Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management

Shi, Yun; Shen, Min; Zheng, Xuqin; Yang, Tao

doi:10.1016/j.eprac.2020.09.016

Cited by 13 publications

(8 citation statements)

References 17 publications

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“…Primary adrenal insufficiency is a rare complication of ICIs, and to date only few cases have been presented in the literature, making an estimate of incidence very difficult (4,96). A recent survey of the WHO VigiBase indicated that out of 50 000 ICI-associated adverse events reported since 2008, there were 451 cases of primary adrenal insufficiency of which 46 were considered definitive (97).…”

Section: Adrenalsmentioning

confidence: 99%

Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline

Husebye

Castinetti

Criseno

et al. 2022

European Journal of Endocrinology

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Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment, but are associated with significant autoimmune endocrinopathies that pose both diagnostic and treatment challenges. The aim of this guideline is to provide clinicians with the best possible evidence-based recommendations for treatment and follow-up of patients with ICI-induced endocrine side effects based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. As these drugs have been used a relatively short time, large systematic investigations are scarce. A systematic approach to diagnosis, treatment and follow-up is needed, including baseline tests of endocrine function before each treatment cycle. We conclude that there is no clear evidence for the benefit of high-dose glucocorticoids to treat endocrine toxicities with the possible exceptions of severe thyroid eye disease and hypophysitis affecting the visual apparatus. With the exception of thyroiditis, most endocrine dysfunctions appear to be permanent regardless of ICI discontinuation. Thus, the development of endocrinopathies does not dictate a need to stop ICI treatment.

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Section: Adrenalsmentioning

confidence: 99%

Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline

Husebye

Castinetti

Criseno

et al. 2022

European Journal of Endocrinology

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“…Primary adrenal insufficiency may be diagnosed on routine bloods showing reduced cortisol with appropriate elevation of pituitary-derived ACTH, but may present clinically with fatigue, orthostatic hypotension, or adrenal crisis ( 112 ). After acute management, long-term corticosteroid (with or without mineralocorticoid) replacement is usually required ( 113 ).…”

Section: Endocrine Iraes: Prevalence and Significancementioning

confidence: 99%

Insights Into the Host Contribution of Endocrine Associated Immune-Related Adverse Events to Immune Checkpoint Inhibition Therapy

et al. 2022

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Blockade of immune checkpoints transformed the paradigm of systemic cancer therapy, enabling substitution of a cytotoxic chemotherapy backbone to one of immunostimulation in many settings. Invigorating host immune cells against tumor neo-antigens, however, can induce severe autoimmune toxicity which in many cases requires ongoing management. Many immune-related adverse events (irAEs) are clinically and pathologically indistinguishable from inborn errors of immunity arising from genetic polymorphisms of immune checkpoint genes, suggesting a possible shared driver for both conditions. Many endocrine irAEs, for example, have analogous primary genetic conditions with varied penetrance and severity despite consistent genetic change. This is akin to onset of irAEs in response to immune checkpoint inhibitors (ICIs), which vary in timing, severity and nature despite a consistent drug target. Host contribution to ICI response and irAEs, particularly those of endocrine origin, such as thyroiditis, hypophysitis, adrenalitis and diabetes mellitus, remains poorly defined. Improved understanding of host factors contributing to ICI outcomes is essential for tailoring care to an individual’s unique genetic predisposition to response and toxicity, and are discussed in detail in this review.

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“…Additionally, in a recent systematic review of the literature on cases diagnosed with PAI induced by ICI, Shi et al [45] reported that 60% of the 15 patients included in the review showed other endocrine toxicities such as thyroid dysfunction in 66.7% of cases, T1DM in 44.4% and hypophysitis in 33.3%, with two patients who developed three concomitant endocrinopathies and one patient four endocrinopathies.…”

Section: Tki-induced Adrenal Insufficiencymentioning

confidence: 99%

“…Malaise, fatigue, nausea, light-headedness, loss of appetite, and weight loss are the most common symptoms of ICI-induced SAI's clinical presentation, similar to that of secondary hypocortisolism. Nevertheless, secondary hypocortisolism is more frequently associated with hypotension and adrenal crisis due to the combination of severe glucocorticoid and mineralocorticoid deficiency [45][46][47][48]. Decreased morning cortisol levels and elevated ACTH levels are usually detected at laboratory testing.…”

Section: Tki-induced Adrenal Insufficiencymentioning

confidence: 99%

Endocrine Toxicities of Antineoplastic Therapy: The Adrenal Topic

Barnabei

Senes

Scoppola

et al. 2022

Cancers

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Immune checkpoint inhibitors (ICIs) have improved survival in patients affected by several solid tumours at the cost of new autoimmune adverse events. Endocrine toxicity is frequently reported in patients treated with these agents, mainly as thyroid dysfunction and hypophysitis. Primary adrenal insufficiency is reported in 1–2% of patients receiving a single ICI, but its rate is approximately 5% in patients treated with a combination of two ICIs. The clinical presentation of adrenal insufficiency may be insidious due to symptoms that are not specific. The same symptoms in cancer patients are frequently multifactorial, rendering the early diagnosis of adrenal insufficiency challenging in this group of patients. As adrenal insufficiency can be fatal if not rapidly diagnosed and treated, oncologists should be aware of its clinical presentations to timely involve endocrinologists to offer patients the appropriate management. In parallel, it is essential to educate patients, their caregivers, and relatives, providing them with detailed information about the risk of adrenal insufficiency and how to manage alarming symptoms at their onset. Finally, large collaborative trials are needed to develop appropriate tests to assess better the personal risk of drug-induced adrenal insufficiency and its early diagnosis and treatment, not only in cancer patients.

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Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management

Cited by 13 publications

References 17 publications

Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline

Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline

Insights Into the Host Contribution of Endocrine Associated Immune-Related Adverse Events to Immune Checkpoint Inhibition Therapy

Endocrine Toxicities of Antineoplastic Therapy: The Adrenal Topic

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