regimen, for 6 months. )e overall response rate was 32%, with 4 pa- which he was started on high-dose prednisone three days tients achieving complete response and the rest achieving prior to presentation. )e patient reports antecedent fatigue partial responses. )e most common adverse reactions and nausea that profoundly worsened after starting high- described in the Checkmate-037 trial occurring in more dose prednisone. On presentation, he appeared in distress. than 10% of the patients were rash, pruritus, cough, upper He was tachycardic with a heart rate of 126 beats per minute, respiratory infections, and peripheral edema [4]. Other tachypneic with a respiratory rate of 24 breaths per minute, clinical trials followed evaluating the efficacy of anti-PD-1 and hypotensive with a blood pressure of 90/50mmHg. His agents in other types of solid tumors. In March 2015, oral mucosa was dry. His labs revealed potassium nivolumab was approved for the treatment of metastatic 9.5mmol/L, sodium 127mmol/L, bicarbonate <10mmol/L, nonsmall cell lung cancer. In November 2015, nivolumab blood glucose 1211mg/dL, anion gap >31mmol, arterial was approved for metastatic renal cell carcinoma. In blood pH 7.14, beta-hydroxybutyrate 13.7mmol/L, lactic May 2016, approval was extended for refractory Hodgkin’s acid 2.4mmol/L, serum creatinine 4.55, positive urine ke- lymphoma. In February 2017, nivolumab was approved for tones, urine glucose >1000mg/dL, and serum lipase locally advanced and metastatic urothelial cancers. )ese 414IU/L. )e patient was admitted to the intensive care unit agents have gained popularity since 2014, and over 1 year, for management of diabetic ketoacidosis (DKA). He has no FDA has expanded the approval of anti-PD-1 agents across prior history of diabetes. He was managed with IV hydration variable cancer types. Currently, clinical trials are studying and insulin drip and later transitioned to subcutaneous the role of PD-1 blockage in myelodysplastic syndromes insulin after the anion gap closed. He required daily insulin and other hematologic malignancies. )e use of checkpoint adjustments, and it was hard to achieve optimal glycemic inhibitors is expected to rise dramatically as we learn more control. During his hospitalization, workup revealed a hemo- about their efficacy across other types of malignancies. globin A1C of 6.9%. His serum C-peptide was undetectable While these medications have proven to be very efficacious <0.1ng/ml. Glutamic acid decarboxylase autoantibodies in fighting refractory cancers, they are not harmless. Some (GADA) and zinc transporter 8 autoantibodies (ZnT8A) an- of the adverse effects are mild and easily controlled; alyzed by ELISA, insulin autoantibodies (IAA) analyzed by however, some can be very serious and fatal. It is imperative radioimmunoassay, islet antigen 2 autoantibodies (IA-2A) for physicians to be educated about the potential adverse analyzed by radiobinding assay, and islet cell antibodies effects of anti-PD-1 immunotherapy. In their attempt (ICA)analyzedbyimmunofluorescenceassaywereallnegative. to augment the immune response, anti-PD-1 agents can To date, the patient is on subcutaneous basal-bolus insulin breach immunologic tolerance by upregulating autoreactive regimen with glargine and lispro, respectively. Our patient did Tcells. Some of the side effects described in the literature are not carry the high-risk HLA haplotype of FD identified in immune-mediated rash, pneumonitis, colitis, thyroiditis, Japanese populations. hepatitis, nephritis, uveitis, adrenalitis, facial nerve paresis, hypophysitis, aseptic meningitis, and fulminant diabetes (FD). FD was first described by Imagawa in Japan. It is 3. Discussion