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Background:
Systematic Review

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

by
Chrysoula Mytareli
1,
Dimitrios C. Ziogas
2,
Athina Karampela
1,
Petros Papalexis
1,
Vasiliki Siampanopoulou
1,
Alexandros Lafioniatis
1,
Olga Benopoulou
3,
Helen Gogas
2 and
Anna Angelousi
1,*
1
First Department of Internal Medicine, Unit of Endocrinology, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
2
First Department of Internal Medicine, Unit of Medical Oncology, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
3
First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(7), 2016; https://doi.org/10.3390/cancers15072016
Submission received: 9 February 2023 / Revised: 23 March 2023 / Accepted: 26 March 2023 / Published: 28 March 2023
(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)

Abstract

:

Simple Summary

Immune checkpoint inhibitors (ICIs) are considered to be the standard of care in multiple types of cancers. However, ICIs are implicated in a wide range of side effects, referred to as immune-related adverse events (irAEs). Endocrine irAEs, especially thyroid dysfunction and hypophysitis, are some of the most frequently reported side effects. However, several other endocrine irAEs have been described less frequently and can be encountered more recurrently as the use of ICIs expands. This systematic review includes all published cases with rare and very rare endocrine irAEs, emphasizing mostly their diagnostic and therapeutic approach as well as their underlying pathogenesis. The aim of our study is to raise clinical awareness related to early diagnosis and proper treatment of these rare but, in some cases, potentially fatal endrocine irAEs.

Abstract

Immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancers, either in adjuvant or metastatic settings. Regarding safety, endocrine adverse events (AEs) are some of the most common AEs in ICI-treated patients, with thyroid dysfunction and hypophysitis being the most frequent disorders. However, there are also some rare and very rare immune-related (ir) endocrine complications (incidence between ≥1/10,000 to <1/1000 and <1/10,000, respectively, according to the established classification) that have been reported in isolated case reports, with limited data about their management. In this systematic review, we summarize all published cases with primary adrenal insufficiency, central diabetes insipidus, primary hypoparathyroidism, lipodystrophy, osteoporosis, hypergonadotrophic hypogonadism, or Cushing disease and discuss their diagnostic and therapeutic approaches as well as the current knowledge on their pathophysiology. In these ICI-treated cancer patients, the presentation of symptoms unrelated to their underlying malignancy has led to further diagnostic tests, including hormonal profile and functional assays which subsequently confirmed endocrinopathy, while the assessment of autoantibodies was rarely available. In most of these cases, the exact pathogenesis remained unknown, and the endocrine dysfunction was permanent, requiring lifelong supplementation. Although endrocine irAEs are rare, physicians must be aware of these irAEs to recognize them on time and treat them appropriately.

1. Introduction

The introduction of immune checkpoint inhibitors (ICIs) (anti-CTLA-4, anti-PD-1 inhibitors, and anti-PD-L1 inhibitors) in adjuvant and metastatic settings has revolutionized the therapeutic approach of several cancer types [1]. Immune checkpoints are small molecules on the cell surface of T lymphocytes which play vital roles in maintaining immune homeostasis and self-tolerance and in modulating the duration and amplitude of immune response against tumor cells [1]. Several monoclonal antibodies target and block inhibitory checkpoints allowing adaptive immunity to attack tumor cells [1]. However, this amplification of the immune response induced by ICIs can also be potentially directed against healthy human tissues and cause a wide range of side effects, with variable degrees of severity, known as immune-related adverse events (irAEs) that include dermatologic, gastrointestinal, respiratory, hepatic, endocrine, and other less common inflammatory toxicities. Four mechanisms have been proposed to explain the onset of irAEs [2]. The first mechanism includes increased T cell activity against antigens that are present both in tumors and in healthy cells. An increase in pre-existing autoantibodies and the expansion of T cell populations capable of releasing proinflammatory cytokines after ICI administration are two other suggested pathogenetic mechanisms, while the last theory suggests that checkpoint molecules (CTLA-4, PD-1, and PD-L1) can be found not only on T lymphocytes but also on other normal cells. Direct binding of ICIs with tissue expressing immune checkpoints may trigger cytotoxic immune reactions that eventually lead to organ-specific toxicity.
IrAEs are evaluated and treated using the Common Terminology Criteria for Adverse Events, the European Society for Medical Oncology guideline, and the American Society of Clinical Oncology guideline [3]. In general, discontinuation of ICI therapy is recommended for grade ≥2–3 irAE toxicities [3]. It is noteworthy that the management of immune-related endocrinopathies is quite different from other irAEs since high-dose corticosteroids are rarely required for the treatment of endocrine complications and, in addition, most endocrine dysfunctions are frequently irreversible regardless of ICI cessation [3]. Thus, the development of endocrinopathies does not necessarily prompt the interruption of ICI treatment [4]. According to the recent European Society of Endocrinology (ESE) clinical practice guideline [4], thyroid dysfunction represents the most common endocrine irAEs. The overall incidence of ICI-induced hypophysitis ranges between 1.8 and 17% [4,5] and ICI-induced diabetes mellitus (DM) between 0.9 and 2% [6].
In addition to the aforementioned relatively frequent endocrine irAEs, several other endocrine disorders have also been reported in the literature whose incidences are difficult to estimate because of their rarity. Herein, we review the existing evidence and collect all currently published cancer cases that underwent immunotherapy and developed these poorly described, yet exceedingly interesting, endocrine irAEs, including primary adrenal insufficiency, central diabetes insipidus, primary hypoparathyroidism, hypergonadotrophic hypogonadism, lipodystrophy, osteoporosis, or Cushing disease. Regardless of the underlying malignancy and the type of administered ICI, the entire diagnostic and therapeutic management is also thoroughly discussed.

2. Materials and Methods

This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISM), http://www.prisma-statement.org, accessed on the 14 October 2022. This study is registered with PROSPERO, number CRD42022367385.

2.1. Data Sources and Search Strategy

The databases PubMed, EMBASE, EMCARE, Web of Science, and COCHRANE Library were searched up to 28 October 2022 to identify potentially relevant studies. After the initial title and abstract screening, we assessed the full texts of studies to be potentially included and hand-searched their reference lists to gather additional relevant publications. The search terms included the following: “primary adrenal insufficiency”, “adrenalitis”, “Addison’s disease”, “diabetes insipidus”, “panhypopituitarism”, “hypoparathyroidism” “hypocalcemia”, “primary hypogonadism”, “orchitis”, “hypergonadotropic hypogonadism”, “infertility”, “spermatogenesis”, “osteoporosis”, “lipodystrophia”, “endocrine complications”, “endocrinopathies”, “immune checkpoint inhibitors”, “PD-1 inhibitor”, “PD-L1 inhibitor”, “CTLA-4 inhibitor”, “pembrolizumab”, “nivolumab”, “ipilimumab”, “atezolizumab”, “cemiplimab”, “avelumab”,”dostarlimab”, “tremelimumab”, “durvalumab”. The above keywords were combined with the Boolean operators AND and OR. The literature search was conducted by two independent investigators (C.M. and A.A.) and the selection of retrieved reports, including the numbers of the records identified or excluded and the reasons for exclusions, are represented in Figure 1. According to the PRISMA 2020 statement, our flow diagram depicts the flow of information through the different phases of the screening process, mapping out the number of records identified, included, and excluded as well as the reasons for exclusions [7]. All available data on clinical and diagnostic features, management, and outcomes of these cases were collected. Data extraction was undertaken by two investigators (A.K. and P.P.) independently. The level of initial agreement was assessed using Kappa statistics. Any discrepancy was resolved by a third independent investigator (D.C.Z.), who reviewed the data extraction.

2.2. Eligibility Criteria for Articles of Inclusion

According to the Food and Drug Administration (FDA) and the European Commission, adverse drug reactions are classified into 5 types: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), and very rare (<1/10,000) [8]. Thus, eligible studies were considered to be all studies (e.g., case reports, case series, cohort studies, etc.) that included cancer patients (regardless of their type of malignancy) who were treated with an ICI-based regimen (as a single agent or in combinatorial regimens with other ICI or chemotherapy) and who experienced rare and very rare endocrine irAEs.

3. Literature Review Results

A total of 825 articles were initially retrieved from the search of the databases. After excluding duplicates (n = 90) and non-English literature (n = 25), 710 articles remained. Two of the authors independently examined all potentially eligible titles and abstracts to identify articles of interest, from which 433 articles were excluded because they did not include primary or clinical or relevant data. Based on the full text assessment of the remaining 277 studies, n = 77 were excluded because they reported other than endocrine irAEs and n = 21 studies were also excluded because they presented a total rate of immunotherapy-induced endocrinopathies without specifying the type of endocrinopathy. Fifty-six studies were further excluded because they reported only common endocrine complications, n = 41 were excluded because the origin of the described endocrine disorders was not specified (primary vs. secondary adrenal insufficiency or primary vs. secondary hypogonadism), and the last n = 20 studies were also excluded because of the detection of metastases in the affected endocrine organ. Nine additional reports were also identified and included in our analysis through hand-searched reference lists. Finally, a total of 71 studies including case reports (n = 56), case series (n = 5), cohort studies (n = 3), one cross-sectional study, one phase I clinical study, and pharmacovigilance retrospective studies (n = 5), were included in our study (Figure 1).

3.1. Primary Adrenal Insufficiency (PAI)

3.1.1. Background

Adrenal insufficiency (AI) induced by ICI is prevalently secondary (SAI), resulting from either an anterior hypophysitis or selective damage of ACTH-producing cells in the pituitary [9]. In a recent systematic review, the incidence of PAI was reported as 5.3% among all ICI-induced AI events (n = 206), whereas the majority of cases (92.7%) was attributed to SAI and the remaining cases (1.9%) were attributed to mixed-type AI [9]. An estimation of the precise incidence of ICI-induced PAI is difficult, because in the majority of the studies there is insufficient data regarding the distinction between PAI and SAI which can often lead to a misdiagnosis, and finally an underestimation of the PAI cases.

3.1.2. Case Studies

There are three pharmacovigilance retrospective studies reporting data on ICI-induced PAI cases. The first study by [10] reported an incidence of ICI-induced PAI of 0.9% (451 PAI cases (45 definite, and 406 possible) out of 50.108 cases with irAEs) according to the WHO’s VigiBase from September 2008 to October 2018. The majority of patients were treated with ICI monotherapy: 58.5% were on anti–PD-1 or anti–PD-L1 treatment and 23.6% on anti–CTLA-4 treatment. Only 18% of patients with ICI-associated PAI had received combination ICI therapy. The median time to onset of symptoms since the initiation of immunotherapy was 120 days (range, 6–576) based on the data of 120 out of 451 patients. ICI-related PAI was associated with significant morbidity (≥90% severe) and mortality (7.3%). The second study by [11] reported an incidence of ICI-induced PAI of 0.86% (1180 PAI cases out of 137.566 cases with irAEs) based on the FDA Adverse Event Reporting System (FAERS) database from 2007 to 2020. The incidence of PAI was 0.77% (578/74,605) in patients on PD-1 inhibitors, 0.68% (160/23,445) in patients on PD-L1 inhibitors, and 0.6% (97/16,071) in patients on CTLA-4 inhibitors. In patients treated with combination therapy of ipilimumab and nivolumab the incidence was 1.47% (345/23,445). Patients on PD-1 inhibitors had a significantly higher risk of PAI compared to PD-L1 inhibitors (χ2 = 5.14, p = 0.022) but a lower risk of PAI compared to the combination therapy group (χ2 = 92.88, p < 0.001). In terms of prognosis, 937 cases (79.4%) had severe PAI compared to 243 cases (20.6%) in which PAI was considered to be mild. Among the severe cases, 53.5% of the cases necessitated hospitalization, 14% were life-threatening cases, and 11.9% of the cases led to death. The last study by [12] reported 11 cases (0.002%) of adrenal complications out of 534.688 cases with irAEs based on the Japanese Adverse Drug Event Report database from April 2004 to June 2018.
Twenty-seven studies with detailed patients’ features have been published from 2013 to 2022 and are included in Table 1 [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]. These studies describe a total of 29 patients who experienced PAI following ICI therapy for various types of malignancy. Patients’ ages ranged from 14 to 79 years (mean ± SD: 58.9 ± 14.4 years). Three patients (10.3%) were treated with anti-CTLA-4 monotherapy, 20 patients (69%) were treated with anti-PD-1/L1 monotherapy, and the remaining six patients (20.7%) were treated with anti-CTLA-4 and anti-PD-1 combination therapy. In at least eight cases [16,21,23,24,27,34,37], ICIs were chosen as the first-line systematic therapy for advanced disease, whereas, in four cases ICI, treatment was combined with a tyrosine kinase inhibitor [13,22,27,29], which has also been implicated for PAI development [40]. The ICI-induced PAI was diagnosed from 10 days to 1 year post ICI initiation. In four cases, PAI was also associated with other autoimmune endocrinopathies such as DM and thyroiditis, leading to a diagnosis of autoimmune polyendocrine syndrome type 2 (APS-2) [13,16,17,28]. The majority of these reported cases (20/27, 74.1%) presented with severe or life-threatening symptoms (grade III/IV). Follow-up data were available for only nine patients from whom the vast majority (7/9, 77.8%) presented permanent PAI requiring lifelong steroid substitution, whereas only two cases experienced remission of their PAI confirmed with physiological response of cortisol in the synacthen test [26,34].
The assessment of antibodies was inconsistently reported throughout the studies. Six cases out of 10 [13,17,23,26,28,39] presented positive 21-hydroxylase antibodies (21-OHAbs), while antibodies were negative in four cases [20,29,35]. The 21-OHAbs and adrenal cortex antibodies (ACA) were both positive in two cases [13,23]. In the rest of the cases with confirmed cortisol deficiency, the diagnosis of PAI was established mainly based on elevated ACTH or plasma renin activity or concentration in combination with low serum aldosterone concentration and electrolyte disturbances. It is worthwhile noting that, in a few cases [16,27,28,30,36,37], the authors concluded a PAI diagnosis without providing data of the “classical” tests which are mandatory for the establishment of PAI.
Adrenal imaging was performed in 20 cases, through computed tomography (CT) (n = 12) or fluorodeoxyglucose positron emission tomography-CT (FDG-PET/CT) (n= 4), ultrasound (n = 1), or CT or MRI (n = 3), and was normal in 14 (70%) cases. Three patients presented adrenal cortical atrophy [13,21,39], one patient presented bilateral adrenal enlargement [25], and two patients [24,30,38] presented symmetrically and smoothly enlarged adrenal glands with increased metabolic activity in PET-FDG suggesting adrenal inflammation.
Finally, a recent population-based cohort study that included 418 patients with melanoma treated with ICIs reported an unusual high incidence (8%) of PAI [41]. However, these findings should be interpreted with caution since no data were provided on the used diagnostic approach.

