1Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece; 2Department of Biological Chemistry, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece; 3Endocrine Unit, Department of Medical Therapeutics, Alexandra Hospital, Athens University School of Medicine, Athens, Greece; 4Endocrine Unit, Athens University, Evgenideion Hospital, Athens, Greece
Cancer immunotherapy has introduced a novel class of drugs known as immune checkpoint inhibitors (ICIs). They enhance antitumour immunity by blocking negative regulators (checkpoints) of T cell function that exist on both immune and tumour cells. ICIs targeting CTLA-4 and PD-1/PDL-1 have dramatically changed the outcome of patients with several advanced-stage malignancies but they may lead to a variety of inflammatory toxicities and autoimmune consequences. The main endocrine immune-related adverse events (IRAEs) include hypophysitis, primary thyroid dysfunction, adrenalitis and type 1 diabetes mellitus. In general, the management of endocrine IRAEs requires assessment of their severity, in moderate or severe cases interruption of the checkpoint inhibitor and use of corticosteroid or alternative immunosuppression and appropriate hormone replacement or treatment when necessary.
Anti-CTLA4, Anti-PD1, Anti-PDL1, Autoimmune consequences, Immune checkpoint inhibitors
Cancer immunotherapy has introduced a novel class of drugs known as immune checkpoint inhibitors (ICIs). They enhance antitumour immunity by blocking negative regulators (checkpoints) of T cell function that exist on both immune and tumour cells. The first agent was approved in 2011 and since then a few of them have been evaluated in clinical trials for the management of advanced neoplasias, such as metastatic melanoma, non-small cell lung cancer, advanced renal cell carcinoma, head and neck cancer and lymphoma (Table 1).1-5 However, because of their mechanism of action these agents can lead to a variety of inflammatory toxicities and autoimmune consequences that can affect the gastrointestinal tract, skin, liver and endocrine system and are hence described as immune-related adverse events (IRAEs). The endocrine immune-related adverse events include hypophysitis, primary thyroid dysfunction, adrenalitis and type 1 diabetes mellitus which present with variable degrees of severity6-11,38 (Table 2) and incidence rates47 (Table 3).
Tumour antigens are presented by dendritic cells to cytotoxic T lymphocytes (CTLs). The activation of T cells is regulated by stimulatory and inhibitory signals that maintain the balance between appropriate recognition and destruction of tumour cells and inappropriate immune overstimulation, which damages normal healthy tissue. This is referred to as the cancer-immunity cycle.12 T cell-mediated inhibitory signalling pathways permit tolerance to tumour antigens. Although there are many T cell checkpoints, antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and programmed cell death 1 ligand 1 (PDL1) have been most extensively evaluated in the clinical setting. The available data refer to ipilimumab and tremelimumab, both CTLA4-abs, nivolumab, pembrolizumab and pidilizumab, all anti-PD1 abs and atezolizumab an anti-PDL1 agent.