a subtype of autoimmune type 1 diabetes that results from a violent and abrupt immune attack leading to a complete Our patient is one of a handful of cases described in the destruction of pancreatic beta cells in genetically predis- literature of FD caused by anti-PD-1 cancer therapy. In FD, posed people. FD is characterized by an abrupt ketoacidosis patients present with severe hyperglycemia or diabetic that presents with severe hyperglycemia but rather low ketoacidosis; however, they have unexpectedly low hemo- hemoglobin A1C, low or undetectable C-peptide levels, flu- globin A1C levels which are probably due to the abrupt onset like symptoms, and elevated pancreatic enzymes [5]. FD has of this endocrinopathy. C-peptide levels, like in our patient, ∗ ∗ been associated with HLA DRB1 04:05-DQB1 04:01 [6]. It are low or undetectable. Islet cell autoantibodies are un- is prevalent in East Asian populations and accounts for detectable which suggest that beta cells are completely a significant proportion of acute onset autoimmune di- destroyed via a process that is not entirely similar to the abetes. After the introduction of anti-PD-1 immunother- pathophysiology of the classically known autoimmune type 1 apy, FD has become a more commonly encountered diabetes. In FD, the islet cells are attacked by autoreactive phenomenon in the Western world. In this paper, we T cells. FD was initially thought to be an entirely cell- present a case of FD in a patient with advanced melanoma mediated phenomenon; however, some patients described who was started on the anti-PD-1 agent nivolumab. in the literature tested positive for 1 or more islet cell Case Reports in Oncological Medicine 3 Table 1: Characteristics of patients reported in the literature so far with fulminant diabetes from anti-PD-1 immunotherapy. Age Anti-PD-1 HbA1C Antibody Study Cancer diagnosis Presentation C-peptide (years)/sex agent (%) positivity 55/F Melanoma Nivolumab DKA 6.9 Undetectable No 83/F NSCLC Nivolumab DKA 7.7 Undetectable GADA GADA, IAA, Hughes et al. [7] 63/M RCC Nivolumab Hyperglycemia 8.2 Low ICA 58/M SCLC Nivolumab DKA 9.7 Undetectable GADA 64/F Melanoma Pembrolizumab Hyperglycemia 7.4 Low No Martin-Liberal 54/F Melanoma Pembrolizumab DKA NA NA GADA et al. [8] 70/M NSCLC Nivolumab DKA 9.8 Low NA Mellati et al. [9] Jaw sarcomatoid squamous 66/F NA DKA 9.4 Undetectable GADA cell carcinoma Gaudy et al. [10] 44/F Melanoma Pembrolizumab DKA 6.85 Undetectable GADA Okamoto et al. 55/F Melanoma Nivolumab Hyperglycemia 7 Undetectable No [11] Miyoshi et al. [5] 66/F Melanoma Nivolumab DKA 7.3 Undetectable No Lowe et al. [12] 54/F Melanoma Nivolumab DKA NA Undetectable GADA Munakata et al. 71/M Hodgkin lymphoma Nivolumab Hyperglycemia 7.3 Undetectable No [13] Ishikawa et al. 54/F Melanoma Nivolumab DKA 7 Low No [14] Li et al. [15] 63/F NSCLC Nivolumab DKA <6.4% NA GADA Araujo ´ et al. [16] 73/F NSCLC Nivolumab DKA 7.2 Undetectable GADA Alzenaidi et al. 47/M Melanoma Nivolumab DKA 8 Undetectable GADA 2017 [17] GADA, IA-2, Godwin et al. [18] 34/F NSCLC Nivolumab DKA 7.1 Undetectable IAA )is study 61/M Melanoma Nivolumab DKA 6.9 Undetectable No DKA: diabetic ketoacidosis; F: female; NSCLC: nonsmall cell lung cancer; SCLC: small cell lung cancer; RCC: renal cell carcinoma; GADA: glutamic acid decarboxylase autoantibodies; IAA: insulin autoantibodies; ICA: islet cell antibodies; NA: not available; IA-2: islet 2 autoantibody. presented with diabetic ketoacidosis, and four with new autoantibodies either at disease onset or later, which sug- gests that a humoral immune response is also implicated in onset hyperglycemia, with or without ketonuria, within the pathophysiology of FD (Table 1). FD was first