3.1.3. Pathophysiology

The pathophysiology of ICI-related PAI remains unknown but is likely mediated by autoimmune activation caused by ICI. Cytotoxic T lymphocytes are considered to be the main cellular mediators of the adrenal gland destruction, while 21-OHAbs in the serum, although not directly involved in the pathogenesis of autoimmune forms of PAI [42], remain reliable disease biomarkers [43]. In addition, adrenal cortex antibodies (ACA) have also been identified in patients with autoimmune PAI, including steroid 17-α-hydroxylase and the cholesterol side-chain cleavage enzyme [43]. Over the course of autoimmune PAI, the three layers of the cortex are progressively destroyed and replaced by fibrous tissue. Despite continuous loss of adrenocortical cells, the disease may underlie subclinically for a long period of time and may not manifest itself until 90% of the cells are destroyed [42].
In the case of ICI-induced PAI, adrenal inflammation has also been confirmed by FDG-PET scan in which both glands appear hypermetabolic. Indeed, there is evidence of both humoral and cell-mediated immune mechanisms directed at the adrenal cortex. The rapid time to occurrence of PAI (a few days in some cases) may reflect a cytotoxic T cell-mediated destruction of the adrenal cortex [10]. Antibodies directed against steroidogenic enzymes have also been reported in cases of ICI-induced PAI, as described above.
Certain genotypes have been associated with an increased risk for developing PAI as an isolated disorder or as part of APS-2 [42,44]. These PAI-related genes encode immunological proteins such as CTLA-4 and human leukocyte antigen (HLA) [42]. Interestingly, in two cases with ICI-related APS-2, HLA typing was performed and revealed DRB1*04 and DQB1*03 high-risk haplotypes [16,17]. In these patients with genetic susceptibility, ICIs could potentially trigger the clinical onset of APS-2.

3.1.4. Clinical Presentation

PAI may manifest as either an acute or chronic condition. In particular, the chronic form of PAI may be overlooked or confused with cancer-related symptoms, as symptoms are rather nonspecific and include weakness, anorexia, musculoskeletal pain, weight loss, abdominal pain, nausea, and vomiting. A specific sign of chronic PAI is hyperpigmentation that predominantly affects areas of the skin subjected to pressure. The onset of PAI is often gradual and may go undetected until an illness or other stress precipitates an adrenal crisis. An adrenal crisis is a life-threatening condition. Clinical features include vomiting, abdominal pain, severe hypotension, or hypovolemic shock associated with hyponatremia, hyperkalemia, or hypoglycemia [45].

3.1.5. Diagnosis

According to the recommendations of the French Endocrine Society [46], a diagnosis of PAI in a patient under treatment with ICI should be considered in the following cases: (i) acute presentation of indicative symptoms or signs as described above, (ii) hyponatremia-related alteration in general status, (iii) isolated electrolyte imbalance (hyponatremia or hyperkalemia). A diagnosis of PAI involves evaluating cortisol levels in the morning, with a low baseline cortisol level (usually below 100 nmol/L or 5 µg/dL) and an ACTH level above two times the upper reference limit being indicative of PAI [45]. In cases where baseline cortisol levels are between 5 and 18 µg/dL, a Synacthen (corticotropin) stimulation test may be performed [46]. A peak cortisol level below 500 nmol/L (18 µg/dL) at 30 or 60 min during the test is considered to be indicative of PAI. In addition to high ACTH levels, PAI is characterized by increased renin activity or concentration and decreased aldosterone concentration, as well as frequently occurring hyperkalemia, hyponatremia, and hypoglycemia [45].
The recent ESE’s guidelines [4] suggest the assessment of serum 21-OHAbs and a non-urgent adrenal CT scan to evaluate adrenal inflammation or atrophy and to rule out other potential secondary causes [4]. However, due to the rarity of PAI, there is not enough data to recommend systematic screening for PAI before or during immunotherapy, unless clinical signs suggest it [46].

3.1.6. Management

Based on the ESE guidelines [45], patients with suspected adrenal crisis should be treated with an immediate parenteral injection of 100 mg (50 mg/m2 for children) hydrocortisone, followed by appropriate fluid resuscitation and 200 mg (50–100 mg/m2 for children) of hydrocortisone/24 h (via continuous IV therapy or 6 hourly injection) prior to the availability of the results of diagnostic tests. Once a patient’s condition is stable and the diagnosis has been confirmed, parenteral glucocorticoid therapy should be tapered over 3–4 days and an oral maintenance dose can be instituted. In case of acute PAI, ICI can be discontinued, but should be reintroduced when the steroid replacement has normalized blood electrolytes and the patient’s symptoms have resolved [4,46].
High-dose glucocorticoids are not recommended for the treatment of chronic PAI since there is no established efficacy and, additionally, they may induce SAI [4]. Thus, it is recommended to initiate hydrocortisone at a dose of 15–25 mg or cortisone acetate 20–30 mg divided into two or three daily doses or a dual-release hydrocortisone tablet 20 mg once daily [47]. Prednisolone at 3–4 mg daily is also an alternative option, while dexamethasone has no place in replacement therapy. Patients with PAI generally receive mineralocorticoid replacement comprised of fludrocortisone 0.05–0.15 mg/day [45]. Patients should be informed regarding the management of PAI and the essential need to increase the dose of glucocorticoid during minor or major stress to prevent adrenal crises. Regardless of ICI discontinuation, PAI remains permanent in most cases and glucocorticoid or mineralocorticoid replacement should not be interrupted abruptly without testing of adrenal function with dynamic tests (standard 250 μg Synacthen test) [4].

3.2. Diabetes Insipidus (DI)

3.2.1. Background

Central DI (CDI), or as it is recently renamed “central arginine vasopressin (AVP) deficiency” [48], is the most common form of DI and is generally the result of hypothalamic-neurohypophysial dysfunction leading to inadequate AVP secretion from the posterior pituitary or inadequate production from the hypothalamus Although hypophysitis is a common ICI complication, involvement of the posterior pituitary with CDI is overall rare, described in 2% and in 3% of anti-CTLA-4- and anti-PD-1-induced hypophysitis cases, respectively [49].

3.2.2. Case Studies

According to the WHO global database of individual case safety reports, between January 2011 and March 2019 [50], 16 CDI cases (0.26%) out of a total 6089 endocrine irAEs were reported. In addition, Zhai et al. [51] reviewed 24 cases (0.4%) of immune-related CDI in a total of 6260 endocrine irAEs reported to the FDA Adverse Event Reporting System (FAERS) database from 2014 to 2019.
ICI treatment has been reported to dysregulate the posterior pituitary–hypothalamic axis in 15 individual cases (12 males and 3 females) included in Table 2 [52,53,54,55,56,57,58,59,60,61,62,63,64,65]. Most patients developed CDI after a period ranging from 28 to 270 days following treatment, with the exception of one patient who developed CDI immediately after receiving sintilimab, a PD-1 inhibitor [61]. Five patients out of these 15 cases, had received monotherapy with CTLA-4 inhibitor (ipilimumab); n = 5 patients with PD-1 inhibitors (n = 4 with nivolumab and n = 1 with sintilimab); n = 2 patients with PD-L1 inhibitor (avelumab, atezolizumab); and n = 3 patients had received combination treatment with nivolumab and ipilimumab (n = 2) or tremelimumab and durvalumab (n = 1). At least five patients [52,57,59,63,64] had received ICIs as first-line systematic therapy for advanced disease. Notably, in one case, whole brain radiotherapy had preceded the ICI therapy, and thus, the mechanism of panhypopituitarism was not clear [53].
In eight patients, CDI developed in the context of panhypophysitis [53,54,55,56,58,59,62,64], while in a further five patients [52,57,60,61,63] CDI developed in the context of isolated damage of the posterior pituitary. Although in one case CDI was accompanied with other anterior dysfunctions, it was considered to be the result of hypothalamitis based on clinical symptoms (severe sleep apnea and temperature dysregulation) and brain imaging (infiltrating, heterogeneously enhancing solitary lesion in the hypothalamus) [58]. It is important to note that the diagnoses of DI were based on the presence of polyuria/polydipsia symptoms, plasma or urine osmolality levels, and/or electrolytical disturbances. In seven cases [52,53,60,64,65], the diagnoses of CDI were well established based on water deprivation tests and/or copeptin levels. In the remaining cases [54,55,57,58,59,61,62,63], diagnoses of CDI were not validated by the recommended algorithm but were based on more “indirect” parameters such as relevant clinical symptoms related with concomitant anterior hypophysitis and/or indicative MRI finding (absent bright spot or hypothalamic mass) or response to desmopressin (improvement of the symptoms and normalization of electrolyte disturbances).

3.2.3. Pathophysiology

The spectrum of ICI-induced hypothalamus–pituitary autoimmunity includes the anterior hypophysitis, infundibulo-neurohypophysis, panhypophysitis, and hypothalamitis, among which the anterior hypophysitis is the most common entity [66]. The higher incidence of anterior pituitary deficiency as compared with the rare manifestation of posterior pituitary dysfunction in ICI-induced hypophysitis may be attributed to the rich vascularity of the anterior pituitary gland with higher exposure to systemic therapy and its associated toxicities [57].
In the few reported ICI-induced CDI cases, the pathophysiological mechanism remained to be unclear, mainly because of the lack of autopsies and subsequent absence of histopathological analyses of patients’ impaired pituitary glands. The histopathological analysis of a single case of a patient with clinical signs of anterior hypophysitis showed that the pituitary gland presented type II and IV hypersensitivity reactions. Interestingly, strong CTLA-4 expression in the pituitary gland was also observed [67]. The posterior pituitary appeared to be normal, consistent with the absence of CDI in this patient. A recent report revealed the expression of PD-L1 receptor on hypothalamic cells which may explain the most frequent hypothalamic toxicity during anti-PD-L1 treatment [68]. Interestingly, all cases with posterior hypophysitis or hypothalamitis had been treated only with anti-PD1/PD-L1 agents or regimens [52,57,58,60,61,63].

3.2.4. Clinical Presentation

Patients with CDI typically present with polyuria, nocturia, and polydipsia due to the initial elevation in serum sodium and osmolality [69]. There may also be symptoms of coexisting anterior pituitary dysfunction or hypothalamic dysfunction [58].

3.2.5. Diagnosis

Hypotonic polyuria (urine output more than 50 mL/kg/24 h and urinary osmolality less than 300 mOsm/kg) associated with high plasma sodium concentration indicates a highly suspected diagnosis of DI. The differential diagnosis between CDI, nephrogenic DI, and primary polydipsia requires dynamic tests such as a water deprivation test. However, a water deprivation test often requires long periods of observation, and has considerable diagnostic limitations [69]. Recently, copeptin (C-terminal peptide of pro-AVP) level, either baseline or after stimulation (with hypertonic saline infusion or with L-arginine stimulation), has proven to be a promising biomarker for polyuria-polydipsia syndrome. Copeptin is co-secreted with AVP and is a surrogate of its secretion as it is a more stable compound. A baseline copeptin level >21.4 pmol/L has been found to be diagnostic of NDI, while an osmotically stimulated copeptin level of <4.9 pmol/L has been found to be diagnostic of CDI [69]. When a patient is treated with an ICI, distinct endocrine complications may mask the presence of CDI. In particular, aldosterone deficiency causes urinary sodium loss and cortisol deficiency impairs free water excretion. It is essential that these conditions be corrected before testing for AVP deficiency [4]. On an unenhanced T1-weighted MRI, CDI generally manifests as a pituitary ”bright spot” absence with or without enlargement (2–3 mm) of the pituitary stalk; however, this finding alone is not necessarily sufficient to support CDI diagnosis. The posterior pituitary bright spot is a manifestation of stored AVP, although it is “normally” missing in 52–100% of the general population [69]. At last, a diagnosis of ICI-induced CDI is established once other more frequent causes of CDI (e.g., traumatic injury, sellar/suprasellar lesions, vascular disorders, infections, or use of other medications such as glucocorticoids and opiates) have been excluded.

