Endocrine Adverse Events of Immune Checkpoint Inhibitors: A Comprehensive Review

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy by enhancing T-cell-mediated tumour eradication. However, their use is associated with immune-related adverse events, with endocrinopathies being the most common. Thyroid dysfunction, hypophysitis, primary adrenal insufficiency (PAI), and insulin-dependent diabetes mellitus are well-documented complications. Thyroid dysfunction typically follows a biphasic course, with transient thyrotoxicosis progressing to hypothyroidism. Hypophysitis primarily affects the anterior pituitary, often leading to isolated adrenocorticotropic hormone deficiency. ICI-induced diabetes mellitus results from autoimmune β-cell destruction, frequently presenting as diabetic ketoacidosis. Primary adrenal insufficiency is rare but requires prompt recognition. Despite these endocrine toxicities, the benefits of ICIs outweigh their risks, and treatment is usually continued with appropriate hormone replacement. Early recognition and management of these endocrinopathies are crucial for optimising patient outcomes. This review summarises the incidence, pathophysiology, diagnosis, and management of ICI-associated endocrine disorders, providing essential insights for oncologists and endocrinologists.

INTRODUCTION

The discovery of immune checkpoint inhibitors (ICIs) has revolutionised the landscape of oncological therapeutics. Tumour cells escape the immune system by intricate molecular mechanisms, thus leading to unchecked tumour proliferation. ICIs, the monoclonal antibodies, act by blocking the key players of the immune system exploited by the tumour cells and thus causing immune-mediated tumour eradication. The first ICI, ipilimumab, was approved by the US Food and Drug Administration (FDA) in 2011. Subsequently, nine ICIs secured regulatory approval.[1,2] These include ipilimumab and tremelimumab (CTLA-4 inhibitors); pembrolizumab, nivolumab, cemiplimab, and dostalimab (PD-1 inhibitors); and atezolizumab, avelumab, and durvalumab (PDL-1 inhibitors).

ICIs are used in the treatment of multiple cancers, including those of the lung, skin, kidney, oesophagus, stomach, colon, liver, and bladder. Their use has resulted in durable remission and enhanced overall survival even in patients with advanced disease stage. Thus, their use has led to changes in the standard of care in cancer treatment. They target the following immunoregulatory molecules:

• Programmed cell death protein 1 (PD-1)

• Programmed cell death ligand 1 (PD-L1)

• Cytotoxic T lymphocyte-associated protein 4 (CTLA-4)

• Lymphocyte activation gene 3 (LAG-3).

However, the benefit comes with an array of immune-related adverse events, the most common among them being endocrine dysfunctions.[2]

Mechanism of action of immune checkpoint inhibitor

The normal immune response in the body in normal health and the action of ICIs are shown in Figure 1. Under normal circumstances, expression of PDL-1 in local tissue and CTLA-4 in T cells following T cell activation control the T cell overactivation. LAG-3 is a transmembrane protein inhibiting major histocompatibility complex (MHC) class II that inhibits activation of T cells.

Figure 1.

Mechanism of action of immune checkpoint inhibitors. In normal health, antigen presentation by antigen-presenting cell (APC) to the T cell receptor (TCR) results in the activation of T cells through the interaction of the b7 receptor in the APC and CD28 in the T cell [Figure 1A]. This activation triggers cytokine release, and this induces the expression of programmed cell death ligand 1 (PD-L1) by the local parenchymal tissue that binds to the programmed cell death protein 1 (PD-1) in the T cell and inhibits unopposed T cell activation [Figure 1B1]. In addition, activated T cells express cytotoxic T lymphocyte-associated protein 4 (CTLA-4) which blocks the b7 (molecules on tumour cells that modulate immune responses), thus terminating the sustained immune activation [Figure 1B2]. Thus, anti-PD1 and CTLA-4 block the PD-1 and CTLA-4 located in the T cell, respectively, and anti-PDL-1 blocks PDL-1 located on the tumour cells, leading to T cell activation [Figure 1C]