CD28 on the T cell surface binds to the B7 co‑stimulatory ligand on antigen-presenting cells to prime and activate the T cell so as to destroy the cancer cells. CTLA4, which is a CD28 homolog, binds with higher affinity to B7 and can compete with CD28 to inhibit T cell activity. This process prevents the T cell from killing the cancer cells. Antibodies to CTLA4 prevent B7 binding and enable upregulation of T cell activity, activation of mitogen-activated protein kinase which results in the formation of activator protein 1 (AP1) complex and induction of IL-2 cytokines which mediate T cell growth.13-15
Anti-PD1 and anti-PDL1
The PD1 (programmed cell death - 1) receptor (also known as CD279) is expressed on the surface of activated T cells. Its ligands, PDL1 (B7-H1; CD274) and PDL2 (B7-DC; CD273) are commonly expressed on the surface of antigen-presenting/dendritic cells or macrophages. PD1 and PDL1/PDL2 belong to the family of immune checkpoint proteins that act as co-inhibitory factors, which can stop or limit the development of the T cell response. PD1/PDL1 interaction forms a biochemical “shield” protecting tumour cells from being destroyed by the immune system. Monoclonal antibodies that target either PD1 or PDL1 can block this binding and boost the immune response against cancer cells.16,17
GENERAL MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS
In general, treatment of moderate or severe IRAEs requires interruption of the checkpoint inhibitor and the use of corticosteroid or alternative immunosuppression.18 For grade 2 (moderate) immune-mediated toxicities, treatment with the checkpoint inhibitor should be withheld and not resumed until symptoms or toxicity is grade 1 or less. Corticosteroids (prednisone 0.5mg/kg/day or equivalent) should be started if symptoms do not resolve within a week. For patients experiencing grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with the checkpoint inhibitor should be permanently discontinued and high doses of corticosteroids (prednisone 1-2mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, steroids can be gradually tapered over at least one month.18
If symptoms do not clearly improve, particularly after approximately three days with intravenous steroids, infliximab (5mg/kg) could be administered rather than continuing with a prolonged course of high-dose IV corticosteroids.18 The need for immunosuppressive therapy to manage IRAEs does not appear to affect the response to checkpoint inhibition with either anti-PD1 antibodies or ipilimumab.19
The specific approach to each endocrine IRAE is further discussed in the individual sections below.
Hypophysitis is a rare inflammatory condition of the pituitary gland with an incidence of 1:1,000,000 in the general population. Byun et al estimated that amongst 2,017 ipilimumab treated patients 184 (9.1%) developed hypophysitis, while this consequence occurred only in 8/613 (1.3%) patients on tremelimumab, in 6/929 (0.4%) on nivolumab and in 5/729 (0.68%) on pembrolizumab therapy.20 A meta-analysis by Abdel-Rahman et al estimated a significantly increased risk of all-grade hypophysitis in patients treated with ICIs versus controls (RR: 22.03, 95% CI: 8.52-56.94).21
In contrast, in another meta-analysis of PD1 inhibitors studies the risk of hypophysitis in patients treated with these agents was not significantly elevated compared with controls (RR: 2.32, 95% CI: 0.574-9.40).22 The authors assumed that this discrepancy could be due to the fact that Abdel-Rahman et al analyzed mainly anti-CTLA4 inhibitors studies (five RCTs evaluating ipilimumab, one evaluating tremelimumab, three for nivolumab and one for pembrolizumab), while all ten RCTs included in their analysis were for PD-1 inhibitors. Notably, PD-1 inhibitors induced a significantly lower risk of hypophysitis when directly compared with ipilimumab (RR: 0.148, 95% CI: 0.043-0.505). This may be explained by the fact that these agents act differently. Anti-CTLA4 therapy can stimulate de novo pituitary-reactive effector T cells and also lead to the production of anti-pituitary antibodies and activation of the complement, while anti-PD1/PDL1 therapy can make existing pituitary reactive effector T cells more active. Moreover, the pituitary gland may express CTLA-4, making it a direct target for anti-CTLA-4 antibodies.23 Of note, the combination of nivolumab/ipilimumab augmented the risk for hypophysitis versus monotherapy with ipilimumab only (RR: 1.94, 95% CI 1.07-3.50).22
Hypophysitis usually develops between 5-36 weeks of treatment but late occurrence at 19 months has also been reported.20,26 Median time to diagnosis of ipilimumab-hypophysitis is nine weeks.24 Clinical manifestations relate either to sellar compression as the pituitary enlarges (headache, visual defects) or to hormonal disturbance due to autoimmune inflammation of the pituitary (hypotension, nausea, abdominal pain, anorexia, weight loss, temperature intolerance, loss of libido, polyuria, polydipsia). Many of these symptoms are nonspecific and could be attributed either to pituitary dysfunction or to the underlying illness. Late onset of hypopituitarism without a clinically evident acute phase of inflammation has been reported suggesting a low-grade immunological process against the pituitary.25
Anterior hypopituitarism is more prevalent than diabetes insipidus, while ACTH and/or TSH deficiency are the most common manifestations.20,26 Hypogonadotropic hypogonadism and low levels of insulin-like growth factor 1 (IGF1) may also be present.20 Both high and low levels of prolactin have been described.24 Older age and male sex may be risk factors for the development of hypophysitis with ICI medications.27
It is prudent to perform a baseline hormonal assessment at the initiation of immunotherapy. We suggest that a detailed questionnaire regarding suspicious symptoms for hypophysitis (headache, nausea, weakness, fatigue, hypotension, hypoglycemia) is carried out and measurement of TSH, fT4, morning cortisol (9am), electrolytes, glucose before each cycle is performed, taking into account that both cancer and hypopituitarism may share common symptoms and laboratory results. In the event of compression symptoms (headache, visual defects) and/or clinical suspicion of hypophysitis, then pituitary MRI and a full endocrine work-up (FSH/LH, E2/TESTO, IGF-1, PRL, TSH, fT4, cortisol (9am), ACTH) should be performed (Figure 1).
