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Immune checkpoint inhibitor (ICI) therapy is rapidly evolving as an effective treatment option for many cancers. This class of immuno-oncology has revolutionized treatment and improved progression-free and overall survival, particularly for patients with advanced melanoma (Larkin et al., 2019). ICIs target specific T-cell inhibition mechanisms of cancer cells, releasing the T cells from inhibition and allowing their attack on cancer cells (Barroso-Sousa et al., 2018). Checkpoint inhibition mechanisms are also responsible for physiologic immune self-tolerance and homeostasis (Chang et al., 2019); the release of inhibition may result in a spectrum of autoimmune-like toxicities classified as immune-related adverse events (irAEs) (Barroso-Sousa et al., 2018; Wood, 2019). The exact mechanism triggering irAEs is not fully understood, but nearly every organ can be affected (Chang et al., 2019; Cukier et al., 2017). The most commonly affected organs are the skin, gastrointestinal tract, lungs, liver, and endocrine system (Gordon et al., 2017).

Endocrine irAEs are increasing in incidence with expanded use of ICIs (Barroso-Sousa et al., 2018). ICI-induced endocrinopathies can present as hyperthyroidism, hypothyroidism,hypophysitis, diabetes mellitus, primary adrenal insufficiency (PAI), or a combination of these in the same patient. The combination of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1) or programmed cell death protein ligand 1 (PD-L1) immunotherapy may result in enhanced antitumor response but also can increase the risk of irAEs (Barroso-Sousa et al., 2018; Guo et al., 2017), including the risk of AI from autoimmune adrenalitis.

Adrenal Function

The adrenal glands consist of two distinct zones: an interior medulla and an outer cortex. Autoimmune adrenalitis is a disorder of the adrenal cortex, the portion of the gland responsible for secretion of steroid hormones, including the glucocorticoid cortisol and the mineralocorticoid aldosterone (Barroso-Sousa et al., 2018; Chang et al., 2019; Cole, 2018). Cortisol levels have a normal diurnal pattern, with peak levels in the early morning and lowest levels around midnight (Bancos et al., 2015; Debono et al., 2009). In response to new physiologic or emotional stress, additional cortisol is released, resulting in widespread effects on carbohydrate and protein metabolism (Cole, 2018). Cortisol is essential to the stress response.

Aldosterone is responsible for sodium reabsorption and potassium excretion by the kidneys, the maintenance of a homeostatic extracellular fluid volume, and, ultimately, regulation of arterial blood pressure (Cole, 2018). Aldosterone release from the adrenal cortex is controlled by the renin–angiotensin system in response to decreased blood pressure, volume depletion, renal hypoperfusion, and/or decreased levels of sodium (Byrd et al., 2018). When reabsorbing sodium and water, aldosterone also eliminates excess potassium from the body. As with other endocrine functions in the body, a negative feedback loop is active for cortisol and aldosterone secretion when a target level is reached and equilibrium is reestablished.

Understanding the function of the adrenal cortex is important in distinguishing between hypophysitis and adrenalitis in patients receiving ICIs. Hypophysitis results in deficient stimulation of glucocorticoid secretion and is a central or secondary AI (SAI). Adrenalitis occurs as a result of adrenal cortex destruction, resulting in PAI, in which hormone secretion signaling fails to trigger glucocorticoid and mineralocorticoid production.

Assessment

The destruction of the adrenal cortex as an ICI-induced event is rare. In single-agent therapy with CTLA4, PD-1, or PD-L1 agents, an ICI incidence rate of 0.3%–1.5% has been reported (Barroso-Sousa et al., 2018). The highest incidence rate (4.2%) has been reported with combination ICI therapy (Barroso-Sousa et al., 2018).

AI can be difficult to diagnose because it exhibits elusive and nonspecific symptoms (Bancos et al., 2015; Chang et al., 2019) (see Figure 1). Advanced practice RNs (APRNs) should be highly suspicious of symptoms when patients receive combination treatment regimens; fatigue, gastrointestinal complaints, and even issues with dehydration are not uncommon in patients with cancer but may be the first signs of AI. Careful assessment includes skin examination for hyperpigmentation and assessment for postural hypotension in addition to regular assessment and review of laboratory results. When APRNs suspect AI, assessment includes differentiating PAI from SAI, and ruling out sepsis and adrenal metastasis (Kumar et al., 2017; Nagasaka et al., 2018). Adrenal crisis can occur when AI is unrecognized, particularly when patients become septic or mount a stress response. Adrenal crisis is a potentially life-threatening event requiring acute treatment with steroid replacement.