Tumour cells manipulate this pathway by upregulating PDL-1 expression, leading to the exhaustion of T cells and immune escape. Hence, inhibiting/blocking the PD-1, PDL-1, CTLA-4, and LAG-3 leads to the activation of T cells and apoptosis of cells expressing these proteins (both tumour and normal cells) [Figure 1C].[3]

Endocrinopathies

Immune checkpoint inhibitors can affect most endocrine glands and cause hormone deficiency.[4] The common endocrinopathies reported include:

• Thyroid dysfunction

• Hypophysitis

• Primary adrenal insufficiency (PAI)

• Diabetes mellitus (DM)

The therapeutic benefit of ICI greatly outweighs the risk of endocrinopathies associated with them. Hence, ICIs are continued in most cases despite these adverse effects.

Thyroid dysfunction

Incidence and risk factors

Thyroid dysfunction is the most common endocrine dysfunction associated with ICI therapy. The presentation may be either as thyrotoxicosis or hypothyroidism, the latter being more common. Typically, ICI-induced thyroid dysfunction follows a biphasic course, beginning with transient thyrotoxicosis due to destructive thyroiditis, which eventually may recover or culminate in subclinical/overt hypothyroidism. The initial phase may go unnoticed in a proportion of patients. Concomitant use of tyrosine kinase inhibitors increases the risk of hypothyroidism.[2] The risk of thyroid dysfunction is highest with combination therapy (CTLA-4 and PD-1), followed by PDL-1/PD-1, and least with CTLA-4 monotherapy.[5,6] However, patients with PDL-1 or PD-1 therapy have been reported to exhibit a higher proportion of hypothyroidism compared to combination therapy (74 vs 23%)[7] and (64 vs 52%)[8] in certain cohorts.

In a meta-analysis by Barroso-Sousa et al., which included more than 7000 patients from 38 studies, the incidence of hypothyroidism and thyrotoxicosis was 6.6% and 2.9%, respectively [Table 1].[5] The retrospective analysis of the US FDA adverse event reporting system over 9 years showed that 2.6% of patients who received ICI developed thyroid dysfunction.[8]

Table 1.

Median time to onset and incidence of endocrinopathies after ICI therapy

Endocrinopathy	Median time to onset after ICI initiation	Incidence
		Overall	CTLA-4 alone	PD-1/PDL-1 alone	Combination of CTL4-A & PD-1
Thyroid dysfunction1
Thyrotoxicosis	6–10 weeks2	2.9%	0.2%–1.7%	0.6%–3.7%	8%–11%
Hypothyroidism	8–16 weeks2	6.6%	2.5%–5.2%	3.9%–8.5%	10.2%–16.4%
Hypophysitis1	6–12 weeks after CTLA-4 or combination therapy 26 weeks after PD-1/PDL-12	1.3%	3.2%	0.4%/ <0.1%	6.4%
Primary adrenal insufficiency3	10 weeks (10–16 weeks)3	-	-	0.7%	4.2%
Diabetes mellitus4,5	7–17 weeks	-	-	1.8%4,5	-

¹Karaviti et al.[6] and Barroso-Sousa et al.[5], ²Kotwal et al.[1], ³Martella et al.[22], ⁴Tsang et al.[19], ⁵Kotwal et al.[18], ⁶Quandt et al.[17]

Studies have demonstrated more thyroid dysfunction in patients with elevated thyroid antibodies prior to ICI initiation.[9] However, up to 23.5% of antibody-negative patients also developed thyroid dysfunction.[10] A study by Muir et al. showed that elevated TPOAb at baseline had a high specificity (97%) but low sensitivity (20%).[11] Hence, baseline antibody testing has not been definitively proven to predict thyroid dysfunction. However, among the patients with ICI-induced thyroiditis, those who are anti-TPO positive have a higher risk of overt hypothyroidism, suggesting more severe destructive thyroiditis.[12]

Pathophysiology

A proposed mechanism for thyroid dysfunction is infiltration with lymphocytes and histiocytes, and proliferation of helper T cells due to suppressed PD-1/PD-L1 inhibitory signals leading to destructive thyroiditis.[13] This probably explains the increased incidence of thyroid dysfunction with PD-1/PDL-1.