3.2.6. Management

Desmopressin is the current standard of care for patients with ICI-related CDI and should be administered while carefully monitoring the sodium and fluid balance over 24 h [4].

3.3. Hypoparathyroidism

3.3.1. Background

Hypoparathyroidism is most commonly the result of inadvertent removal or irreversible damage of parathyroid glands, in a clinical scenario of anterior neck surgery. Autoimmune hypoparathyroidism is the most frequent form of non-iatrogenic hypoparathyroidism in adults and it can either be isolated or part of autoimmune polyendocrine syndrome type-1 (APS-1) [70]. However, it is classified as an orphan disease by the European Commission (ORPHA:36913). Although rare, autoimmune hypoparathyroidism has been recorded to be manifested following the use of ICIs for cancer treatment.

3.3.2. Case Studies

There were two pharmacovigilance retrospective studies that reported ICI-induced hypoparathyroidism. Data from 2014 to 2019 in the FAERS database [51] and data from VigiBase between January 2011 and March 2019 [50] revealed 18 ICI-induced hypoparathyroidism cases out of 6260 cases (0.28%) of endocrine irAEs and 11 ICI-induced hypoparathyroidism cases out of 6089 cases (0.18%) of endocrine irAEs, respectively.
The analytical data from nine cases of ICI-related hypoparathyroidism are also summarized in Table 3 [71,72,73,74,75,76,77,78,79]. Patients’ ages ranged between 53 to 76 years. Four patients were treated with anti-PD-1 monotherapy, one patient was treated with anti-CTLA-4 monotherapy, and four patients were treated with a combination of ipilimumab and nivolumab. In at least three of these patients [71,73,78], ICIs were used as first-line monotherapy for advanced cancer stage. The time from ICI initiation to the onset of hypoparathyroidism ranged between 1 month and 1.5 years. In terms of prognosis, seven of nine (77.8%) patients presented with acute severe hypocalcemia (Grade III/IV) requiring hospitalization. The diagnosis was based on hypocalcemia along with low PTH levels in all patients. Various autoantibody measurements were performed in six out of the nine patients. Ca2+-sensing receptor (CaSR) antibodies were analyzed in five patients and were found to be positive in four of the patients [71,74,76,77] and nonspecific in the last patient [75]. In addition to CaSR antibodies, NACHT leucine-rich repeat protein 5 (NALP5) antibodies and antibodies against cytokines were also measured in two of the patients [71,74] and they were found to be negative. In the last case, anti-parathyroid antibodies were measured and were also found to be negative [72]. Hypoparathyroidism was not described as a component of APS-1 in any of the above cases. According to the available follow-up data, all cases required continuous calcium and active vitamin D supplementation.

3.3.3. Pathophysiology

The mechanism of ICI-related hypoparathyroidism remains unclear. Even though the expression of PD-1/PD-L1 or CTLA-4 is unknown in normal parathyroid tissue, PD-1 expression was demonstrated in 30% of 28 parathyroid carcinomas and in 49% of 63 parathyroid adenomas [80]. The underlying mechanism of ICI-related hypoparathyroidism likely involves the activation of CaSR antibodies that inhibit PTH secretion [71,74,76,77] or/and increased T-cell activity against parathyroid tissue [75].

3.3.4. Clinical Presentation

Hypoparathyroidism may be associated with a spectrum of clinical manifestations, ranging from mild (perioral numbness, paresthesias of the hands and feet, muscle cramps) to severe (carpopedal spasm, laryngospasm, and focal or generalized seizures) symptoms of neuromuscular irritability. The duration, severity, and rate of development of hypocalcemia determine the clinical presentation [70].

3.3.5. Diagnosis

Persistent hypocalcemia (total serum calcium concentration <2.1 mmol/L) with a low or inappropriately normal parathyroid hormone (PTH) level and hyperphosphatemia is, in the absence of hypomagnesemia, diagnostic of hypoparathyroidism [81]. A possible autoimmune etiology of the patient’s hypoparathyroidism should be suspected if no history of past radiation to the neck or prior neck surgery or familial hypocalcemic disorders are present.
As nonsurgical hypoparathyroidism is extremely rare, APS-I should be considered in every patient with hypoparathyroidism [82]. The testing for autoantibodies to type 1 interferons (detected in 95% of patients with APS-1) is a cost-effective tool for first-line screening [83]. The disease is the most common endocrine component of APS-1, manifested in more than 80% of adult patients with APS1. In APS-1 patients, NALP5 is the main immunological target in the parathyroid cells [82]. Measurement of CaSR antibodies may also be helpful in the diagnosis of autoimmune hypoparathyroidism [84]. However, in general, identification of autoimmune hypoparathyroidism is a diagnostic challenge due to the lack of specific immunological markers [85]. Consequently, a diagnosis of ICI-associated hypoparathyroidism is based on clinical criteria.

3.3.6. Management

According to the recent ESE guidelines [4], immune-related hypoparathyroidism is treated similarly to hypoparathyroidism due to other causes. The major goal is to correct symptomatic hypocalcemia and to avoid short- and long-term complications, especially cardiological complications such as prolongation of the QT interval. Oral calcium and vitamin D supplementation is the standard treatment used, while recombinant PTH and high dose use of glucocorticoids are not recommended. In the case of acute severe symptoms, intravenous calcium gluconate along with oral calcium supplements and active vitamin D are required [70].

3.4. Lipodystrophy

3.4.1. Background

Lipodystrophy syndromes are a heterogeneous group of diseases, characterized by selective absence of adipose tissue. There are four major subtypes according to the pattern of adipose tissue loss and the manner of acquisition: congenital generalized lipodystrophy (CGL), acquired generalized lipodystrophy (AGL), familiar partial lipodystrophy (FPLD), and acquired partial lipodystrophy (APL) [86]. Recently, AGL and APL have been reported during ICI therapy.

3.4.2. Case Studies

Seven case reports were recognized that described immune-related lipodystrophy (Table 4) [87,88,89,90,91,92,93]. Six patients were females, and one patient was male with ages between 34 and 67 years. All patients were on anti-PD-1 agents. In five patients, ICIs were used as the first-line treatment for advanced disease [87,88,89,90,91]. The onset of lipodystrophy symptoms ranged from 6 weeks to approximately 1.5 years from ICI initiation.
All but one patient developed AGL. The majority of patients also presented metabolic abnormalities. Three of the patients developed new-onset DM [87,91,93], while two patients experienced deterioration of their preexisting DM [88,92]. The same patients also presented excessive hypertriglyceridemia [87,88,91,92,93], while three patients had also developed hepatic steatosis [87,91,93]. Leptin and adiponectin levels were measured in five patients. All [87,88,91,92] but one patient [89] had low serum levels of adipocytokines. Regarding leptin levels, hypo- and hyperleptinemia have both been described, making leptin measurement unreliable as a disease marker.
Treatment was focused on managing the metabolic abnormalities. Glucocorticoid treatment was suggested in three cases of AGL. In the literature, there was no report of a patient who had been treated with metreleptin (recombinant human methionyl leptin).

3.4.3. Pathophysiology

Although the mechanism of ICI-associated lipodystrophy has not been studied sufficiently, there is evidence of an immune-mediated destruction of adipose tissue. Inflammation and infiltration of fat tissue with CD3+ and/or cytotoxic CD8+ lymphocytes identified in histopathological analyses of subcutaneous fat of ICI-treated patients, strongly suggest an immune-mediated reaction against adipose tissue [87,88,89,91,92,93].

3.4.4. Clinical Presentation

The main feature of lipodystrophy is the selective loss of subcutaneous adipose tissue leading to local body deformation. Although patients with AGL comorbidities such as insulin-resistant DM, dyslipidemia, non-alcoholic fatty liver disease, renal or reproductive dysfunction, as well as heart disease are frequent and potentially severe, they are rarely present in patients with APL [94].

3.4.5. Diagnosis

The diagnosis of lipodystrophy was usually made clinically based on history, physical examination, and a metabolic profile indicating non-responsive to therapy. In addition, a substantial subset of patients with lipodystrophy exhibited low leptin level. However, there was no defined serum leptin level that established or ruled out the diagnosis [94]. The identification of underlying etiology may be challenging in the context of cancer immunotherapy, given the lack of specific testing and wide differential diagnosis. However, an ICI-related mechanism should be suspected if further evaluation (physical features, family history, disease onset, past history and medical treatment, clinical and serological evaluation for autoimmune diseases, and genetic testing) rules out alternative causes.

3.4.6. Management

For the generalized form, treatment of the accompanying metabolic symptoms is of primary concern. Currently, metreleptin is the only drug approved specifically for lipodystrophy [94]. Further studies should evaluate the role of leptin replacement therapy in ICI-associated AGL.

3.5. Osteoporosis

3.5.1. Background

Osteoporosis is developed under multiple factors, including genetic factors as well as a range of other acquired and modifiable risk factors. Recently, there has been increasing interest to study the immune involvement in its pathogenesis [95]. Although current guidelines provide no evidence of direct or indirect effect of ICI therapy on bone metabolism, some published data have proposed that immune activation by ICIs may adversely impact bone remodeling.

3.5.2. Case studies

Three published case series described skeletal-related events (SRE) in patients undergoing ICI therapy for different types of cancer (Table 5). One of the case studies [96] identified three patients without a prior diagnosis of osteoporosis presenting with new fractures during the course of anti-PD-1 therapy. Their ages ranged from 52 to 79 years and none of them had apparent pre-existing bone loss risk factors including focal bone radiation, family history of osteoporosis, tobacco or alcohol abuse, renal disease, or prolonged corticosteroid use. The study reported three more patients who developed new destructive or resorptive bony lesions that were not consistent with metastases during ICI treatment. At the biochemical level, elevated or high-normal bone turnover markers (C-telopeptides/bone-specific alkaline phosphatase) were reported in five out of these six patients, while inflammatory markers (C-reactive protein/erythrocyte sedimentation rate) were elevated in all patients.
The second case series by [97] reported four patients with no previous history of osteopenia or osteoporosis who developed osteoporotic fractures while being treated systemically with ICIs. Patients were from 62 to 70 years old at the time of development of SRE, and mainly females (3 patients of 4). Pre-existing risk factors for osteoporosis included smoking in three patients (<40 pack/years), mild renal failure in two patients, and long-term use of proton pump inhibitors (PPIs) in all four patients.
Moreover, an analysis of the worldwide pharmacovigilance database FAERS from 2014 to 2020 reported a statistically significant odds ratio (OR) for pathological fracture (n = 46, OR = 3.17, 95% CI 2.37–4.24), spinal compression fracture (n = 42, OR = 2.51, 95% CI 1.91–3.40), and femoral neck fracture (n = 26, OR = 2.38, 95% CI 1.62–3.50) in patients treated with ICI (specially with PD-1 inhibitors) compared to patients who received any other drug reported in FAERS [97]. Potential confounding clinical conditions or suspicious drugs were reported in limited cases.
The last study by [98] evaluated the changes in plasma levels of bone turnover markers (collagen C-terminal telopeptide (CTX-1) and N-terminal propeptide of type I procollagen (PINP)) in 44 patients (median age = 70 years) affected by non-small cell lung cancer (n = 36) or renal cell cancer (n = 8) after 3 months of anti-PD-1 monotherapy. The patients had neither prior history of osteoporosis nor preexisting risk factors. CTX-1 levels were significantly increased, while PINP levels showed a trend of decreasing compared to baseline levels before ICI initiation. Interestingly, 4 of these 44 patients (9%) developed new diagnosed lumbar fractures during the 3-month follow-up. Notably, in at least four patients who developed skeletal effects, ICIs were used as the first-line treatment for advanced disease [96].

3.5.3. Pathophysiology

The immune system is considered to play an integral role in the pathogenesis of osteoporosis [95]. Activated immune cells either directly or indirectly through the secretion of various cytokines and factors regulate bone remodeling. Immune activation induced by ICIs may impact bone metabolism, leading to bone resorption stimulation. In the setting of ICIs, activated T cells that secrete cytokines (TNF-α, IL-1, -4, -6, IL-17, and IFN-γ) have been associated not only with tumor cell destruction [99] but also with osteoclast formation and skeletal degradation [100].

3.5.4. Clinical Presentation

Osteoporosis has no clinical manifestations until there is a fracture. Fractures may cause acute pain and loss of function but may also occur without symptomatology [101].

3.5.5. Diagnosis

The operational definition of osteoporosis is based on a T-score for bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) at the femoral neck or spine. Diagnostic work-up will depend on the severity of the disease, the age at presentation. and the presence or absence of vertebral fractures [101]. A correlation among clinical history, time course, and the absence of risk factors or underlying diseases, remains the major key to differentiate a case of ICI-related osteoporosis from the other causes.

3.5.6. Management

The treatment of osteoporosis consists of lifestyle measures and pharmacologic therapy. Lifestyle measures include adequate calcium and vitamin D, exercise, smoking cessation, counseling on fall prevention, and moderation of alcohol use. Anti-resorptive and anabolic agents are alternative effective treatment options for certain subsets of patients [101].