described weeks to months following treatment onset. )e mean in the literature in the setting of anti-PD-1 immunotherapy hemoglobin A1C was 7.7%. C-peptide levels in all cases were in early 2015, shortly after the drugs were approved by the either undetectable or in the low normal range on pre- FDA. Patients who develop FD become insulin dependent sentation but eventually became undetectable. Two patients for life. It can manifest 1 week to a few months after starting tested positive for 3 out of 4 islet antibodies, nine patients the therapy. Diagnosis should be prompt because of the tested positive for GADA only, and the rest had negative increased risk of death within the first 24 hours. It is worth antibody titers. Few of these patients had HLA haplotypes mentioning that these drugs can upset the gastrointestinal associated with the development of autoimmune type 1 tract and cause nausea, vomiting, and abdominal pain that diabetes. )ese cases illustrate that anti-PD-1 agents affect the Tcells regulatory pathways triggering both humoral and can all be managed symptomatically. It is important to distinguish these drug adverse effects from DKA symptoms cell-mediated autoimmunity [7] (Table 1). [5]. Our patient must have had high blood glucose levels days to weeks prior to presentation. )e high-dose pred- 4. Conclusion nisone that he was started on for the rash definitely played a major role in exacerbating his condition. Anti-PD-1 immunotherapy has shown great efficacy in )ere are around 19 cases described to date of fulminant refractory cancers. PD-1/PD-1L is a complex pathway in- diabetes in 6 male and 13 female patients after receiving anti- volved in autoimmunity, and many of the details of its PD-1 agents with either nivolumab or pembrolizumab, with molecular signaling remain unclear to date. )is complexity or without other chemotherapeutic drugs, for different types accounts for the selective emergence of autoimmune dis- of advanced cancers like melanoma, small and nonsmall cell eases in some patients but not others [3]. Although there are lung cancer, renal cell carcinoma, and Hodgkin’s lymphoma. no formal guidelines for managing the adverse effects of )e mean age is 59.7 years. Fifteen of these patients anti-PD-1 immunotherapy, most of these are managed with 4 Case Reports in Oncological Medicine diabetes,” ,e Tohoku Journal of Experimental Medicine, high-dose steroids. )is can be critical in autoimmune di- vol. 239, no. 2, pp. 155–158, 2016. abetes. Hyperglycemia with no ketoacidosis can be a “silent” [6] A. Imagawa and T. Hanafusa, “Fulminant type 1 diabetes—an adverse drug reaction, because it is not felt or seen like, for important subtype in East Asia,” Diabetes Metabolism Research example, colitis and rash, respectively. We recommend and Reviews, vol. 27, no. 8, pp. 959–964, 2011. obtaining baseline hemoglobin A1C levels and conducting [7] J. Hughes, N. Vudattu, M. Sznol et al., “Precipitation of au- routine blood glucose checks in patients on anti-PD-1 toimmune diabetes with anti-PD-1 immunotherapy,” Tohoku agents, especially in those presenting with other drug re- Journal of Experimental Medicine, vol. 38, no. 4, pp. e55–e57, actions that require high-dose steroids. )is can help detect early hyperglycemia and prevent fulminant diabetes, which [8] J. Martin-Liberal, A. J. Furness, K. Joshi, K. S. Peggs, can be fatal, if not managed promptly. S. A. Quezada, and J. Larkin, “Anti-programmed cell death-1 therapyand insulin-dependent diabetes: acase report,” Cancer Immunology, Immunotherapy, vol. 64, no. 6, pp. 765–767, Abbreviations [9] M. Mellati, K. D. Eaton, B. M. Brooks-Worrell et al., DKA: Diabetic ketoacidosis “Anti–PD-1 and anti–PDL-1 