Diagnosis

The initial symptoms may depend on the phase of the illness. Patients presenting in the thyrotoxic phase may have mild-to-severe symptoms, or the phase may be even missed in asymptomatic ones. Hypothyroidism follows the thyrotoxic phase by a few weeks as in destructive thyroiditis [Table 1].[1] In the meta-analysis by Barroso-Sousa et al., less than 1% of patients with thyroid dysfunction presented with severe (requiring hospitalisation) or life-threatening symptoms.

More often, thyroid dysfunction, especially hypothyroidism, is diagnosed during monitoring of thyroid functions (thyrotropin stimulating hormone [TSH], free T4 [FT4]) in between or at the end of ICI therapy. In the thyrotoxic phase, the TSH is usually suppressed with normal or elevated FT4. While interpreting thyroid function, the reference range provided by the laboratory should be considered. Low or suppressed TSH with high FT4 occurs in thyrotoxicosis or hyperthyroidism. While elevated TSH with normal FT4 occurs in subclinical hypothyroidism, overt hypothyroidism will have elevated TSH and low FT4. As the association of thyroid dysfunction with ICI therapy is well established, further investigation is rarely required. Ultrasonogram with Doppler shows heterogenous, hypoechoic hypovascular thyroid gland. Radioiodine uptake scan/technetium 99m scan and TSH receptor antibody may help in establishing the diagnosis in the thyrotoxic phase but is seldom required unless symptoms persist for >6 weeks.[1,2,7,14] About 10% of those with overt hypothyroidism may recover,[12] and in others, it is often permanent due to the destructive nature of the disease.[1]

Management

The thyrotoxic phase most often is managed with beta-blockers for sympathetic symptoms and NSAIDs for pain relief. Glucocorticoids are seldom required. Hypothyroidism is treated with thyroxine replacement at a dose of 1–1.6 mcg/kg/day. The elderly and those with compromised cardiac functions need initiation at a smaller dose and further up titration.[4]

Hypophysitis

Incidence and risk factors

Hypophysitis due to ICI more often affects the anterior pituitary than the posterior pituitary. Although hypophysitis commonly presents with isolated adrenocorticotropic hormone (ACTH) deficiency, it can result in deficiency of all anterior pituitary hormones and rarely AVP deficiency. ICI-induced hypophysitis is most common with combination therapy of CTLA-4 and PD-1/PDL-1, followed by CTLA-4 monotherapy, and rare with PD-1/PDL-1 monotherapy [Table 1].[5,12] In addition, few studies have noted male gender and old age (age > 65 years) to be associated with ICI hypophysitis.[15,16]

Pathogenesis

Although the exact pathogenesis is not clear, a preclinical study in mice showed that repeated injections of anti-CTLA-4 monoclonal antibody led to the development of CTLA-4 antibody against the CTLA-4 protein normally expressed in the human and murine pituitary. These antibodies binding the CTLA-4 targets led to lymphocytic infiltration and pituitary inflammation. This may explain the higher frequency and shorter time to development of hypophysitis with CTLA-4 inhibitors.[4,17]

