Isolated Adrenocorticotropic Hormone Deficiency and Severe Hypercalcemia After Destructive Thyroiditis in a Patient on Nivolumab Therapy With a Malignant Melanoma

Takebayashi, Kohzo; Ujiie, Atsushi; Kubo, Mio; Furukawa, Sho; Yamauchi, Mototaka; Shinozaki, Hiroyuki; Suzuki, Toshimitsu; Naruse, Rika; Hara, Kenji; Tsuchiya, Takafumi; Iwamoto, Toshihiko

doi:10.14740/jocmr3257w

Cited by 25 publications

(17 citation statements)

References 21 publications

(22 reference statements)

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“…The paucity and non-specificity of symptoms seems to be responsible for delayed diagnosis of PD1/PDL1 inhibitor-induced hypophysitis, or sometimes misdiagnosis both in previous reports [ 9 , 12 , 14 , 15 , 17 ] and herein; this point is illustrated in the present study by fortuitous diagnosis via systematic laboratory monitoring for three of the patients. The correct diagnosis is, however, crucial since pituitary deficiencies can affect quality of life, tolerance to cancer treatment, or even be life-threatening in the case of ACTH deficiency in already fragile patients.…”

Section: Discussionmentioning

confidence: 50%

“…The descriptions of PD1 and PDL1 inhibitor-induced hypophysitis are more recent, probably because these drugs have been approved more recently than the approval of CTLA4 inhibitor. Some case reports described isolated adrenocorticotropic hormone (ACTH) deficiency associated with PD1 and PDL1 inhibitors [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Anti-PD1 and Anti-PDL1-Induced Hypophysitis: A Cohort Study of 17 Patients with Longitudinal Follow-Up

Levy

Abeillon

Dalle

et al. 2020

JCM

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Hypophysitis, secondary to programmed cell death 1 protein (PD1) and programmed cell death 1 ligand 1 (PDL1) inhibitors, were thought to be rare, with only a few studies describing more than one case with long-term follow-up. The aim of the present study was to describe the clinical, laboratory, and morphological characteristics of PD1/PDL1 inhibitor-induced hypophysitis, and its long-term course. This cohort study was conducted at the University Hospital of Lyon, France, with longitudinal follow-up of patients. Seventeen cases of PD1/PDL1 inhibitor-induced hypophysitis were included. The median time to onset of hypophysitis was 28 weeks (range: 10–46). At diagnosis, 16 patients complained of fatigue, 12 of nausea or loss of appetite, while headache was rare. We found no imaging pituitary abnormality. All patients presented adrenocorticotropic hormone (ACTH) deficiency; other pituitary deficiencies were less common (n = 7). At last follow-up (median: 13 months), ACTH deficiency persisted in all but one patient and one patient recovered from gonadotropic deficiency. PD1/PDL1 inhibitor-induced hypophysitis is a clinical entity different from those associated to cytotoxic T-lymphocyte antigen-4 (CTLA4) inhibitors, with less obvious clinical and radiological signs, and probably a different mechanism. The paucity of symptoms demonstrates the need for systematic hormonal follow-up for patients receiving PD1/PDL1 inhibitors.

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Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Anti-PD1 and Anti-PDL1-Induced Hypophysitis: A Cohort Study of 17 Patients with Longitudinal Follow-Up

Levy

Abeillon

Dalle

et al. 2020

JCM

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“…Previously published cases of hypophysitis associated with anti-PD-1 agents were identified by searching PubMed for all English-language articles through December 1, 2018 utilizing the terms 'nivolumab hypophysitis', 'pembrolizumab hypophysitis', 'nivolumab adrenal insufficiency', 'pembrolizumab adrenal insufficiency', 'nivolumab hypopituitarism', 'pembrolizumab hypopituitarism', 'nivolumab ACTH', 'pembrolizumab ACTH'. Twenty-three case reports and letters were identified (7, 8, 9, 10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29). The full text of one manuscript could not be obtained (7).…”

Section: Methodsmentioning

confidence: 99%

“…Limitations in the existing common terminology criteria for adverse events (CTCAE), which contains multiple imprecise and overlapping endocrine categories, likely impact the accuracy of endocrine irAE reports in these trials. Clinical descriptions of patients diagnosed with hypophysitis following treatment with anti-PD-1 medications are very sparse and consist of case reports and letters with little or no longitudinal information (7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29). To our knowledge, no cohort study examining such patients has been published.…”

