Adrenal Insufficiency Related to Anti-Programmed Death-1 Therapy

Ariyasu, Ryo; Horiike, Atsushi; Yoshizawa, Takahiro; Dotsu, Yosuke; Koyama, Junji; Saiki, Masafumi; Sonoda, Tomoaki; Nishikawa, Shingo; Kitazono, Satoru; Yanagitani, Noriko; Nishio, Makoto

doi:10.21873/anticanres.11814

Cited by 27 publications

(22 citation statements)

References 13 publications

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“…Another abnormality of our case was eosinophilia, which emerged 2 months before the onset of adrenocortical crisis and resolved 1.5 months after the hormone replacement. This phenomenon has been described in other reports, and some physicians suggest that eosinophilia may be an early predictor of adrenocortical insufficiency 25…”

Section: Discussionsupporting

confidence: 68%

“…Considering the potential adverse effects of high-dose hormones, we gave our patient a physiological replacement dose of prednisone, and his clinical disorders disappeared soon after prednisone administration. In fact, we noticed that most reported cases of nivolumab-induced hypophysitis were given replacement treatment 18,19,21,22,25. Another critical issue is whether nivolumab can continue to be used in patients experiencing serious hypophysitis.…”

Section: Discussionmentioning

confidence: 99%

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<p>A case of small-cell lung cancer with adrenocorticotropic hormone deficiency induced by nivolumab</p>

Zhu

Wang

2019

OTT

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Anti-programmed death-1 (anti-PD-1) monoclonal antibodies, such as nivolumab, have been used for the treatment of various types of cancers, and excellent efficacy has been shown in some patients. The adverse effects of anti-PD-1 antibodies relating to autoimmunity are different from traditional chemotherapeutic drugs and may involve many organs including the endocrine system. We herein describe a case of adrenocorticotropic hormone deficiency during the treatment of advanced small-cell lung cancer, probably caused by nivolumab-induced hypophysitis. The case showed nonspecific, insidious, as well as potentially life-threatening characters of immune-related adverse effects. It is important for physicians to acknowledge clinical features of the rare side effect and take appropriate and prompt treatment.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

<p>A case of small-cell lung cancer with adrenocorticotropic hormone deficiency induced by nivolumab</p>

Zhu

Wang

2019

OTT

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“…However, studies have suggested associations between certain human leucocyte antigen haplotypes, such as HLA-DR15, and the development of ICI-related hypopituitarism with secondary AI [ 38 ]. Several laboratory abnormalities, such as eosinophilia [ 12 ] and hyponatremia [ 8 ], also can precede ICI-related secondary AI. Cases have been reported of ICI-related IAD developing after transient elevations in plasma ACTH and cortisol levels [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Isolated Adrenocorticotropic Hormone Deficiency Associated with Severe Hyperkalemia During Pembrolizumab Therapy in a Patient with Ureteral Cancer and an Ileal Conduit: A Case Report and Literature Review

Hinata¹,

Ohara²,

Sakurai³

et al. 2021

Am J Case Rep

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Patient: Female, 78-year-old Final Diagnosis: Isolated adrenocorticotropic hormone deficiency Symptoms: Anorexia • general weakness • muscle pain Medication: Hydrocortisone Clinical Procedure: Endocrine test Specialty: Endocrinology and Metabolic Objective: Unusual clinical course Background: Immune checkpoint inhibitors (ICIs) are anticancer medications that enhance the antitumor immune response. The clinical benefit afforded by ICIs, however, can be accompanied by immune-related adverse events (IRAEs). One of the common endocrine IRAEs is hypophysitis, which often causes hypopituitarism with secondary adrenal insufficiency (AI). Secondary AI, including isolated adrenocorticotropic hormone (ACTH) deficiency (IAD), is often associated with hyponatremia. Here, we report an unusual case of ICI-related IAD associated with severe hyperkalemia. Case Report: A 78-year-old woman who had an ileal conduit, chronic kidney disease, type 2 diabetes mellitus, and hyper-tension and was taking an angiotensin II receptor blocker began treatment for advanced ureteral cancer with the anti-programmed cell death protein 1 inhibitor pembrolizumab. The therapy effectively controlled the cancer, but 4 1/2 months after starting it, the patient developed anorexia, general weakness, and muscle pain and was diagnosed with IAD associated with severe hyperkalemia and hyperchloremic metabolic acidosis. She recovered after prompt administration of corticosteroids and treatment with sodium bicarbonate, glucose/insulin, and cation exchange resins. Conclusions: Hyperkalemia is a common symptom of primary AI but is less common in patients with central AI because a lack of ACTH does not cause aldosterone deficiency and mineralocorticoid action is preserved. The present case demonstrates the need for physicians to be aware of severe hyperkalemia as a life-threatening complication of secondary AI induced by ICIs, particularly in patients with predisposing factors, such as kidney dysfunction, diabetes mellitus, an ileal conduit, and renin-angiotensin-aldosterone system inhibitor use.

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“…Although this study focused on ipilimumab, either alone or in combination, the PD-1 inhibitors such as nivolumab or pembrolizumab are also reported to cause pituitary dysfunction, but mostly isolated ACTH deficiency [21]. This can still result in life threatening cortisol deficiency, but thyroid abnormalities when seen are usually the result of primary hyper or hypothyroidism, rather than secondary hypothyroidism.…”

Section: Discussionmentioning

confidence: 99%

Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH

Siddiqui

Lai

Spain

et al. 2020

J Endocrinol Invest

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Purpose Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis. Methods A retrospective cohort study was performed for all patients ( n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis. Results and conclusions Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance ( P = 0.053). A significant fall in FT4 ( P < 0.001), TSH index ( P < 0.001) and standardised TSH index ( P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis. Electronic supplementary material The online version of this article (10.1007/s40618-020-01297-3) contains supplementary material, which is available to authorized users.

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Adrenal Insufficiency Related to Anti-Programmed Death-1 Therapy

Abstract: Most anti-PD1-related adrenal insufficiency cases involved an isolated ACTH deficiency. Eosinophilia may be an early indicator before the onset of symptoms.

Cited by 27 publications

References 13 publications

<p>A case of small-cell lung cancer with adrenocorticotropic hormone deficiency induced by nivolumab</p>

<p>A case of small-cell lung cancer with adrenocorticotropic hormone deficiency induced by nivolumab</p>

Isolated Adrenocorticotropic Hormone Deficiency Associated with Severe Hyperkalemia During Pembrolizumab Therapy in a Patient with Ureteral Cancer and an Ileal Conduit: A Case Report and Literature Review

Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH

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