Diagnosis

In contrast to patients with ICI-induced thyroid dysfunction, a large proportion (39%–88%) of patients with hypophysitis present with clinical symptoms that lead to their diagnosis.[5,18] More than one-third present with severe/life-threatening symptoms.[5] They present with symptoms of mass effect (headache, visual field defects, diplopia) or symptoms of hypocortisolaemia such as nausea, fatigue, hypotension, altered mentation, and seizures. Secondary hypothyroidism seldom presents with symptoms, and symptoms of hypogonadism are difficult to interpret in the setting of illness (malignancy). The diagnosis is made by assessment of pituitary hormone axes (random or stimulated cortisol, ACTH, FT4, LH, FSH, testosterone, oestradiol). Low cortisol with low or normal ACTH (5–46 pg/mL) suggests secondary hypocortisolaemia/secondary adrenal insufficiency (needs to be interpreted with respect to the last dose of glucocorticoid during ongoing chemotherapy). In the case of ACTH-stimulated cortisol, a cortisol value of ≥ 18 μg/dL is considered normal. Isolated ACTH deficiency is the most common presentation. Among patients with ICI-induced hypophysitis, secondary hypocortisolaemia is the most common (90%) hormone deficit, followed by central hypothyroidism (20%) and secondary hypogonadism.[10] A low or inappropriately normal TSH with low FT4 suggests central hypothyroidism (beware that non-thyroidal illness syndrome and initial stages of ICI-induced thyroiditis may have the same picture). Hypogonadism is defined in males as the presence of symptoms of sexual symptoms such as decreased erections and libido and erectile dysfunction and low age-adjusted serum testosterone values (<300 ng/dL) and in females as amenorrhea with inappropriately low FSH and LH levels. LH, FSH, and gonadal steroids should be interpreted in the background of severity of illness and may need a repeat testing few months later.[1,2] magnetic resonance imaging (MRI) pituitary may show pituitary enlargement with intense contrast enhancement [Supplementary Figure SF1A ^{(107.4KB, tif)} ]; however, it is important to note that more than one-third (37%) of patients may have normal pituitary in MRI, more so when it is due to PD-L1/PDL-1 inhibitors [Supplementary Figure SF1B ^{(107.4KB, tif)} ].[19,20]

Management

Replacement of the hormone deficits (glucocorticoid – hydrocortisone (20–25 mg/day or 10–12 mg/m²) or prednisolone (5–7.5 mg/day), thyroxine) based on the axis involvement remains the mainstay of management. Hyponatremia due to secondary hypocortisolaemia requires replacement of glucocorticoids and fluid hydration, and symptomatic patients may require 3% saline as well. All patients with hypocortisolaemia should be educated about stress dosing and should be provided with a written treatment plan for stress. Replacement of sex steroids is required if hypogonadism persists and is found to be permanent (1). Patients with compressive symptoms due to pituitary enlargement require high-dose glucocorticoids.[4]

Diabetes mellitus

Incidence and risk factors

Diabetes mellitus is a less common endocrine toxicity secondary to ICI therapy. It is more common with PD-L/PDL-1 therapy, and rare with CTLA-4 monotherapy [Table 1]. DM is usually insulin-dependent with low c-peptide.[20,21,22] Presence of diabetes autoantibody increases the risk of development of DM following ICI therapy. A study by Stamatouli et al.[23] showed that 40% of the patients with ICI-induced DM tested positive for at least one diabetes autoantibody, and those positive for autoantibody developed diabetes after fewer cycles than those without autoantibodies.

Pathogenesis

ICI-induced DM is caused by the destruction of pancreatic β cells by self-reactive T cells. Preclinical studies in mice have shown that disruption of the PD-L/PDL-1 signalling leads to T cell-mediated destruction of pancreatic β cells, causing diabetes.[24,25] This explains the higher frequency of diabetes following PD-1/PDL-1 therapy.

Diagnosis

About 60%–75% presenting with ICI-induced DM present with diabetes ketoacidosis (DKA). The spectrum of disease ranges from rapid-onset deterioration of β cell function leading to insulin-deficient diabetes to worsening of type 2 diabetes with preservation of β cell function. Insulin-deficient diabetes with rapid-onset deterioration of β cell function will have low c-peptide level or low normal c-peptide during acute presentation such as DKA.[20,21,22]

Management

Patients presenting with DKA should be managed with fluid therapy and insulin infusion followed by a basal-bolus insulin regime. In addition, patients with worsening pre-existing diabetes and severe hyperglycaemia require insulin therapy. After stabilisation and optimisation of glycaemic control for 3–4 weeks, patients who are antibody negative and have adequate c-peptide reserve may be given a trial of oral antidiabetic drug therapy.[1]

Primary adrenal insufficiency (PAI)