3.6. Hypergonadotropic Hypogonadism

ICIs may evoke disorders in the reproductive activity either inducing secondary hypogonadism in the context of hypophysitis with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) insufficiency (secondary hypogonadism) or rarely targeting directly the gonads (testes and ovaries) causing impaired oogenesis/spermatogenesis and consequently fertility compromise [102]. The incidence of secondary hypogonadism increases to 85% of the ICI-treated cases with hypophysitis, while primary hypogonadism has been described only in anecdotal cases (Table 6).
Primary hypogonadism, affecting sperm and/or testosterone production, has been described in 13 male patients treated with ICIs. However, it was unclear whether these cases represented true irAEs. In at least nine patients, ICIs were used as a first-line systematic treatment for advanced disease [104,105,106,107]. However, in another three patients, there were also additional risk factors which could be incriminated for impaired spermatogenesis (radiotherapy to inguinal lymph nodes (n = 1), alcohol abuse (n = 1), prior history of orchitis (n = 1)), and thus, ICI treatment could not be identified as fully responsible for the hypogonadism [106]. Moreover, notably, a baseline (before any treatment) spermogram was available and was normal in only one case [106]. Testicular biopsies, when performed, revealed an inflammation infiltrate without any specific finding of a potential ICI-related pathogenetic mechanism. Notably, PD-L1 and PD-L2 are normally expressed along the female reproductive tract, with differential expression depending on menopausal status, serving as potential direct targets of ICI therapy [108]. However, to the best of our knowledge, to date, no case of ICI-related primary hypogonadism has been described in the female population.

3.7. Cushing Disease (CD)

Cushing disease (CD) is an extremely rare adverse event which was described thoroughly in a single case report in [109] in the context of destructive hypophysitis during immunotherapy with nivolumab and ipilimumab for the treatment of metastatic melanoma. The patient was a 53-year-old female who presented typical signs and symptoms of CD manifested within the 9th and the 11th week of the immunotherapy initiation. Biochemical testing confirmed an ACTH-dependent hypercortisolism. Hormonal pituitary assessment also showed concomitant gonadotroph and thyreotroph deficiency. Inferior petrosal sinus sampling determined the pituitary origin of the ACTH hypersecretion and a pituitary MRI showed enlargement of the pituitary gland. Four weeks after the diagnosis of CD, permanent SAI was developed, while no recurrence of CD was observed. According to a population-based analysis of 4489 patients with melanoma, ICI-treated patients had a greater risk to develop CD (HR = 11.8, 95% CI 1.4–97.2) compared to those who did not receive immunotherapy [41].

4. Future Aspects

It would be interesting and rather challenging to be able to predict the occurrence of endocrine irAEs in candidates for immunotherapy. Some data suggest that certain biochemical biomarkers measured at baseline before any ICI treatment could predict irAEs. For instance, thyroid-stimulating hormone levels or antithyroid antibodies, as well as cytokines (interleukins IL-2 and IL-1b) measured at baseline could predict thyroid dysfunction. Similarly, specific HLA alleles or anti-pituitary antibodies screening before ICI treatment could predict the occurrence of hypopituitarism and especially deficiency of ACTH [110].

5. Conclusions

A systemic registry of all endocrine irAEs could prove to be very important for the evaluation of their exact frequency. It is also mandatory before attributing an endocrine irAEs to ICI therapy to run a specific diagnostic pathway exploring the autoimmune background (antibodies, biopsy) following the current guidelines. Indeed, the diagnosis of rare and very rare irAEs remains to be doubtful, particularly in multi-treated cases in whom ICIs are the second- or third-line option, and thus, there is an accumulative toxicity from previous therapies. The diagnosis and the management of rare and very rare endocrine irAEs should both be guided by a multidisciplinary team on an individualized basis. Physicians and healthcare providers should be aware of the manifestation of these endocrine toxicities, despite their rarity, for their early diagnosis and treatment. As the use of ICIs expands, it is also important to develop registries with long-term follow-up to better monitor, record, and understand these rare immune related endocrinopathies.

Author Contributions

Conceptualization: H.G. and D.C.Z.; Formal analysis: C.M., A.A., A.K. and P.P.; Investigation: V.S., A.L. and O.B.; Methodology: C.M. and A.A.; Supervision: H.G., A.A. and D.C.Z.; Writing original draft: C.M., A.A. and D.C.Z.; Writing—review and editing: D.C.Z., H.G. and O.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

H.G. has received grants and personal fees by Roche, BMS, MSD, and Novartis and personal fees by Amgen and Pierre Fabre, outside the submitted work. All other authors declare no conflicts of interest.

