The Diagnosis and Management of Endocrine Side Effects of Immune Checkpoint Inhibitors
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Background: The immunologically mediated side effects of immune checkpoint inhibitors (CPI) often involve the endocrine system as well, and they can even be fatal, as in the case of unrecognized hypophysitis. Distinguishing such side effects from tumor-related changes is often difficult, because their clinical features can be nonspecific.
Methods: This review is based on publications retrieved by a selective search in PubMed, with special attention to international recommendations.
Results: Depending on their target molecules, the CPI now in use differ from one another in the incidence of side effects such as autoimmune thyroid disease (4–16%), hypophysitis (0.1–18%), adrenalitis (0.7–8%), and autoimmune diabetes mellitus (0–7.6%). The typical clinical warning signs and laboratory constellations of hypophysitis include exhaustion, hyponatremia, and headache. Hypo- and hyperthyroidism and primary adrenocortical insufficiency likewise have nonspecific manifestations. Autoimmune diabetes mellitus often takes a fulminant course. Patients being treated with CPI should be monitored at close intervals, at least as frequently as the administration of the drug, so that endocrine side effects can be recognized in time. In case of doubt, glucocorticoid supplementation should be given whenever hypocortisolism is suspected, even before endocrine evaluation is completed and the results are available. Interrupting or discontinuing CPI treatment is rarely indicated.
Conclusion: With the increasing number of patients being treated with CPI, more and more physicians from a wide variety of specialties, not necessarily working in specialized centers, now have to consider immunologically mediated endocrine side effects in the differential diagnosis, and treat them properly when they arise. These things should be done in collaboration with endocrinologists. The ongoing study of such side effects of the CPI now in use, and of those that will be introduced in the future, is important and will lead to improved understanding.
The development of immune checkpoint inhibitors (CPI) is a milestone in oncology. The CPIs currently in use are directed against two target molecules:
- cytotoxic T-lymphocyte-associated protein 4 (CTLA4)
- programmed cell death-protein 1 (PD-1) (on T- and B-lymphocytes and monocytes) and PD-1 ligands that interact with it (mainly PD-L1, on antigen-presenting cells).
The molecules CTLA4 and PD-1/PD-L1 play a key physiological role in T-cell regulation and protect against excessive activation of the immune system. At present, various antibodies against CTLA4 (ipilimumab), PD-1 (nivolumab, pembrolizumab, cemiplimab), and PD-L1 (avelumab, durvalumab, atezolizumab) are available for a number of indications (malignant melanoma, non-small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, urothelial carcinoma, squamous cell carcinoma). Depending on the substance class, however, there is a risk of an autoimmune reaction causing severe side effects. Such immune-related adverse events (IRAE) arise under treatment with CTLA4 inhibitors in 81–93% of cases (34% with grade 3/4 severity) and somewhat less commonly under treatment with PD-1/PD-L1 inhibitors (69–79%; 14% grade 3/4) (1, 2, e1). These side effects can involve numerous organ systems, including the gastrointestinal tract (colitis), the lungs (pneumonitis), the liver (hepatitis), the skin, and the central nervous system (2).
The most common autoimmune-mediated endocrine side effects of CPI are autoimmune thyropathy and hypophysitis. Rarer endocrine side effects include autoimmune adrenalitis and autoimmune diabetes mellitus, which usually takes a fulminant course (Table) (3, 4). CPI-induced diabetes insipidus and hypoparathyroidism have also been described in case reports (e2, e3). The incidence of autoimmune side effects cannot be determined precisely from the approval studies, because the reported side effects and laboratory changes were not uniformly documented. In most cases (63–100%), CPI-induced endocrine side effects arise in the first 12 weeks of treatment with ipilimumab, and over a much broader period of time (0-48 weeks) under anti-PD-1-based therapy (5). Due to the long term effects of CPI, the development of endocrine IRAE up to 15 months after the end of treatment has been reported (e4).
Multiple medical disciplines are involved in the treatment of patients who take CPI. Both specialists and primary care physicians need to be aware of the endocrine side effects of these drugs. In the absence of a specific German guideline for the management of immune-mediated endocrine side effects, the following recommendations have been issued by the German Society for Endocrinology (Deutsche Gesellschaft für Endokrinologie, DGE), based in part on the existing European and American guidelines in oncology (6, 7) and endocrinology (8, 9). These recommendations were created by members of the thyroid section, section of adrenal gland/hypertension and steroids as well as section of diabetes, obesity and metabolism of the DGE and by the working groups on endocrine and neuroendocrine oncology and on the pituitary gland and pituitary tumors.
Frequency and clinical manifestations
While monotherapy with PD-1/PD-L1-inhibitors only rarely causes hypophysitis, treatment with anti-CTLA4 antibodies and, above all, combination therapy causes hypophysitis in approximately 10% of patients (Table) (3, 10, 11). This complication is more common in men than in women, and its incidence rises with age (12).