PAI is one of the rare endocrine dysfunctions associated with ICI therapy. It is more common with PD-1/PDL-1 therapy and rare with CTLA-4 monotherapy. The incidence is higher with combination therapy [Table 1]. The real incidence may be still lower as most of the reporting studies report as adrenal insufficiency and do not discriminate between primary and secondary forms.[26] In an analysis of ICI-induced PAI from WHO VigiBase records, the definite PAI constituted 10% of the reported cases.[27]

In view of the rarity of the event, the exact pathogenesis is not known. In an analysis from WHO VigiBase records, about 90% of patients with PAI had significant symptoms at presentation contributing to morbidity.[27] In the acute form, patients present with symptoms of adrenal crisis such as nausea, vomiting, and abdominal pain. In the chronic form, they present with fatigue and weight loss, and these symptoms may overlap with symptoms of malignancy. Biochemical abnormalities include hyponatremia, hyperkalaemia, metabolic acidosis, hypoglycaemia, anaemia, and mild eosinophilia. The diagnosis is confirmed by documentation of low cortisol with elevated ACTH (normal ACTH: 5–46 pg/mL; >2 times the ULN is considered elevated) levels. The imaging of the adrenal is usually normal during the initial stages, and in chronic cases, adrenal atrophy may set in. However, imaging of the adrenal is important to rule out adrenal metastases or haemorrhage. PAI is treated by replacement of glucocorticoid (hydrocortisone (20–25 mg/day or 10–12 mg/m²) or prednisolone (5–7.5 mg/day); they require mineralocorticoid (fludrocortisone 50–150 mcg/day) as well.[26]

Adrenal crisis should be managed promptly with immediate intravenous hydrocortisone; 50–100 mg/m², maximum 100 mg stat, followed by 200 mg over 24 h in divided doses. Simultaneously, aggressive fluid resuscitation with isotonic saline (0.9% NaCl) should be initiated to correct hypotension and electrolyte imbalances. In addition, the precipitating cause needs to be identified and treated.

Other rare endocrinopathies

The rare endocrinopathies associated with ICI therapy include hypoparathyroidism[28,29] and acquired lipodystrophy.[30,31] In addition, there is a concern about possible direct effects on the reproductive system, leading to impairment of spermatogenesis in males[32] and ovulation in females.[33]

Association between immune-related endocrinopathy and drug efficacy

Development of immune-related adverse event (irAE) has been associated with survival advantage in patients treated with ICI and hence with ICI-related endocrinopathies. A meta-analysis by Hussaini et al.[34] that included 51 studies found a positive association between irAE and overall survival of patients. Patients with irAE were more likely to have a good response to ICI, progression-free survival, and overall survival. Among the ICI-associated endocrinopathies, thyroiditis has the strongest association with survival, with about 50% lesser mortality compared to the group without thyroiditis.[35]

Screening protocol for endocrinopathies

There is no standard protocol for screening of irAEs. Thyroiditis being the most common endocrinopathy following ICI therapy, thyroid function may be measured prior to initiation, and as the median time to onset is about 6 weeks, screening may be done every 4–8 weeks in the initial 6 months and later once in 12 weeks till the completion of ICI therapy. Screening for other endocrinopathies may be done based on clinical suspicion. The proposed protocol for screening is given in Figure 2.

Figure 2.

Screening protocol for immune checkpoint inhibitor-induced endocrinopathies

CONCLUSION

Immune checkpoint-associated endocrinopathies usually occur within a few months of treatment initiation, and most deficiencies are permanent, requiring lifelong replacement. ICI discontinuation is usually not required if the endocrinopathy is appropriately diagnosed and managed. Awareness about this entity is important for oncologists and endocrinologists for timely diagnosis and treatment. The association between irAE and cancer outcomes needs more investigation.

Author contributions

R.R.: Conceptualization. R.R., D.N.: Manuscript writing. R.R.: Manuscript review.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence

NA.

Supplementary Figure 1 (SF1)

MRI of patients with immune checkpoint induced hypophysitis (Nivolumab – PD 1 induced) managed at our centre. Figure SF1A shows an MRI with bulky pituitary and contrast enhancement. Figure SF1B shows an MRI with normal pituitary

Funding Statement

Nil.