monoclonal antibodies causing ICU: Intensive care unit type 1 diabetes,” Diabetes Care, vol. 38, no. 9, pp. e137–e138, PD-1: Antiprogrammed death 1 receptor PD-1L: Programmed death ligand [10] C. Gaudy, C. Clevy, ´ S. Monestier et al., “Anti-PD1 pem- GADA: Glutamic acid decarboxylase autoantibodies brolizumab can induce exceptional fulminant type 1 diabetes,” IAA: Insulin autoantibodies Diabetes Care, vol. 38, no. 11, pp. e182–e183, 2015. IA-2A: Islet antigen 2 autoantibodies [11] M. Okamoto, M. Okamoto, K. Gotoh et al., “Fulminant type 1 ICA: Islet cell antibodies diabetes mellitus with anti-programmed cell death-1 therapy,” ZnT8A: Zinc transporter 8 autoantibodies. Journal of Diabetes Investigation, vol. 7, no. 6, pp. 915–918, [12] J. R. Lowe, D. J. Perry, A. K. Salama, C. E. Mathews, Consent L. G. Moss, and B. A. Hanks, “Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus sec- Consent to publish was obtained from the patient. ondary to combination ipilimumab and nivolumab immu- notherapy,” Journal for Immuno,erapy of Cancer, vol. 4, Conflicts of Interest no. 1, p. 89, 2016. [13] W. Munakata, K. Ohashi, N. Yamauchi, and K. Tobinai, )e authors declare that there are no conflicts of interest “Fulminant type I diabetes mellitus associated with nivolumab regarding the publication of this article. in a patient with relapsed classical Hodgkin lymphoma,” International Journal of Hematology, vol. 105, no. 3, Authors’ Contributions pp. 383–386, 2016. [14] K. Ishikawa, T. Shono-Saito, T. Yamate et al., “A case of Nora Chokr identified the case, came up with the idea of the fulminant type 1 diabetes mellitus, with a precipitous decrease article, performed literature search, and wrote and edited the in pancreatic volume, induced by nivolumab for malignant article. Elizabeth Guadalupe and Hafsa Farooq performed melanoma: analysis of HLA and CTLA-4 polymorphisms,” the literature search and edited and reviewed the article. All European Journal of Dermatology, vol. 27, no. 2, pp. 184-185, authors read and approved the final manuscript. 2017. [15] L. Li, A. Masood, S. Bari, S. Yavuz, and A. B. Grosbach, “Autoimmune diabetes and thyroiditis complicating treat- Acknowledgments ment with nivolumab,” Case Reports in Oncology, vol.10, no.1, pp. 230–234, 2017. )e authors thank Dr. Shoshana Streiter, Dr. Pia Dogbey, [16] M. Araujo, ´ D. Ligeiro, L. Costa et al., “A case of fulminant type and Dr. Jadwiga Stepczynski for reviewing the article and 1 diabetes following anti-PD1 immunotherapy in a genetically providing feedback and mentorship. susceptible patient,” Immunotherapy, vol. 9, no. 7, pp. 531– 535, 2017. References [17] A. A. Alzenaidi, J. Dendy, and L. Rejjal, “Autoimmune di- abetes presented with diabetic ketoacidosis induced by im- [1] J. Sunshine and J. M. Taube, “PD-1/PD-L1 inhibitors,” Current munotherapy in an adult with melanoma,” Journal of the Opinion in Pharmacology, vol. 23, pp. 32–38, 2015. Louisiana State Medical Society, vol. 169, no. 2, p. 49, 2017. [2] J. D. Wolchok, “PD-1 blockers,” Cell, vol. 162, no. 5, p. 937, [18] J. L. Godwin, S. Jaggi, I. Sirisena et al., “Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoa- [3] S. Dai, R. Jia, X. Zhang, Q. Fang, and L. Huang, “)e cidosis in a patient with metastatic lung cancer,” Journal for PD-1/PD-Ls pathway and autoimmune diseases,” Cellular Immuno,erapy of Cancer, vol. 5, no. 1, 2017. Immunology, vol. 290, no. 1, pp. 72–79, 2014. [4] L. A. Raedler, “Opdivo (nivolumab): second pd-1 inhibitor receives FDA approval for unresectable or metastatic mela- noma,” American Health and Drug Benefits, vol. 8, pp. 180–183, [5] Y. Miyoshi, O. Ogawa, and Y. 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