References

  1. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Postow, M.A.; Sidlow, R.; Hellmann, M.D. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N. Engl. J. Med. 2018, 378, 158–168. [Google Scholar] [CrossRef] [PubMed]
  3. Haanen, J.; Obeid, M.; Spain, L.; Carbonnel, F.; Wang, Y.; Robert, C.; Lyon, A.R.; Wick, W.; Kostine, M.; Peters, S.; et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 2022, 33, 1217–1238. [Google Scholar] [CrossRef]
  4. Husebye, E.S.; Castinetti, F.; Criseno, S.; Curigliano, G.; Decallonne, B.; Fleseriu, M.; Higham, C.E.; Lupi, I.; Paschou, S.A.; Toth, M.; et al. Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: An ESE clinical practice guideline. Eur. J. Endocrinol. 2022, 187, G1–G21. [Google Scholar] [CrossRef] [PubMed]
  5. Barroso-Sousa, R.; Barry, W.T.; Garrido-Castro, A.C.; Hodi, F.S.; Min, L.; Krop, I.E.; Tolaney, S.M. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncol. 2018, 4, 173–182. [Google Scholar] [CrossRef]
  6. De Filette, J.; Andreescu, C.E.; Cools, F.; Bravenboer, B.; Velkeniers, B. A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors. Horm. Metab. Res. 2019, 51, 145–156. [Google Scholar] [CrossRef] [Green Version]
  7. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Bmj 2021, 372, n71. [Google Scholar] [CrossRef]
  8. Available online: https://health.ec.europa.eu/system/files/2016-11/smpc_guideline_rev2_en_0.pdf (accessed on 1 October 2022).
  9. Cui, K.; Wang, Z.; Zhang, Q.; Zhang, X. Immune checkpoint inhibitors and adrenal insufficiency: A large-sample case series study. Ann. Transl. Med. 2022, 10, 251. [Google Scholar] [CrossRef]
  10. Grouthier, V.; Lebrun-Vignes, B.; Moey, M.; Johnson, D.B.; Moslehi, J.J.; Salem, J.E.; Bachelot, A. Immune Checkpoint Inhibitor-Associated Primary Adrenal Insufficiency: WHO VigiBase Report Analysis. Oncologist 2020, 25, 696–701. [Google Scholar] [CrossRef]
  11. Lu, D.; Yao, J.; Yuan, G.; Gao, Y.; Zhang, J.; Guo, X. Immune checkpoint inhibitor-associated new-onset primary adrenal insufficiency: A retrospective analysis using the FAERS. J. Endocrinol. Investig. 2022, 45, 2131–2137. [Google Scholar] [CrossRef]
  12. Hasegawa, S.; Ikesue, H.; Nakao, S.; Shimada, K.; Mukai, R.; Tanaka, M.; Matsumoto, K.; Inoue, M.; Satake, R.; Yoshida, Y.; et al. Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database. Pharmacoepidemiol. Drug Saf. 2020, 29, 1279–1294. [Google Scholar] [CrossRef] [PubMed]
  13. Paepegaey, A.C.; Lheure, C.; Ratour, C.; Lethielleux, G.; Clerc, J.; Bertherat, J.; Kramkimel, N.; Groussin, L. Polyendocrinopathy Resulting From Pembrolizumab in a Patient With a Malignant Melanoma. J. Endocr. Soc. 2017, 1, 646–649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Akarca, F.K.; Can, O.; Yalcinli, S.; Altunci, Y.A. Nivolumab, a new immunomodulatory drug, a new adverse effect; adrenal crisis. Turk. J. Emerg. Med. 2017, 17, 157–159. [Google Scholar] [CrossRef] [PubMed]
  15. Agrawal, K.; Agrawal, N. Lambert-Eaton Myasthenic Syndrome Secondary to Nivolumab and Ipilimumab in a Patient with Small-Cell Lung Cancer. Case Rep. Neurol. Med. 2019, 2019, 5353202. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Gunjur, A.; Klein, O.; Kee, D.; Cebon, J. Anti-programmed cell death protein 1 (anti-PD1) immunotherapy induced autoimmune polyendocrine syndrome type II (APS-2): A case report and review of the literature. J. Immunother. Cancer 2019, 7, 241. [Google Scholar] [CrossRef] [Green Version]
  17. Lanzolla, G.; Coppelli, A.; Cosottini, M.; Del Prato, S.; Marcocci, C.; Lupi, I. Immune Checkpoint Blockade Anti-PD-L1 as a Trigger for Autoimmune Polyendocrine Syndrome. J. Endocr. Soc. 2019, 3, 496–503. [Google Scholar] [CrossRef] [Green Version]
  18. Iqbal, I.; Khan, M.A.A.; Ullah, W.; Nabwani, D. Nivolumab-induced adrenalitis. BMJ Case Rep. 2019, 12, e231829. [Google Scholar] [CrossRef]
  19. Kagoshima, H.; Hori, R.; Kojima, T.; Okanoue, Y.; Fujimura, S.; Taguchi, A.; Shoji, K. Adrenal insufficiency following nivolumab therapy in patients with recurrent or metastatic head and neck cancer. Auris Nasus Larynx 2020, 47, 309–313. [Google Scholar] [CrossRef]
  20. Abdallah, D.; Johnson, J.; Goldner, W.; Addasi, N.; Desouza, C.; Kotwal, A. Adrenal Insufficiency From Immune Checkpoint Inhibitors Masquerading as Sepsis. JCO Oncol. Pract. 2021, 17, 212–214. [Google Scholar] [CrossRef]
  21. Harsch, I.A.; Gritsaenko, A.; Konturek, P.C. An analysis of early morning acth levels in the first case of pembrolizumab-induced adrenalitis as a delayed immune-related event (dire)—Case study. Wiad. Lek. 2020, 73, 396–400. [Google Scholar] [CrossRef]
  22. Özyurt, E.; Özçelik, S.; Sürmeli, H.; Çelik, M.; Ayhan, M.; Özçelik, M. Side effects of immune-checkpoint inhibitors: Can multiple side effects be seen in a patient? J. Oncol. Pharm. Pract. 2022, 28, 462–465. [Google Scholar] [CrossRef] [PubMed]
  23. Bischoff, J.; Fries, C.; Heer, A.; Hoffmann, F.; Meyer, C.; Landsberg, J.; Fenske, W.K. It’s Not Always SIAD: Immunotherapy-Triggered Endocrinopathies Enter the Field of Cancer-Related Hyponatremia. J. Endocr. Soc. 2022, 6, bvac036. [Google Scholar] [CrossRef] [PubMed]
  24. Trainer, H.; Hulse, P.; Higham, C.E.; Trainer, P.; Lorigan, P. Hyponatraemia secondary to nivolumab-induced primary adrenal failure. Endocrinol. Diabetes Metab. Case Rep. 2016, 2016, 16-0108. [Google Scholar] [CrossRef] [PubMed]
  25. Min, L.; Ibrahim, N. Ipilimumab-induced autoimmune adrenalitis. Lancet Diabetes Endocrinol. 2013, 1, e15. [Google Scholar] [CrossRef] [Green Version]
  26. Deligiorgi, M.V.; Trafalis, D.T. Reversible primary adrenal insufficiency related to anti-programmed cell-death 1 protein active immunotherapy: Insight into an unforeseen outcome of a rare immune-related adverse event. Int. Immunopharmacol. 2020, 89, 107050. [Google Scholar] [CrossRef]
  27. Salinas, C.; Renner, A.; Rojas, C.; Samtani, S.; Burotto, M. Primary Adrenal Insufficiency during Immune Checkpoint Inhibitor Treatment: Case Reports and Review of the Literature. Case Rep. Oncol. 2020, 13, 621–626. [Google Scholar] [CrossRef]
  28. Dasgupta, A.; Tsay, E.; Federman, N.; Lechner, M.G.; Su, M.A. Polyendocrine Autoimmunity and Diabetic Ketoacidosis Following Anti-PD-1 and Interferon α. Pediatrics 2022, 149, e2021053363. [Google Scholar] [CrossRef]
  29. Figueroa-Perez, N.; Kashyap, R.; Bal, D.; Anjum Khan, S.; Pattan, V. Autoimmune Myasthenia, Primary Adrenal Insufficiency, and Progressive Hypothyroidism Due to Pembrolizumab and Axitinib Combination Regimen. Cureus 2021, 13, e16933. [Google Scholar] [CrossRef]
  30. Bacanovic, S.; Burger, I.A.; Stolzmann, P.; Hafner, J.; Huellner, M.W. Ipilimumab-Induced Adrenalitis: A Possible Pitfall in 18F-FDG-PET/CT. Clin. Nucl. Med. 2015, 40, e518–e519. [Google Scholar] [CrossRef] [Green Version]
  31. Knight, T.; Cooksley, T. Emergency Presentations of Immune Checkpoint Inhibitor-Related Endocrinopathies. J. Emerg. Med. 2021, 61, 140–146. [Google Scholar] [CrossRef]
  32. Coskun, N.S.S.; Simsir, I.Y.; Göksel, T. A case with a primary adrenal insufficiency secondary to nivolumab. Eur. Respir. J. 2016, 48, PA4853. [Google Scholar] [CrossRef]
  33. Hobbs, K.B.; Yackzan, S. Adrenal Insufficiency: Immune Checkpoint Inhibitors and Immune-Related Adverse Event Management. Clin. J. Oncol. Nurs. 2020, 24, 240–243. [Google Scholar] [CrossRef] [PubMed]
  34. Gaballa, S.; Hlaing, K.M.; Mahler, N.; Moursy, S.; Ahmed, A. A Rare Case of Immune-Mediated Primary Adrenal Insufficiency With Cytotoxic T-Lymphocyte Antigen-4 Inhibitor Ipilimumab in Metastatic Melanoma of Lung and Neck of Unknown Primary. Cureus 2020, 12, e8602. [Google Scholar] [CrossRef] [PubMed]
  35. Afreen Idris Shariff, D.A.D.A. Primary Adrenal Insufficiency from Immune Checkpoint Inhibitors. AACE Clin. Case Rep. 2018, 4, 232–234. [Google Scholar] [CrossRef] [Green Version]
  36. Kojadinovic, A.; Mundi, P.S. Primary Adrenal Insufficiency and Acute Cardiomyopathy in a Patient With Colorectal Cancer Treated With Dual Immune Checkpoint Inhibitors. Clin. Colorectal. Cancer 2021, 20, e249–e252. [Google Scholar] [CrossRef] [PubMed]
  37. Hanna, R.M.; Selamet, U.; Bui, P.; Sun, S.F.; Shenouda, O.; Nobakht, N.; Barsoum, M.; Arman, F.; Rastogi, A. Acute Kidney Injury after Pembrolizumab-Induced Adrenalitis and Adrenal Insufficiency. Case Rep. Nephrol. Dial. 2018, 8, 171–177. [Google Scholar] [CrossRef] [PubMed]
  38. Galliazzo, S.; Morando, F.; Sartorato, P.; Bortolin, M.; De Menis, E. A Case of Cancer-Associated Hyponatraemia: Primary Adrenal Insufficiency Secondary to Nivolumab. Endocr. Metab. Immune Disord. Drug Targets 2022, 22, 363–366. [Google Scholar] [CrossRef]
  39. Hescot, S.; Haissaguerre, M.; Pautier, P.; Kuhn, E.; Schlumberger, M.; Berdelou, A. Immunotherapy-induced Addison’s disease: A rare, persistent and potentially lethal side-effect. Eur. J. Cancer 2018, 97, 57–58. [Google Scholar] [CrossRef]
  40. Colombo, C.; De Leo, S.; Di Stefano, M.; Vannucchi, G.; Persani, L.; Fugazzola, L. Primary Adrenal Insufficiency During Lenvatinib or Vandetanib and Improvement of Fatigue After Cortisone Acetate Therapy. J. Clin. Endocrinol. Metab. 2019, 104, 779–784. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Schonfeld, S.J.; Tucker, M.A.; Engels, E.A.; Dores, G.M.; Sampson, J.N.; Shiels, M.S.; Chanock, S.J.; Morton, L.M. Immune-Related Adverse Events After Immune Checkpoint Inhibitors for Melanoma Among Older Adults. JAMA Netw. Open 2022, 5, e223461. [Google Scholar] [CrossRef] [PubMed]
  42. Hellesen, A.; Bratland, E.; Husebye, E.S. Autoimmune Addison’s disease—An update on pathogenesis. Ann. Endocrinol. 2018, 79, 157–163. [Google Scholar] [CrossRef] [PubMed]
  43. Mitchell, A.L.; Pearce, S.H. Autoimmune Addison disease: Pathophysiology and genetic complexity. Nat. Rev. Endocrinol. 2012, 8, 306–316. [Google Scholar] [CrossRef] [PubMed]
  44. Husebye, E.S.; Anderson, M.S.; Kämpe, O. Autoimmune Polyendocrine Syndromes. N. Engl. J. Med. 2018, 378, 2542–2544. [Google Scholar] [CrossRef] [PubMed]
  45. Bornstein, S.R.; Allolio, B.; Arlt, W.; Barthel, A.; Don-Wauchope, A.; Hammer, G.D.; Husebye, E.S.; Merke, D.P.; Murad, M.H.; Stratakis, C.A.; et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2016, 101, 364–389. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Castinetti, F.; Borson-Chazot, F. Immunotherapy-induced endocrinopathies: Insights from the 2018 French Endocrine Society Guidelines. Bull. Cancer 2019, 106, 492–496. [Google Scholar] [CrossRef] [PubMed]
  47. Johannsson, G.; Nilsson, A.G.; Bergthorsdottir, R.; Burman, P.; Dahlqvist, P.; Ekman, B.; Engström, B.E.; Olsson, T.; Ragnarsson, O.; Ryberg, M.; et al. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: A prospective randomized trial of a novel hydrocortisone dual-release formulation. J. Clin. Endocrinol. Metab. 2012, 97, 473–481. [Google Scholar] [CrossRef] [Green Version]
  48. Arima, H.; Cheetham, T.; Christ-Crain, M.; Cooper, D.; Gurnell, M.; Drummond, J.B.; Levy, M.; McCormack, A.I.; Verbalis, J.; Newell-Price, J.; et al. Changing the name of diabetes insipidus: A position statement of The Working Group for Renaming Diabetes Insipidus. Endocr. J. 2022, 69, 1281–1284. [Google Scholar] [CrossRef]
  49. Di Dalmazi, G.; Ippolito, S.; Lupi, I.; Caturegli, P. Hypophysitis induced by immune checkpoint inhibitors: A 10-year assessment. Expert Rev. Endocrinol. Metab. 2019, 14, 381–398. [Google Scholar] [CrossRef]
  50. Bai, X.; Lin, X.; Zheng, K.; Chen, X.; Wu, X.; Huang, Y.; Zhuang, Y. Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: A disproportionality analysis using the WHO adverse drug reaction database, VigiBase. Endocrine 2020, 69, 670–681. [Google Scholar] [CrossRef]
  51. Zhai, Y.; Ye, X.; Hu, F.; Xu, J.; Guo, X.; Zhuang, Y.; He, J. Endocrine toxicity of immune checkpoint inhibitors: A real-world study leveraging US Food and Drug Administration adverse events reporting system. J. Immunother. Cancer 2019, 7, 286. [Google Scholar] [CrossRef] [Green Version]