Case Example

After completing four cycles of combination ipilimumab and nivolumab, B.K., a 58-year-old man, presented to the medical oncology clinic. His clinical response to treatment was described as excellent, and he was scheduled to begin nivolumab maintenance therapy. B.K.’s vital signs on arrival to the clinic were remarkable for a blood pressure of 75/50 mmHg and a pulse rate of 111 beats per minute. B.K. reported issues with increasing fatigue and anorexia, as well as dizziness on standing and difficulty sleeping that had worsened during the previous two weeks. He denied nausea, vomiting, and diarrhea. His physical examination was negative for signs of sepsis and was otherwise unremarkable. B.K.’s medical history included essential hypertension and anxiety; he reported taking his antihypertensive medication prior to arrival. B.K. was admitted to outpatient infusion for laboratory tests and hydration. Laboratory results revealed a serum creatinine level of 3.8 mg/dl, a potassium level of 5.1 mEq/L, and a serum sodium level of 124 mmol/L. To rule out ICI-induced endocrinopathy, B.K. was admitted to the hospital so that an endocrinologist could evaluate him.

On admission, B.K.’s hydration treatment continued, and he was evaluated for potential immune-related endocrinopathy. Additional orders included a complete metabolic profile and an adrenocorticotropic hormone (ACTH) stimulation test, with a baseline cortisol level of less than 0.05 mcg/dl, then levels of 2.3 mcg/dl (30 minutes later) and 2.8 mcg/dl (60 minutes later). In addition, a morning ACTH level drawn with the baseline cortisol was elevated, suggesting PAI. B.K.’s low blood pressure, postural hypotension, and sodium and potassium levels normalized. He was discharged on steroid supplementation with immediate plans for endocrinologist-managed follow-up, additional workup, and education.

Confirmation of Diagnosis and Treatment

An ACTH stimulation test is recommended for confirmatory diagnosis of adrenalitis (see Figure 2). Additional testing includes a plasma ACTH test, paired with an unstimulated morning cortisol level, to differentiate between diagnoses of PAI and hypophysitis; in patients with a confirmed cortisol deficit, an elevated level of ACTH suggests PAI, whereas a low level of ACTH suggests SAI (Barroso-Sousa et al., 2018; Bornstein et al., 2016). To further determine a diagnosis of PAI and confirm mineralocorticoid deficiency, clinical recommendations include evaluating plasma renin and aldosterone levels (Bornstein et al., 2016). Diagnosis may be difficult and may require ongoing laboratory testing to confirm. To establish a diagnosis, factors include the state of adrenal atrophy and depletion of stored hormones (Barroso-Sousa et al., 2018; Pazderska & Pearce, 2017). Concomitant endocrine irAE assessment is important, and continued monitoring is recommended (Chang et al., 2019).

Depending on patient presentation, steroid replacement may begin immediately. Hydrocortisone is the agent of choice for glucocorticoid replacement, and its initiation with fluid resuscitation often corrects laboratory abnormalities (Bornstein et al., 2016). For patients with PAI with continued hyponatremia or postural hypotension, mineralocorticoid replacement with fludrocortisone is recommended (Bornstein et al., 2016). Replacement of glucocorticoid and mineralocorticoid should be titrated based on clinical assessment of signs and symptoms.

Patient Education

Patients who develop ICI-induced AI will likely need lifelong treatment. To prevent adrenal crisis and other complications, clinicians should teach patients about long-term management. Patients who are educated about their ICI treatment and AI can then inform subsequent healthcare professionals who are unfamiliar with irAEs. Individuals must understand “sick-day rules,” which require steroid dose adjustment during stressful events, fever, and illness; they should also be able to recognize precipitating signs and symptoms of an imminent adrenal crisis (Barroso-Sousa et al., 2018). Patients should be prepared with medical alert identification and trained to use a glucocorticoid injection kit in the event of an emergency. Individuals diagnosed with PAI should be assessed by an endocrine specialist at least once annually, including evaluation for glucocorticoid and mineralocorticoid over- or under-replacement (Barroso-Sousa et al., 2018; Nieman, 2019).

Conclusion

Although ICI-induced AI is rare, it may become more common with more ICI indications. Prompt recognition and treatment are essential to providing quality care and managing potentially life-threatening effects. AI may be permanent, requiring long-term management. APRNs, as members of interprofessional care teams, have an important role to play in the identification, treatment, education, and long-term management of AI. APRNs can facilitate proper evaluation and referral for patients with suspected AI. Patients with AI do have an increased mortality risk, primarily because of cardiovascular and infectious diseases (Makin et al., 2019). However, with appropriate treatment and education, risks can be anticipated and reduced.

About the Author(s)

Kiera B. Hobbs, BSN, RN, OCN^®, is a staff nurse in outpatient oncology infusion at Baptist Health Lexington in Kentucky and an MSN student in the School of Nursing at Loyola University Chicago in Illinois; and Susan Yackzan, PhD, APRN, MSN, AOCN^®, is the director of clinical oncology practice and a nurse scientist in the cancer service line at Baptist Healthcare System in Lexington, KY. The authors take full responsibility for this content. Hobbs was supported by a Graduate Scholarship in Cancer Nursing Practice (GSCNP-19-207-01) from the American Cancer Society. Hobbs can be reached at kiera.hobbs@bhsi.com, with copy to CJONEditor@ons.org.