Figure 1. Proposed algorithm for the management of immune related adverse events. FSH: follicle stimulating hormone, LH: luteinizing hormone, E2: estradiol, TESTO: testosterone, IGF-1: insulin growth factor-1, PRL: prolactin, fT4: free T4, TSH: thyroid stimulating hormone.
If morning cortisol is less than 250nmol/l or random cortisol less than 150nmol/l with vague symptoms, then replacement therapy with glucocorticoids should be initiated (Figure 1). In the case of clinical suspicion of adrenal insufficiency or when morning cortisol is <350nmol/l, further dynamic ACTH testing is recommended.
Differential diagnosis should exclude the new occurrence of brain metastases, therefore an MRI is mandatory to rule out this possibility and to check pituitary status. Pituitary morphology may change during the disease course, from mild to moderate diffuse enlargement with homogenous or heterogeneous enhancement after contrast administration and stalk thickening at disease onset, to subsequent atrophy of the gland and finally empty sella. Importantly, a normal MRI does not rule out hypophysitis and management should be based on clinical presentation and hormonal evaluation. Occasionally, changes of pituitary morphology may precede function or biochemical disturbances; this may resolve after 1-8 weeks of glucocorticoid therapy.27
The management of hypophysitis primarily involves hormone replacement and consideration of ICIs discontinuation and/or high-dose (immunosuppressive) steroid use. Although congruence between treatment plans is lacking, it is suggested that for patients with grade 1 (mild) hypophysitis, immunotherapy may be continued, while for all other grades of toxicities treatment should be withheld and high-dose systemic steroids (prednisolone 0.5-2mg/kg/day or equivalent), with subsequent tapering to a physiological replacement dose of hydrocortisone or prednisolone, should be initiated (Figure 1).28 Immunotherapy can be restarted once the patient improves clinically and toxicity is grade 1 or less. Appropriate HRT should be added if necessary. Relevant guidelines have recently been published by the European Society of Medical Oncology (ESMO).28
While the thyrotroph axis and gonadotroph function may recover, this is not common with corticotroph function. Meanwhile, low prolactin may predict lack of recovery function with a specificity of 88.9%, sensitivity of 50%, negative predictive value of 57.1%, positive predictive value of 85.7% and accuracy of 66.7%.29
Primary thyroid disorders
The pattern of primary thyroid disturbances includes subclinical or overt hypothyroidism, painless thyroiditis with transient thyrotoxicosis, subclinical or overt hyperthyroidism and thyroid eye disease.8,30-33
Abdel-Rahman et al estimated that the risk of all-grade hypothyroidism and hyperthyroidism associated with ICIs therapy is significantly elevated versus controls. Relative risks were 8.26 (95% CI: 4.67-14.62) and 5.48 (95% CI: 1.33-22.53), respectively.21
In a meta-analysis of PD-1 inhibitors studies the risk of hyperthyroidism was significantly increased compared to anti-CTLA4 (RR 2.45, 95% CI: 1.19-5.03), while the risk of hypothyroidism, although elevated, did not reach significance (RR: 4.13, 95% CI: 0.85-20.17).22 The combination of nivolumab/ipilimumab increased the risk of all-grade hyperthyroidism (RR: 9.13 95% CI: 3.07-27.11) and hypothyroidism (RR: 2.01 (95% CI: 0.60-6.70), although again this was not significant for the latter.22