  52. Brilli, L.; Calabrò, L.; Campanile, M.; Pilli, T.; Agostinis, C.; Cerase, A.; Maio, M.; Castagna, M.G. Permanent diabetes insipidus in a patient with mesothelioma treated with immunotherapy. Arch. Endocrinol. Metab. 2020, 64, 483–486. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Terán Brage, E.; Heras Benito, M.; Navalón Jiménez, M.B.; Vidal Tocino, R.; Del Barco Morillo, E.; Fonseca Sánchez, E. Severe Hyponatremia Masking Central Diabetes Insipidus in a Patient with a Lung Adenocarcinoma. Case Rep Oncol. 2022, 15, 91–98. [Google Scholar] [CrossRef] [PubMed]
  54. Grami, Z.; Manjappachar, N.; Reddy Dereddi, R. Diabetes Insipidus in Checkpoint Inhibitor Treatment and Acute Myeloid Leukemia. Crit. Care Med. 2020, 48, 144. [Google Scholar] [CrossRef]
  55. Dillard, T.; Yedinak, C.G.; Alumkal, J.; Fleseriu, M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: Serious immune related adverse events across a spectrum of cancer subtypes. Pituitary 2010, 13, 29–38. [Google Scholar] [CrossRef] [PubMed]
  56. Nallapaneni, N.N.; Mourya, R.; Bhatt, V.R.; Malhotra, S.; Ganti, A.K.; Tendulkar, K.K. Ipilimumab-induced hypophysitis and uveitis in a patient with metastatic melanoma and a history of ipilimumab-induced skin rash. J. Natl. Compr. Canc. Netw. 2014, 12, 1077–1081. [Google Scholar] [CrossRef] [PubMed]
  57. Gunawan, F.; George, E.; Roberts, A. Combination immune checkpoint inhibitor therapy nivolumab and ipilimumab associated with multiple endocrinopathies. Endocrinol. Diabetes Metab. Case Rep. 2018, 2018, 17-0146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Tshuma, N.; Glynn, N.; Evanson, J.; Powles, T.; Drake, W.M. Hypothalamitis and severe hypothalamic dysfunction associated with anti-programmed cell death ligand 1 antibody treatment. Eur. J. Cancer 2018, 104, 247–249. [Google Scholar] [CrossRef]
  59. Barnabei, A.; Carpano, S.; Chiefari, A.; Bianchini, M.; Lauretta, R.; Mormando, M.; Puliani, G.; Paoletti, G.; Appetecchia, M.; Torino, F. Case Report: Ipilimumab-Induced Panhypophysitis: An Infrequent Occurrence and Literature Review. Front. Oncol. 2020, 10, 582394. [Google Scholar] [CrossRef]
  60. Deligiorgi, M.V.; Siasos, G.; Vergadis, C.; Trafalis, D.T. Central diabetes insipidus related to anti-programmed cell-death 1 protein active immunotherapy. Int. Immunopharmacol. 2020, 83, 106427. [Google Scholar] [CrossRef]
  61. Yu, M.; Liu, L.; Shi, P.; Zhou, H.; Qian, S.; Chen, K. Anti-PD-1 treatment-induced immediate central diabetes insipidus: A case report. Immunotherapy 2021, 13, 1255–1260. [Google Scholar] [CrossRef]
  62. Fosci, M.; Pigliaru, F.; Salcuni, A.S.; Ghiani, M.; Cherchi, M.V.; Calia, M.A.; Loviselli, A.; Velluzzi, F. Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis. Endocrinol. Diabetes Metab. Case Rep. 2021, 2021, 20-0123. [Google Scholar] [CrossRef] [PubMed]
  63. Zhao, C.; Tella, S.H.; Del Rivero, J.; Kommalapati, A.; Ebenuwa, I.; Gulley, J.; Strauss, J.; Brownell, I. Anti-PD-L1 Treatment Induced Central Diabetes Insipidus. J. Clin. Endocrinol. Metab. 2018, 103, 365–369. [Google Scholar] [CrossRef] [PubMed]
  64. Angelousi, A.; Papalexis, P.; Karampela, A.; Marra, M.; Misthos, D.; Ziogas, D.; Gogas, H. Diabetes insipidus: A rare endocrine complication of immune check point inhibitors: A case report and literature review. Exp. Ther. Med. 2023, 25, 10. [Google Scholar] [CrossRef] [PubMed]
  65. Amereller, F.; Deutschbein, T.; Joshi, M.; Schopohl, J.; Schilbach, K.; Detomas, M.; Duffy, L.; Carroll, P.; Papa, S.; Störmann, S. Differences between immunotherapy-induced and primary hypophysitis-a multicenter retrospective study. Pituitary 2022, 25, 152–158. [Google Scholar] [CrossRef] [PubMed]
  66. Barnabei, A.; Corsello, A.; Paragliola, R.M.; Iannantuono, G.M.; Falzone, L.; Corsello, S.M.; Torino, F. Immune Checkpoint Inhibitors as a Threat to the Hypothalamus-Pituitary Axis: A Completed Puzzle. Cancers 2022, 14, 1057. [Google Scholar] [CrossRef]
  67. Caturegli, P.; Di Dalmazi, G.; Lombardi, M.; Grosso, F.; Larman, H.B.; Larman, T.; Taverna, G.; Cosottini, M.; Lupi, I. Hypophysitis Secondary to Cytotoxic T-Lymphocyte-Associated Protein 4 Blockade: Insights into Pathogenesis from an Autopsy Series. Am. J. Pathol. 2016, 186, 3225–3235. [Google Scholar] [CrossRef] [Green Version]
  68. Iervasi, E.; Strangio, A.; Saverino, D. Hypothalamic expression of PD-L1: Does it mediate hypothalamitis? Cell Mol. Immunol. China 2019, 16, 625–626. [Google Scholar] [CrossRef]
  69. Christ-Crain, M.; Bichet, D.G.; Fenske, W.K.; Goldman, M.B.; Rittig, S.; Verbalis, J.G.; Verkman, A.S. Diabetes insipidus. Nat. Rev. Dis. Prim. 2019, 5, 54. [Google Scholar] [CrossRef]
  70. Shoback, D. Clinical practice. Hypoparathyroidism. N. Engl. J. Med. 2008, 359, 391–403. [Google Scholar] [CrossRef]
  71. Dadu, R.; Rodgers, T.E.; Trinh, V.A.; Kemp, E.H.; Cubb, T.D.; Patel, S.; Simon, J.M.; Burton, E.M.; Tawbi, H. Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: Diagnosis and long-term follow-up. J. Immunother. Cancer 2020, 8, e000687. [Google Scholar] [CrossRef]
  72. El Kawkgi, O.M.; Li, D.; Kotwal, A.; Wermers, R.A. Hypoparathyroidism: An Uncommon Complication Associated With Immune Checkpoint Inhibitor Therapy. In Mayo Clinic Proceedings: Innovations, Quality & Outcomes; Mayo Foundation for Medical Education and Research; Elsevier Inc.: Amsterdam, The Netherlands, 2020; Volume 4, pp. 821–825. [Google Scholar]
  73. Win, M.A.; Thein, K.Z.; Qdaisat, A.; Yeung, S.J. Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. Am. J. Emerg. Med. 2017, 35, e1035–e1039. [Google Scholar] [CrossRef] [PubMed]
  74. Piranavan, P.; Li, Y.; Brown, E.; Kemp, E.H.; Trivedi, N. Immune Checkpoint Inhibitor-Induced Hypoparathyroidism Associated With Calcium-Sensing Receptor-Activating Autoantibodies. J. Clin. Endocrinol. Metab. 2019, 104, 550–556. [Google Scholar] [CrossRef] [Green Version]
  75. Trinh, B.; Sanchez, G.O.; Herzig, P.; Läubli, H. Inflammation-induced hypoparathyroidism triggered by combination immune checkpoint blockade for melanoma. J. Immunother. Cancer 2019, 7, 52. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Umeguchi, H.; Takenoshita, H.; Inoue, H.; Kurihara, Y.; Sakaguchi, C.; Yano, S.; Hasuzawa, N.; Sakamoto, S.; Sakamoto, R.; Ashida, K. Autoimmune-Related Primary Hypoparathyroidism Possibly Induced by the Administration of Pembrolizumab: A Case Report. J. Oncol. Pract. 2018, 14, 449–451. [Google Scholar] [CrossRef] [PubMed]
  77. Lupi, I.; Brancatella, A.; Cetani, F.; Latrofa, F.; Kemp, E.H.; Marcocci, C. Activating Antibodies to The Calcium-sensing Receptor in Immunotherapy-induced Hypoparathyroidism. J. Clin. Endocrinol. Metab. 2020, 105, 1581–1588. [Google Scholar] [CrossRef]
  78. Mahmood, I.; Kuhadiya, N.D.; Gonzalaes, M. Pembrolizumab-Associated Hypoparathyroidism: A Single Case Report. In AACE Clinical Case Reports; Elsevier Inc.: Amsterdam, The Netherlands, 2021; Volume 7, pp. 23–25. [Google Scholar]
  79. Horinouchi, H.; Yamamoto, N.; Fujiwara, Y.; Sekine, I.; Nokihara, H.; Kubota, K.; Kanda, S.; Yagishita, S.; Wakui, H.; Kitazono, S.; et al. Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer. Investig. New. Drugs 2015, 33, 881–889. [Google Scholar] [CrossRef] [Green Version]
  80. Pan, B.; Wang, A.; Pang, J.; Zhang, Y.; Cui, M.; Sun, J.; Liang, Z. Programmed death ligand 1 (PD-L1) expression in parathyroid tumors. Endocr. Connect. 2019, 8, 887–897. [Google Scholar] [CrossRef]
  81. Bollerslev, J.; Rejnmark, L.; Marcocci, C.; Shoback, D.M.; Sitges-Serra, A.; van Biesen, W.; Dekkers, O.M. European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults. Eur. J. Endocrinol. 2015, 173, G1–G20. [Google Scholar] [CrossRef] [Green Version]
  82. Husebye, E.S.; Perheentupa, J.; Rautemaa, R.; Kämpe, O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J. Intern. Med. 2009, 265, 514–529. [Google Scholar] [CrossRef]
  83. Husebye, E.S.; Anderson, M.S.; Kämpe, O. Autoimmune Polyendocrine Syndromes. N. Engl. J. Med. 2018, 378, 1132–1141. [Google Scholar] [CrossRef]
  84. Khan, A.A.; Koch, C.A.; Van Uum, S.; Baillargeon, J.P.; Bollerslev, J.; Brandi, M.L.; Marcocci, C.; Rejnmark, L.; Rizzoli, R.; Shrayyef, M.Z.; et al. Standards of care for hypoparathyroidism in adults: A Canadian and International Consensus. Eur. J. Endocrinol. 2019, 180, P1–P22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Betterle, C.; Garelli, S.; Presotto, F. Diagnosis and classification of autoimmune parathyroid disease. Autoimmun. Rev. 2014, 13, 417–422. [Google Scholar] [CrossRef] [PubMed]
  86. Fiorenza, C.G.; Chou, S.H.; Mantzoros, C.S. Lipodystrophy: Pathophysiology and advances in treatment. Nat. Rev. Endocrinol. 2011, 7, 137–150. [Google Scholar] [CrossRef] [PubMed]
  87. Haddad, N.; Vidal-Trecan, T.; Baroudjian, B.; Zagdanski, A.M.; Arangalage, D.; Battistella, M.; Gautier, J.F.; Lebbe, C.; Delyon, J.; PATIO group. Acquired generalized lipodystrophy under immune checkpoint inhibition. Br. J. Dermatol. 2020, 182, 477–480. [Google Scholar] [CrossRef]
  88. Bedrose, S.; Turin, C.G.; Lavis, V.R.; Kim, S.T.; Thosani, S.N. A case of acquired generalized lipodystrophy associated with pembrolizumab in a patient with metastatic malignant melanoma. AACE Clin. Case Rep. 2020, 6, e40–e45. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Gnanendran, S.S.; Miller, J.A.; Archer, C.A.; Jain, S.V.; Hwang, S.J.E.; Peters, G.; Miller, A. Acquired lipodystrophy associated with immune checkpoint inhibitors. Melanoma Res. 2020, 30, 599–602. [Google Scholar] [CrossRef]
  90. Drexler, K.; Zenderowski, V.; Berneburg, M.; Haferkamp, S. Facial lipodystrophy after immunotherapy with Nivolumab. J. Dtsch. Dermatol. Ges. 2021, 19, 1513–1515. [Google Scholar] [CrossRef]
  91. Jehl, A.; Cugnet-Anceau, C.; Vigouroux, C.; Legeay, A.L.; Dalle, S.; Harou, O.; Marchand, L.; Lascols, O.; Caussy, C.; Thivolet, C.; et al. Acquired Generalized Lipodystrophy: A New Cause of Anti-PD-1 Immune-Related Diabetes. Diabetes Care 2019, 42, 2008–2010. [Google Scholar] [CrossRef]
  92. Falcao, C.K.; Cabral, M.C.S.; Mota, J.M.; Arbache, S.T.; Costa-Riquetto, A.D.; Muniz, D.Q.B.; Cury-Martins, J.; Almeida, M.Q.; Kaczemorska, P.C.; Nery, M.; et al. Acquired Lipodystrophy Associated With Nivolumab in a Patient With Advanced Renal Cell Carcinoma. J. Clin. Endocrinol. Metab. 2019, 104, 3245–3248. [Google Scholar] [CrossRef]
  93. Eigentler, T.; Lomberg, D.; Machann, J.; Stefan, N. Lipodystrophic Nonalcoholic Fatty Liver Disease Induced by Immune Checkpoint Blockade. Ann. Intern. Med. USA 2020, 172, 836–837. [Google Scholar] [CrossRef]
  94. Brown, R.J.; Araujo-Vilar, D.; Cheung, P.T.; Dunger, D.; Garg, A.; Jack, M.; Mungai, L.; Oral, E.A.; Patni, N.; Rother, K.I.; et al. The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J. Clin. Endocrinol. Metab. 2016, 101, 4500–4511. [Google Scholar] [CrossRef] [PubMed]
  95. Zhang, W.; Gao, R.; Rong, X.; Zhu, S.; Cui, Y.; Liu, H.; Li, M. Immunoporosis: Role of immune system in the pathophysiology of different types of osteoporosis. Front. Endocrinol. 2022, 13, 965258. [Google Scholar] [CrossRef] [PubMed]
  96. Moseley, K.F.; Naidoo, J.; Bingham, C.O.; Carducci, M.A.; Forde, P.M.; Gibney, G.T.; Lipson, E.J.; Shah, A.A.; Sharfman, W.H.; Cappelli, L.C. Immune-related adverse events with immune checkpoint inhibitors affecting the skeleton: A seminal case series. J. Immunother. Cancer 2018, 6, 104. [Google Scholar] [CrossRef] [PubMed]
  97. Filippini, D.M.; Gatti, M.; Di Martino, V.; Cavalieri, S.; Fusaroli, M.; Ardizzoni, A.; Raschi, E.; Licitra, L. Bone fracture as a novel immune-related adverse event with immune checkpoint inhibitors: Case series and large-scale pharmacovigilance analysis. Int. J. Cancer 2021, 149, 675–683. [Google Scholar] [CrossRef] [PubMed]
  98. Pantano, F.; Tramontana, F.; Iuliani, M.; Leanza, G.; Simonetti, S.; Piccoli, A.; Paviglianiti, A.; Cortellini, A.; Spinelli, G.P.; Longo, U.G.; et al. Changes in bone turnover markers in patients without bone metastases receiving immune checkpoint inhibitors: An exploratory analysis. J. Bone Oncol. 2022, 37, 100459. [Google Scholar] [CrossRef]