Section: Introductionmentioning

confidence: 99%

Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis

Faje

Reynolds

Zubiri

et al. 2019

European Journal of Endocrinology

124

113

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Objective Little has been published describing hypophysitis after nivolumab or pembrolizumab treatment. We aimed to (i) assess the risk of hypophysitis following nivolumab or pembrolizumab treatment, (ii) characterize the clinical presentation and outcomes in these patients and (iii) compare these patients to hypophysitis following ipilimumab and ipilimumab plus nivolumab (combo). We hypothesized that headaches, pituitary enlargement on MRI and multiple anterior pituitary hormone deficiencies would occur less often in the nivolumab/pembrolizumab group versus ipilimumab or combo hypophysitis patients. Design and methods We conducted a multi-center retrospective review utilizing the Research Patient Database registry to evaluate individuals diagnosed with hypophysitis following treatment with nivolumab/pembrolizumab (n = 22), ipilimumab (n = 64) and combo (n = 20). Encounter notes, radiologic imaging and laboratory results for these patients were comprehensively reviewed. Results Hypophysitis was rare following treatment with nivolumab/pembrolizumab (0.5%, 17/3522) compared to ipilimumab (13.6%, 34/250), P < 0.0001. Hypophysitis was diagnosed later in nivolumab/pembrolizumab (median: 25.8 weeks, interquartile range (IR): 18.4–44.0) compared to ipilimumab (9.3, IR: 7.2–11.1) or combo patients (12.5, IR: 7.4–18.6), P < 0.0001 for both. Headache and pituitary enlargement occurred less commonly in nivolumab/pemrolizumab patients (23% and 5/18, respectively) compared to ipilimumab (75%, 60/61) and combo (75%, 16/17) treatment groups (P < 0.0001 versus ipilimumab and P = 0.001 versus combo for headache and P < 0.0001 for both for enlargement). Conclusions This study represents the first comprehensive cohort analysis of nivolumab or pembrolizumab-associated hypophysitis in a large patient group. Hypophysitis occurs rarely with these medications, and these patients have a distinct phenotype compared to hypophysitis after treatment with ipilimumab or ipilimumab plus nivolumab.

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“…Nonetheless, it is believed to be significantly underdiagnosed. Besides opiate use, other conditions that can lead to isolated ACTH deficiency include autoimmune conditions, lymphocytic neurohypophysitis, and immune checkpoint inhibitors [4][5][6][7][8]. Despite the fact that it has been decades since the first reported case, this remains a poorly understood entity.…”

Section: Discussionmentioning

confidence: 99%

Isolated Adrenocorticotropic Hormone Deficiency Secondary to Chronic Opiate Use

Raj

Jacob

Elshimy

et al. 2020

Cureus

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Although opiate use can result in various endocrine disorders, isolated adrenocorticotropic hormone (ACTH) deficiency resulting in secondary adrenal insufficiency remains uncommon. We present a case of a 54-year-old woman with a history of chronic opiate use who presented with a four-month history of worsening fatigue and syncopal episodes. Laboratory workup revealed a low ACTH with low baseline cortisol and normal levels of rest of the anterior pituitary hormones. The imaging study did not reveal any pituitary abnormality. The patient was diagnosed with opiate-induced isolated ACTH deficiency. Her symptoms improved after treatment with hydrocortisone. This case would further improve clinician's awareness towards opiate-induced endocrinopathies, including isolated ACTH deficiency, which can present with nonspecific signs and symptoms, creating a diagnostic challenge.

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Isolated Adrenocorticotropic Hormone Deficiency and Severe Hypercalcemia After Destructive Thyroiditis in a Patient on Nivolumab Therapy With a Malignant Melanoma

Cited by 25 publications

References 21 publications

Anti-PD1 and Anti-PDL1-Induced Hypophysitis: A Cohort Study of 17 Patients with Longitudinal Follow-Up

Anti-PD1 and Anti-PDL1-Induced Hypophysitis: A Cohort Study of 17 Patients with Longitudinal Follow-Up

Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis

Isolated Adrenocorticotropic Hormone Deficiency Secondary to Chronic Opiate Use

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