In a series of 126 patients treated with ipilimumab for melanoma, one developed primary hypothyroidism, while eight (6%) developed subclinical hypothyroidism and 20 (16%) subclinical hyperthyroidism. Of the 46 patients who were treated with anti-PD1 inhibitors for melanoma, six (13%) developed primary hypothyroidism, a further six (13%) subclinical hypothyroidism and six (13%) developed subclinical hyperthyroidism. Of the 23 patients treated with the combination of ipilimumab and nivolumab for melanoma, four patients (22.2%) developed hypothyroidism, one of whom had a preceding episode of hyperthyroidism, and two had preceding subclinical hyperthyroidism. One patient (5.6%) had subclinical hypothyroidism and a further four patients (22.2%) had subclinical hyperthyroidism without subsequent hypothyroidism. Destructive thyroiditis was more common than Graves’ disease.31 In a study of 93 pembrolizumab treated patients 13 (14%) developed abnormal thyroid function tests. Thyroiditis occurred in seven patients (54%), four of whom recovered. New onset hypothyroidism, either overt or subclinical, developed in three patients. Thyroperoxidase (TPO) antibodies were positive only in 4/13 (31%) and diffusely increased 18-FDG uptake of the thyroid gland was observed in 7/11 (64%) patients. The authors noticed an increased number of circulating CD56+CD16+ NK cells and an elevated surface expression of HLA-DR in the inflammatory intermediate CD14+CD16+ monocytes and assumed that this may explain the destruction of the thyroid.33
The onset of thyroid disease usually occurs after 2-4 cycles of therapy. Aggravation of existing autoimmunity has been reported;33-35 however, whether individual genetic susceptibility plays a role has not yet been established. Delivanis et al reported recovery of pembrolizumab-induced thyroiditis in 4/7 (57%) patients.33 It is noteworthy that two cases with hyperthyroidism who required high-dose systemic corticosteroids for the management of other immune-related toxicities did not become hypothyroid.31 The authors assumed that immunosuppressive therapy may prevent the development of hypothyroidism in those with ICIs-related thyroiditis. This is in contrast to the situation in ipilimumab-induced hypophysitis, where high dose steroids have not been shown to reverse pituitary dysfunction.37
TFTs, thyroid autoantibodies and TSH-receptor antibodies and a radionuclide thyroid uptake scan may aid in proper diagnosis.
It is suggested that in patients with symptomatic hyperthyroidism treatment with beta-blockers (propranolol or atenolol/metoprolol) should be started. Symptoms of transient hyperthyroidism due to destructive thyroiditis may be alleviated with beta blockers, as in that case antithyroid drugs are not indicated.28 In the case of painful thyroiditis prednisolone 0.5mg/kg may be started with subsequent tapering. In the event of positive anti-TSH receptor antibodies carbimazole may be initiated. Treatment with ICIs should be interrupted until recovery from symptoms.28
In the case of hypothyroidism, thyroxine replacement 0.5-1.5 μg/Kg should be initiated. In subclinical hypothyroidism, substitution with thyroid hormone should be considered in the case of fatigue or other complaints that could be attributed to hypothyroidism. ICIs may be continued.28
A decrease in TSH levels across two measurements with normal or lowered fT4 may indicate the development of hypophysitis and thus weekly cortisol measurements should also be performed.28
Case reports of primary adrenal dysfunction with the use of immune checkpoint inhibitors have been published, while patients receiving these drugs require education on the potential risks of hypocortisolemia, which may be fatal if left untreated.