  99. Yamazaki, N.; Kiyohara, Y.; Uhara, H.; Iizuka, H.; Uehara, J.; Otsuka, F.; Fujisawa, Y.; Takenouchi, T.; Isei, T.; Iwatsuki, K.; et al. Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma. Cancer Sci. 2017, 108, 1022–1031. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Weitzmann, M.N. The Role of Inflammatory Cytokines, the RANKL/OPG Axis, and the Immunoskeletal Interface in Physiological Bone Turnover and Osteoporosis. Scientifica 2013, 2013, 125705. [Google Scholar] [CrossRef] [Green Version]
  101. Kanis, J.A.; Cooper, C.; Rizzoli, R.; Reginster, J.Y. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2019, 30, 3–44. [Google Scholar] [CrossRef] [Green Version]
  102. Garutti, M.; Lambertini, M.; Puglisi, F. Checkpoint inhibitors, fertility, pregnancy, and sexual life: A systematic review. ESMO Open 2021, 6, 100276. [Google Scholar] [CrossRef]
  103. Brunet-Possenti, F.; Opsomer, M.A.; Gomez, L.; Ouzaid, I.; Descamps, V. Immune checkpoint inhibitors-related orchitis. Ann. Oncol. Engl. 2017, 28, 906–907. [Google Scholar] [CrossRef]
  104. Quach, H.T.; Robbins, C.J.; Balko, J.M.; Chiu, C.Y.; Miller, S.; Wilson, M.R.; Nelson, G.E.; Johnson, D.B. Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy. Oncologist 2019, 24, 872–876. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Rabinowitz, M.J.; Kohn, T.P.; Peña, V.N.; Samarska, I.V.; Matoso, A.; Herati, A.S. Onset of azoospermia in man treated with ipilimumab/nivolumab for BRAF negative metastatic melanoma. In Urology Case Reports; Elsevier Inc.: Amsterdam, The Netherlands, 2021; Volume 34, p. 101488. [Google Scholar]
  106. Salzmann, M.; Tosev, G.; Heck, M.; Schadendorf, D.; Maatouk, I.; Enk, A.H.; Hartmann, M.; Hassel, J.C. Male fertility during and after immune checkpoint inhibitor therapy: A cross-sectional pilot study. Eur. J. Cancer 2021, 152, 41–48. [Google Scholar] [CrossRef]
  107. Scovell, J.M.; Benz, K.; Samarska, I.; Kohn, T.P.; Hooper, J.E.; Matoso, A.; Herati, A.S. Association of Impaired Spermatogenesis With the Use of Immune Checkpoint Inhibitors in Patients With Metastatic Melanoma. JAMA Oncol. 2020, 6, 1297–1299. [Google Scholar] [CrossRef] [PubMed]
  108. Kim, A.E.; Nelson, A.; Stimpert, K.; Flyckt, R.L.; Thirumavalavan, N.; Baker, K.C.; Weinmann, S.C.; Hoimes, C.J. Minding the Bathwater: Fertility and Reproductive Toxicity in the Age of Immuno-Oncology. JCO Oncol. Pract. 2022, 18, 815–822. [Google Scholar] [CrossRef] [PubMed]
  109. Lupu, J.; Pages, C.; Laly, P.; Delyon, J.; Laloi, M.; Petit, A.; Basset-Seguin, N.; Oueslati, I.; Zagdanski, A.M.; Young, J.; et al. Transient pituitary ACTH-dependent Cushing syndrome caused by an immune checkpoint inhibitor combination. Melanoma Res. 2017, 27, 649–652. [Google Scholar] [CrossRef]
  110. Shalit, A.; Sarantis, P.; Koustas, E.; Trifylli, E.M.; Matthaios, D.; Karamouzis, M.V. Predictive Biomarkers for Immune-Related Endocrinopathies following Immune Checkpoint Inhibitors Treatment. Cancers 2023, 15, 375. [Google Scholar] [CrossRef]
Figure 1. Flow diagram of the literature search strategy, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines.
Figure 1. Flow diagram of the literature search strategy, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines.
Cancers 15 02016 g001
Table 1. Cases in the literature presenting ICI-related primary adrenal insufficiency (PAI).
Table 1. Cases in the literature presenting ICI-related primary adrenal insufficiency (PAI).
ReferenceType of Study, (n)Age (y)Sex (M, Male and F, Female)MalignancyDrug ICI CategoryPrevious Therapies Laboratory EvaluationAdrenal Imaging Findings after ICI Initiation (Method)Grade of AEOnset after ICI Initiation (Days)Outcome of AEFollow-Up
(Days)
Abdallah et al., 2020 [20]Case report
(n = 1)
70FPancreatic adenocarcinomaNivolumabPD-1 AbNDNormal sodium and potassium levels, low F and increased ACTH levels, 21-OH Abs (-)Normal (ND)IVAfter 3rd doseND90
Agrawal et al., 2019 [15]Case report
(n = 1)
59MSCLCIpilimumab + NivolumabCTLA-4+PD-1 AbLung radiotherapy and chemotherapyLow F and increased ACTH levelsNDII120NDND
Akarca et al., 2017 [14]Case report
(n = 1)
52MNSCLCNivolumabPD-1 AbNDHyponatremia and hyperkalemia, low F and increased ACTH levelsNormal (ND)IV14NDND
Bacanovic et al., 2015 [30]Case report
(n = 1)
79NDNDIpilimumabCTLA-4 AbNDNDSymmetrically and smoothly enlarged, hypermetabolic (FDG-PET/CT)NDNDNDND
Bischoff et al., 2022 [23]Case report
(n = 1)
53FMelanomaPembrolizumaPD-1 AbSurgeryHyponatremia, hyperkalemia, low F and increased ACTH levels, ACA (+), 21-OH Abs (+)Normal
(FDG-PET/CT)
III-IV168NDND
Coskun et al., 2016 [32]Case report
(n = 1)
50MLung adenocarcinomaNivolumabPD-1 AbNDHyponatremia, hyperkalemia, low F and increased ACTH levelsNormal (Ultrasound)III10NDND
Dasgupta et al., 2022 [28]Case report-APS-2 (n = 1)14FHepatocellular carcinomaNivolumabPD-1 AbChemotherapy Normal morning F and ACTH levels, 21-OH Abs (+) aNDINDNDND
Deligiorgi et al., 2020 [26]Case report
(n = 1)
42MRectal adenocarcinomaNivolumabPD-1 AbSurgery and chemotherapy Hyponatremia, low F and increased ACTH levels, low PAC levels, 21-OH Abs (+)Normal
(CT)
III–IV112Recovery after 12 weeks 630
Figuerora-Perez et al., 2021 [29]Case report
(n = 1)
73MRenal cell carcinomaPembrolizumabPD-1 AbSurgery and axitinibLow F and increased ACTH levels, low PAC levels, high PRA,
21-OH Abs (-)
NDIINDNDND
Gaballa et al., 2020 [34]Case report
(n = 1)
76MMelanomaIpilimumabCTLA-4 AbNoneHyponatremia with normal potassium, low F and elevated ACTH levels, PAC levels undetectable, increased PRA levels Normal
(CT)
IIIAfter
4 cycles
Recovery16 cycles
of nivolumab
Galliazzo et al., 2022 [38]Case report
(n = 1)
74MNSCLCNivolumabPD-1 AbNDHyponatremia, low F and increased ACTH levels, low PAC levels,
21-OHAbs (-)
Normal (CT)NDNDNDND
Gunjur et al., 2019 [16]Case report- APS-2
(n = 1)
78FMelanomaPembrolizumab PD-1 AbNoneHyponatremia with normal potassium, Pathological cosyntropin stimulation test (Synacthen),
HLA-DRB1*04
genotype
(DR4 serotype)
Normal
(FDG-PET/CT)
III–IV63Persistence365
Hanna et al., 2018 [37]Case report
(n = 1)
70MLung adenocarcinomaPembrolizumabPD-1 AbNonePathological cosyntropin stimulation test (Synacthen)NDIII–IVNDNDND
Harsch et al., 2020 [21]Case report
(n = 1)
62FMelanomaPembrolizumabPD-1 AbNoneHyponatremia with normal potassium, low F and increased ACTH levelsInconspicuous adrenal glands
(CT)
III–IV365NDND
Hescot et al., 2018 [39]Case report
(n = 1)
33FCervical squamous cell cancerPembrolizumabPD-1 AbNDHyponatremia with normal potassium, low F and increased ACTH levels, 21-OH Abs (+)Adrenal hypoplasia
(CT)
III–IV147Recurrence365
Hobbs et al., 2020 [33]Case report
(n = 1)
58MNDIpilimumab + NivolumabCTLA-4 Ab+
PD-1 Ab
NDHyponatremia with hyperkalemia, low F and increased ACTH levelsNDIIIAfter
4 cycles
NDND
Iqbal et al., 2019 [18]Case report
(n = 1)
65FNCSLCNivolumabPD-1 AbNDHyponatremia with hyperkalemia, low F and increased ACTH levels, low PAC levels with increased PRANormal (CT)IIINDPersistenceND
Kagoshima et al., 2019 [19]Case report
(n = 1)
57FTongue squamous cell carcinomaNivolumabPD-1 AbSurgery, radiotherapy and chemotherapy Low F and normal ACTH levels, CRH test in favor of PAINDIINDNDND
Knight et al., 2021 [31]Prospective study
(n = 1)
59MRenal cell carcinomaIpilimumab + NivolumabCTLA-4 Ab+ PD-1 AbNDHyponatremia, low F and increased ACTH levelsNDIII–IVNDNDND
Kojadinovic et al., 2021 [36]Case report
(n = 1)
64ΜColorectal cancerPembrolizumab (9 cycles), pembrolizumab+ IpilimumabPD-1 Ab
+CTLA-4 Ab
Surgery and multiple cycles of chemotherapyHyponatremia and low F levels, pathological cosyntropin stimulation test (Synacthen)NDII14 after initiation of dual therapy Persistence 567
Lanzolla et al., 2019 [17]Case report- APS-2
(n = 1)
50MLung adenocarcinomaAtezolizumabPD-L1 AbChemotherapy Hyponatremia with normal potassium, low F and increased ACTH levels, low PAC levels with increased PRA, 21-OH Abs (+),
HLA typing: DRB1*04 and DQB1*03 haplotypes
Normal (CT)III84NDND
Min et al., 2013 [25]Case report- mixed AI (PAI + SAI)
(n = 1)
56FMelanomaIpilimumabCTLA-4 AbNDLow F and increased ACTH levelsReversible bilateral
enlargement
(CT)
IIAfter
4 doses
NDND
Ozyurt et al., 2021 [22]Case report
(n = 1)
66MRenal cell carcinomaNivolumabPD-1 AbSunitinibHyponatremia with hyperkalemia, low F and increased ACTH levels, (under steroids)NDII21Persistence 60
Paepegaey et al., 2017 [13]Case report-APS-2 (n = 1)55FMelanomaPembrolizumabPD-1 AbSurgery, chemotherapy and sorafenibHyponatremia with hyperkalemia, low F and increased ACTH levels, PAC undetectable with increased PRA levels, ACA (+),
21-OH Abs (+)
Atrophied adrenal glands
(CT)
IV258NDND
Salinas et al., 2020 [27]Case series
(n = 3)
60,
65,
76
M(all)Renal cell carcinoma(all)Ipilimumab + nivolumab
(n = 1)
Nivolumab (n = 2)
-CTLA-4 Ab+
PD-1 Ab
-PD-1 Ab (n = 2)
Cabozantinib (n = 1), none (n = 2)Hyponatremia and pathological cosyntropin stimulation test (Synacthen) (n = 2)
Pathological cosyntropin stimulation test (Synacthen) (n = 1)
Normal (n = 3)
(CT)
IV
IV
III
140
183
150
NDND
Shariff et al., 2018 [35]Case report
(n = 1)
49MMelanomaIpilimumab + nivolumabCTLA-4 Ab+ PD-1 AbChemotherapyHyponatremia with hypokalemia, low F levels and increased ACTH levels, low PAC with increased PRA levels, 21-OH Abs (-)Normal (ND)III74Persistence420
Trainer et al., 2016 [24]Case study
(n = 1)
43FMelanomaNivolumab PD-1 AbSurgeryHyponatremia, low F and increased ACTH levels, low PAC with increased PRA levelsSymmetrically
and smoothly enlarged, increased
FDG activity in both adrenal glands (FDG-PET/CT)
III56Persistence365
Abbreviations: ICI, immune checkpoint inhibitors; ND, no data; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; AE, adverse effect; NSCLC, non-small cell lung cancer; F, morning cortisol level; ACTH, adrenocorticotropic hormone, ACA: adrenal cortex antibody; 21-OH Abs: 21-hydroxylase antibodies; CRH: corticotropin-releasing hormone; PAC: plasma aldosterone concentration; PRA, plasma renin activity. a A case of developing overt PAI.
Table 2. Cases in the literature presenting with ICI-induced central diabetes insipidus (CDI).
Table 2. Cases in the literature presenting with ICI-induced central diabetes insipidus (CDI).
ReferenceType
of Study, (n)
Age
(y)
Sex (M, Male and F, Female)MalignancyDrugICI CategoryPrevious TherapiesDysfunction
of Pituitary
Dysfunction of Hypothalamus Onset after Initiation of
ICI (Days)
Outcome of AELaboratory EvaluationMRI FindingsGrade of AEFollow-Up
(Days)
Amereller et al., 2021 [65]Retrospective study (n = 2)NDM (n = 1),
F (n = 1)
NDIpilimumabCTLA-4 AbNDNDNDNDNDSerum and urine osmolarity, serum Na, water deprivation test (+)NDNDND
Angelousi et al., 2022 [64]Case report
(n = 1)
53FMelanomaNivolumabPD-1 AbMultiple surgeriesPanhypopituitarismND240PersistedLow urine osmolality, increased plasma osmolality, water deprivation test (+), low baseline copeptin levelsAbsent bright spotII180
Barnabei et al., 2020 [59]Case report
(n = 1)
64MMelanomaIpilimumabCTLA-4 AbOcular proton beam radiotherapyPanhypopituitarismNo60Transient (5 days)Low urine osmolality, increased plasma osmolality, normal serum Na Absent bright spot I1230
Brage et al., 2022 [53]Case report
(n = 1)
46MAdenocarcinoma of the lungNivolumab PD-1 AbWhole brain radiotherapy,
erlotinib
osimertinib and chemotherapy
PanhypopituitarismNo62NDLow urine osmolarity, water deprivation test (+)NDI0
Brilli et al., 2020 [52]Case report
(n = 1)
68MMesotheliomaTremelimumab and durvalumab CTLA-4 Ab + PD-L1 AbNoneIsolated posterior pituitaryNo60PersistedNormal levels of serum sodium,
plasma osmolality and urinary specific gravity
test, water deprivation test (+)
NormalND570
Deligiorgi et al., 2020 [60]Case report
(n = 1)
71MAdenocarcinoma of the lung Nivolumab PD-1 AbSurgery and chemotherapyIsolated posterior pituitaryNo90NDHypernatremia, high plasma
osmolarity and hyposthenuria, undetectable
serum
AVP
NormalIVND a
Dillard et al., 2009 [55]Case report
(n = 1)
50M Adenocarcinoma of prostateIpilimumabCTLA-4 AbNDPanhypopituitarismNo84Transient (3 weeks)NDNormalIIIND
Fosci et al., 2021 [62]Case report
(n = 1)
62MHypopharynx cancer NivolumabPD-1 Ab Surgery and chemotherapy PanhypopituitarismNo3550 days bLow urine osmolarity,
high plasma osmolality, response to desmopressin
Enlarged stalk I50 b
Grami et al., 2019 [54]Case report
(n = 1)