In the review by Byun et al, two cases of primary adrenal insufficiency are reported amongst 256 patients (0.8%) treated with ipilimumab.20,38,39 Trainer et al described a patient with hyponatremia secondary to nivolumab-induced primary adrenal failure. The patient’s FDG PET CT scan demonstrated bilateral increased FDG activity in the adrenals consistent with autoimmune adrenalitis.40 Adrenal insufficiency of unspecified cause has been reported in patients treated with tremelimumab, nivolumab and the combination of anti-CTLA4 and anti-PD1 agents.42 Unfortunately, most of the reports do not specify the etiology of adrenal insufficiency. Overall, the relative risk of adrenal insufficiency of any cause was significantly elevated (RR: 3.87 (95% CI: 1.12-13.41) as described in a review by Abdelrahman et al.21
Although hyponatremia can occur in patients with ACTH deficiency, the possibility of primary adrenal failure should also be considered and investigated by measurement of renin, aldosterone and ACTH. There have been reports of radiological evidence of adrenalitis with normal endocrine function, following ICIs therapy, consistent with a subclinical form of adrenalitis.39 When adrenal enlargement is observed in patients receiving immune checkpoint drugs, assessment of adrenal function through the measurement of ACTH and cortisol levels, as well as a Synacthen stimulation test, should be performed so as to rule out primary adrenal insufficiency.
Type 1 diabetes mellitus
Type 1 diabetes mellitus (T1DM) is a rare complication of anti-PD1 or anti-PDL1 agents. Antibodies against islet cell antigens have been detected in a few of the reported cases.43,44 Time to development ranges from less than 1 month to 1 year. Insulin therapy is the mainstay of treatment. The use of glucocorticoids was not able to reverse T1DM in a patient treated with pembrolizumab for metastatic melanoma.45
The proposed mechanism for the development of T1DM is that lower PD-1 expressing CD4+ cells may lead to activation of autoreactive T cells that can infiltrate pancreatic islet cells and ultimately lead to T1DM.41 It is suspected that high-risk HLA class I and II genotypes may be associated. It is recommended that clinicians managing patients undergoing anti‑PD1 or anti-PDL1 therapy should carefully monitor patients for elevated levels of blood sugar, while antibodies against islet cell (ICA) and glutamic acid decarboxylase (GAD) and C-peptide should be measured in order to distinguish between T1DM and T2DM (Figure 1).
ICIs targeting CTLA-4 and PD-1/PDL-1 have dramatically changed the outcome of patients with several advanced-stage malignancies. However, their use is associated with unique IRAEs (hypophysitis, thyroid disorders, adrenalitis, type 1 diabetes mellitus) which, though mostly transient and mild, can occasionally be fatal. At the time this manuscript was being prepared a case of primary hypoparathyroidism caused by ipilimumab and nivolumab and manifesting with acute severe symptomatic hypocalcemia was reported as a new IRAE.46 Rapid identification of these IRAEs and appropriate treatment can improve the outcome of immunotherapy.
It is important that patients on ICIs are informed about the potential endocrine sequelae of these treatments and especially the risk of developing cortisol deficiency due to either pituitary or adrenal failure. Close monitoring and constant vigilance for the occurrence of IRAEs are necessary. As T-cell checkpoint inhibitors are now achieving regulatory approval in many types of cancer, more data on conducting the long-term follow-up of these patients is urgently required.
The relative risk of hypophysitis is high in those treated with anti-CTLA4 agents.
When compared with ipilimumab, the risk of all-grade hyperthyroidism and hypothyroidism with PD-1 inhibitors monotherapy seems to be higher, while the risk of all-grade hypophysitis is lower.
Patients treated with a nivolumab/ipilimumab combination therapy have a significantly increased risk of all-grade hyperthyroidism and hypophysitis when compared with ipilimumab monotherapy.
Adrenalitis and type 1 diabetes mellitus are rare IRAEs of immune checkpoint inhibitors.
Long-term follow-up of patients treated with T-cell checkpoint inhibitors is needed so that more data may be gathered on the immune-related endocrinopathies.
DECLARATION OF INTEREST
The authors declare that they have no conflict of interest.
This study was not funded.
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Address for correspondence:
Georgia Ntali, MD, Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, 10676 Athens, Greece; E-mail: firstname.lastname@example.org
Received: 02-08-2017, Accepted: 20-12-2017