30MAcute myeloid leukemiaIpilimumab + nivolumabCTLA-4 Ab + PD-1 AbChemotherapy and allogenic stem cell transplantPanhypopituitarismNoNDNDLow urine osmolarity, high serum Na, response to desmopressinNDIIIND
Gunawan et al., 2018 [57]Case report
(n = 1)
52MMelanomaIpilimumab+
nivolumab
CTLA-4Ab + PD-1 AbSmall bowel resectionIsolated posterior pituitaryNo28NDHigh serum Na, response to desmopressinNDIND
Nallapanemi et al., 2014 [56]Case report
(n = 1)
62MMelanomaIpilimumabCTLA-4 AbVemurafenib+IL-2PanhypopituitarismNo1215moWater deprivation test (+)NDII180
Tshuma et al., 2018 [58]Case report
(n = 1)
74FBladder cancer AtezolizumabPD-L1 AbSurgery + neoadjuvant chemotherapy PanhypopituitarismYes270ΝDHigh serum Na, low urinary NaHypothalamic massI365
Yu et al., 2021 [61]Case report
(n = 1)
60MHodgkin lymphomaSintilimab PD-1AbChemotherapyIsolated posterior pituitaryNoImmediateTransient (3 months)High serum osmolality, high serum Na, low urine-specific gravity, response to desmopressinNodular signalII90
Zhao et al., 2017 [63]Case report
(n = 1)
73MMerkel cell carcinomaAvelumabPD-L1 AbNoneIsolated posterior pituitaryNo112Transients (6 weeks)High serum os-
molarity, low urine
osmolarity, low urine specific gravity, high serum Na, response to desmopressin
Normal I240
Abbreviations: ICI, immune checkpoint inhibitors; MRI, magnetic resonance imaging; AE, adverse events; ND, no data; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; IL-2, interleukin-2; Na, sodium levels; AVP, arginine vasopressin. a The patient deceased before initiation of treatment with desmopressin. b The patient deceased 50 days after desmopressin initiation.
Table 3. Cases in the literature presenting with ICI-induced hypoparathyroidism.
Table 3. Cases in the literature presenting with ICI-induced hypoparathyroidism.
ReferenceType of StudyAge
(y)
Sex (M, Male and F, Female)MalignancyDrugICI CategoryPrevious TherapiesLaboratory EvaluationGrade of AEOnset after Initiation of
ICI (Days)
Outcome
of
AE
Follow-Up (Days)
Dadu et al., 2020 [71]Case report
(n = 1)
73MMelanomaIpilimumab + nivolumab CTLA-4Ab + PD-1 AbNoneLow Ca, P and Mg levels, undetectable PTH levels, low 25-OHD3
CaSR-Abs (+), NALP5 Abs (-),
Cytokine Abs (-)
IV28Persisted1185
Horinouchi et al., 2015 [79]Phase I study
(n = 1)
NDNDNSCLCIpilimumabCTLA-4 AbChemotherapy NDI/IIND NDND
Kawkgi et al., 2020 [72]Case report
(n = 1)
76MMelanomaIpilimumab + nivolumabCTLA-4Ab + PD-1 AbNDLow Ca, P and Mg levels, undetectable PTH levels, normal 25-OHD3 levels, anti-PTH Abs (-)III220(combination therapy),
160 (nivolumab monotherapy)
Persisted77
Lupi et al., 2020 [77]Case report
(n = 1)
53MLung adenocarcinomaPembrolizumabPD-1 AbNDLow Ca, normal P and Mg levels, inappropriate normal PTH levels, low25-OHD3
CaSR Abs (+)
IV510 Persisted270
Mahmood et al., 2020 [78]Case report
(n = 1)
71MLung adenocarcinomaPembrolizumabPD-1 AbSurgery and lung radiotherapyLow Ca and PTH levels II45Persisted210
Piranavan et al., 2018 [74]Case report
(n = 1)
61FSCLCNivolumabPD-1 AbChemotherapy and radiotherapy Low Ca, P and Mg levels, low PTH levels, normal 25-OHD3 levels,
CaSR Abs (+),
NALP5 Abs (-), Cytokine Abs (-)
IV120 NDND
Trinh et al., 2019 [75]Case report
(n = 1)
53NDMelanomaIpilimumab + nivolumabCTLA-4Ab + PD-1 AbNDLow Ca and Mg levels, normal P, normal 25-OHD3 levels, low PTH levels, CaSR Abs insignificant titersIV28 Persisted14
Umeguchi et al., 2018 [76]Case report
(n = 1)
64MNSCLCPembrolizumab PD-1 AbChemotherapy and lung radiotherapyLow Ca levels, increased P levels, normal 1,25-(OH)2 D3, low PTH levels,
CaSR Abs (+)
III42PersistedND
Win et al., 2017 [73]Case report
(n = 1)
73MMelanomaIpilimumab +
nivolumab
CTLA-4Ab
+PD-1 Ab
Local excisionLow Ca and Mg levels, low 25-OHD3 levels, low
PTH levels
IV45Persisted120
Abbreviations: ICI, immune checkpoint inhibitors; ND, no data; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; Ab, antibody; AE, adverse effect; (N)SCLC, (non-)small-cell lung cancer; Ca, corrected calcium level; Mg, magnesium level; PTH, parathormone level; P, phosphate level; 25-OHD3, 25-hydroxy-cholecalciferol; 1,25-(OH)2 D3, 1,25-dihydroxycholecalciferol; CaSR Abs, Ca-sensing receptor-activating autoantibodies; NALP5 Abs, NACHT leucine-rich-repeat protein 5 antibodies.
Table 4. Cases in the literature presenting ICI-related acquired lipodystrophy.
Table 4. Cases in the literature presenting ICI-related acquired lipodystrophy.
ReferenceType of Study, (n)Age(y)Sex (M, Male and F, Female)MalignancyDrugICI Category Previous TherapiesType of
Lipodystrophy
Laboratory EvaluationOnset
after Initiation of ICI (Days)
Grade of AETreatment of AEOutcome of AE
Bedrose et al., 2020 [88]Case report
(n = 1)
67MMelanomaPembrolizumabPD-1 AbNoneGeneralizedHyperglycemia and hypertriglyceridemia, normal values of liver enzymes, low leptin and adiponectin levels 42IIInsulin + pioglitazone,
Statin + fibrate+ omega-3 fatty acids
ND
Drexler et al., 2021 [90]Case report
(n = 1)
41FMelanomaNivolumabPD-1 AbInguinal lymph node dissection and local excisionFacialNormal values of cholesterol, triglycerides, HbA1C474IISteroidsPersistence
Eigentler et al., 2019 [93]Case report
(n = 1)
45FMelanomaNivolumab PD-1 AbLocal excision and IFN-a GeneralizedHyperglycemia, hypertriglyceridemia, increased liver enzymes 360IISteroids,
insulin and then,
overlapping courses of empagliflozin,
liraglutide
and pioglitazone
Improvement in metabolic abnormalities
Gnanendran et al., 2020 [89]Case report
(n = 1)
34FMelanomaNivolumabPD-1 AbLocal excisionGeneralizedNormal values of glucose, HbA1C, LDL
high leptin levels
270IISteroidsPersistence
Haddad et al., 2019 [87]Case report
(n = 1)
47FMelanomaPembrolizumab PD-1 AbNoneGeneralizedPrediabetes, low leptin and adiponectin levels, hypertriglyceridemia60IIITreatment
for
metabolic abnormalities
Persistence
Jehl et al., 2019 [91]Case report
(n = 1)
62FMelanomaNivolumabPD-1 AbLocal excision GeneralizedDM, hypertriglyceridemia,
increased liver enzymes, low leptin and adiponectin levels
540IIIInsulin + metfrominImprovement in metabolic abnormalities
Kruschewsky Falcao et al., 2019 [92]Case report
(n = 1)
57FRenal cell carcinomaNivolumabPD-1 AbLocal excision and sunitinib, pazobanib GeneralizedDM, hypertriglyceridemia, high LDL, low leptin levels 60IISteroidsImprovement in metabolic abnormalities
Abbreviations: ICI, immune checkpoint inhibitors; ND, no data; PD-1, programmed cell death protein 1; Ab, antibody; AE, adverse effect; IFN-a, interferon-a; DM, diabetes mellitus; LDL, low density lipoprotein; HbA1C, hemoglobin A1C.
Table 5. Cases in the literature presenting ICI-related skeletal events.
Table 5. Cases in the literature presenting ICI-related skeletal events.
ReferenceType of StudyAge (y)Sex (M, Male and F, Female)MalignancyDrug/ICI CategoryPrevious TherapiesSkeletal AELaboratory EvaluationGrade of AEOnset after ICI Initiation
Filippini et al., 2021 [97]Case series
(n = 4)
67.8 (mean age)M (n = 1),
F (n = 3)
Squamous cell carcinoma (n = 4)Anti-PD-1 Ab (n = 2)
Anti-PD-L1 Ab (n = 2)
NDDorsal vertebral (D12) fracture
Calcaneal fracture
Lumbar vertebral (L1) fracture
Multiple vertebral (D7-L5) fractures
NDIIFrom 2.5 to 15.5 months
Moseley et al., 2018 [96]Case series
(n = 6)
59.3 (mean age)M (n = 5),
F (n = 1)
Melanoma (n = 4), RCC (n = 1), lung adenocarcinoma (n = 1)Pembrolizumab/PD-1 Ab (n = 2), Nivolumab/PD-1 Ab (n = 2), Nivolumab + ipilimumab/PD-1 Ab
+ CTLA-4 Ab (n = 2)
Wide local excision
+ axillary lymph node dissection + GM-CSF
secreting allogeneic melanoma cell vaccine (n = 1)
wide local excision + IFN-a+IL-2 (n = 1),
none (n = 4)
1st patient: compression vertebral fractures (T6, T7, T10, T11, and T12); rib and pelvic fractures
2nd patient: compression vertebral fractures (T6–12, L1)
3rd patient: compression vertebral fracture (T11); lumbar osteomalacia
4th patient: Resorptive bone lesion of left shoulder
5th patient: Resorptive bone lesion of right wrist
6th patient: Resorptive bone lesion of right clavicle
Elevated or high normal CTX and/or bsALP levels (n = 5),
Elevated CRP and/or ESR (n = 6)
II1st patient: After 20 doses of pembrolizumab therapy
2nd patient: 8 cycles of nivolumab and IL-21
3rd patient: 10 months
4th patient: 8 months
5th patient: 18 months
6th patient: ND
Pantano et al., 2022 [98]Case series
(n = 4)
NDNDNDNDNDLumbar fractures Relatively increased CTX-1 levels 1
Relatively decreased PINP levels 1
IIND
Abbreviations: ICI, immune checkpoint inhibitors; RCC, renal cell cancer; NSCLC, non-small cell lung cancer; AE, adverse effects; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-a, interferon a; IL-2, interleukin-2; CTX, C-telopeptides; bsALP, bone-specific alkaline phosphatase; 25OHD, 25-hydroxy vitamin D; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; ND, no data,;CTX-1, collagen C-terminal telopeptide; PINP, N-terminal propeptide of type I procollagen. 1 Mean levels of all (44) patients studied after 3-month ICI use. CTX-1 levels significantly increased, while PINP levels decreased compared to baseline levels (before ICI initiation).
Table 6. Cases in the literature presenting ICI-induced primary (hypergonadotropic) hypogonadism.
Table 6. Cases in the literature presenting ICI-induced primary (hypergonadotropic) hypogonadism.
ReferenceType of Study, (n)Age
(y)
Sex (M, Male and F, Female)MalignancyDrugICI CategoryPrevious TherapiesClinical Presentation Laboratory EvaluationTesticular BiopsyOnset after Initiation of ICI (Days)Duration of AE (Days)Follow
up (Days)
Brunet-Possenti et al., 2016 [103]Case report
(n = 1)
54MMelanomaIpilimumab + nivolumabCTLA-4 Ab+
PD-1 Ab
NDBilateral orchitisLow testosterone with high LH levelsND147 28
Quach et al., 2019 [104]Case report
(n = 1)
69MMelanomaPembrolizumabPD-1 AbPartial hepatectomy and RFA of liver lesions.Bilateral epididymo-orchitisNDND603580
Rabinowitz et al., 2021 [105] Case report
(n = 1)
30MMelanomaIpilimumab + nivolumab CTLA-4 Ab+
PD-1 Ab
NoneInfertilitySpermogram: Azoospermia,
Hormone profile: Low testosterone levels with high FSH and normal LH levels
Sertoli-only pathology730 (time of evaluation)Persisted180
Salzamann et al., 2021 [106]Cross-sectional pilot study
(n = 4)
44,
51,
30,
36
MNDIpilimumab + nivolumab (n = 2),
Pembrolizumab(n = 1),
PD-L1 Ab (n = 1)
CTLA-4 Ab+
PD-1 Ab (n = 2),
PD-1 Ab (n = 1),
PD-L1 Ab (n = 1)
RT to inguinal lymph nodes (n = 1), Chemotherapy (4 years before) (n = 1),
ND (n = 2)
NoneSpermogram: Azoospermia (n = 3), Oligoasthenoteratozoospermia (n = 1)
Hormone profile: normal (n = 2), high FSH levels (n = 2)
No signs of inflammation (n = 2),
Inflammation infiltrate (n = 2)
>120NDND
Scovell et al., 2020 [107]Cohort study
(n = 6)
NDMMelanomaIpilimumab/nivolumab/pembrolizumabCTLA-4 Ab/
PD-1 Ab
NoneNDNDSertoli-only syndrome (n = 3),
focal active spermatogenesis (n = 1), hypospermatogenesis (n = 2)
NDNDND
Abbreviations: ICI, immune-check point inhibitors; ND, no data; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1:,programmed cell death protein 1; PDL1, programmed cell death ligand 1; RFA, radiofrequency ablation; RT, radiotherapy; Ab, antibody; AE, adverse effect; Testo, testosterone level; LH, luteinizing hormone level; FSH, follicle stimulating hormone level; E2, estradiol level; UNL, upper normal limit
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Mytareli, C.; Ziogas, D.C.; Karampela, A.; Papalexis, P.; Siampanopoulou, V.; Lafioniatis, A.; Benopoulou, O.; Gogas, H.; Angelousi, A. The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events. Cancers 2023, 15, 2016. https://doi.org/10.3390/cancers15072016

AMA Style

Mytareli C, Ziogas DC, Karampela A, Papalexis P, Siampanopoulou V, Lafioniatis A, Benopoulou O, Gogas H, Angelousi A. The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events. Cancers. 2023; 15(7):2016. https://doi.org/10.3390/cancers15072016

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Mytareli, Chrysoula, Dimitrios C. Ziogas, Athina Karampela, Petros Papalexis, Vasiliki Siampanopoulou, Alexandros Lafioniatis, Olga Benopoulou, Helen Gogas, and Anna Angelousi. 2023. "The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events" Cancers 15, no. 7: 2016. https://doi.org/10.3390/cancers15072016

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