The symptoms are often nonspecific at first, including exhaustion, fatigue, and, in about half of all patients, headache, which should be asked about specifically. In cancer patients, such symptoms often arouse suspicion of other underlying conditions, e.g., tumor progression. CPI-associated increases in pituitary size are often mild and transient; visual field defects arise only when the gland becomes much larger than normal and extends beyond the sella turcica to involve the optic chiasm. Pituitary insufficiency is the most significant clinical manifestation of hypophysitis. Anti-CTLA4 therapy or anti-CTLA4/anti-PD-1 combination therapy commonly leads to insufficiency of the corticotropic (80%), thyrotropic (84%), and/or gonadotropic (76%) axes, and less frequently an impairment of somatotropic function (29%) (13). Anti-PD-1 monotherapy often causes only an isolated impairment of the corticotropic axis, with the corresponding clinical manifestations of hypocortisolism: weakness, exhaustion, hypotension, hyponatremia, and sometimes hypoglycemia (11). Central diabetes insipidus is also possible, but has only been described in rare cases (e2). Ipilimumab has been reported to cause hypophysitis more commonly when given in higher doses (14, 15, 16), but the pattern of involved hormonal deficiencies is probably not dose-dependent (17).
CPI-induced hypophysitis differs markedly from classic autoimmune hypophysitis in its clinical features. The latter mostly affects women (71%) and patients in early middle age (mean, 41 years; range, 16-81) and is associated with a larger mass lesion than CPI-induced hypophysitis. Among patients with autoimmune hypophysitis, 15% develop visual disturbances, and 50% develop diabetes insipidus (18, 19).
Diagnostic evaluation and differential diagnosis
As the clinical features of CPI-induced hypophysitis are nonspecific, an endocrine evaluation should be obtained before each CPI application in the first 4–6 months (at least once every four weeks), so that hypophysitis, in case it develops, can be identified at an early stage (6, 9, 20). On the basis of international recommendations and our own experience, we recommend that this evaluation should include sodium, potassium, thyroid-stimulating hormone (TSH), free thyroxine (f4), and cortisol (Figure 1). Circadian fluctuations of the cortisol concentration may complicate the interpretation of basal concentrations, but measurement early in the morning is not always possible as a practical matter. In case of clinical suspicion or unusual findings on routine testing—e.g., hyponatremia, which may indicate hypocortisolism—it may be necessary to repeat the cortisol measurement in the morning and to obtain specialized consultation from an endocrinologist. If hypocortisolism is suspected, a basal adrenocorticotropic hormone (ACTH) measurement serves to distinguish primary from secondary (pituitary) adrenocortical insufficiency. The usual standard diagnostic test, i.e., the ACTH stimulation test, is only of limited value, because the cortisol response may still be normal in the first 6-12 weeks after the onset of corticotropic insufficiency (8). In case of clinical suspicion of hypocortisolism, substitution therapy with hydrocortisone should be started immediately, without waiting for the results of the laboratory tests.
Before start of CPI therapy, and whenever there is concrete suspicion of pituitary insufficiency during treatment, the following hormone levels should be measured:
- in men: luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone
- in postmenopausal women: FSH
- in women with abnormal menstrual cycles who are not taking oral contraceptives: FSH, LH, estradiol.
In premenopausal women who are not taking oral contraceptives and have regular menstrual cycles, gonadotropic function is presumed to be normal. It must be kept in mind that the interpretation of laboratory findings may be complicated by severe underlying disease causing, for example, low gonadotropin and TSH levels.
In addition to laboratory evaluation, magnetic resonance imaging (MRI) of the pituitary gland is also required to exclude other intrasellar masses in the differential diagnosis (pituitary adenoma, metastasis of the patient’s underlying malignancy) (Figure 2a).
Hypocortisolism with acute manifestations is treated with fluid replacement and intravenous glucocorticoid administration, with a 100 mg bolus of hydrocortisone at first, followed by a continuous infusion of 100–200 mg of hydrocortisone over 24 hours (or equivalent doses of other glucocorticoids) (21) (Figure 3). We also recommend endocrinological consultation. After stabilization in this manner, hydrocortisone substitution can be continued orally and, in the further course of treatment, reduced to a maintenance dose of 15–25 mg of hydrocortisone equivalent per day, with approximately two-thirds of the total dose being given in the morning and the remaining third in the early afternoon (22, e5). All patients with primary or secondary adrenocortical insufficiency are given a patient passport (e6) and a standardized patient education program. This structured program is established by the German Society of Endocrinology and has been scientifically validated (23).
Depending on the findings of the endocrine evaluation, thyrotropic insufficiency can be treated with levothyroxine (beginning at least 12–24 hours after the start of glucocorticoid substitution), and gonadotropic insufficiency with testosterone in men or estradiol/gestagen in premenopausal women. Gonadotropic and thyrotropic function often recover over the long term, but, according to current evidence, the corticotropic axis generally remains permanently impaired (17, 18, 19, 20, 21, 22, 23, 24).
Because the temporary interruption of CPI therapy does not affect the functional long-term course of CPI-associated hypophysitis (10), and patients often urgently need to be treated for their underlying malignancy, CPI therapy can be continued in most cases. Only if the pituitary gland is markedly enlarged, producing symptoms of mass effect such as visual disturbances and severe headache, should one consider discontinuing CPI therapy and giving steroids (methylprednisolone, 0.5–1 mg/kg of body weight). When this is done, a switch to hydrocortisone substitution is often possible within 4 weeks (6). High-dose glucocorticoid therapy has no effect on either the functional or the structural changes of the pituitary gland (17, 24, 25) and should, therefore, only be used for narrow indications. A study in patients with melanoma revealed that high-dose glucocorticoid therapy for hypophysitis was associated with lower overall survival (hazard ratio [HR]: 0.24; 95% confidence interval: [0.07; 0.61]) (25).
Primary thyroid abnormalities
Frequency and clinical manifestations
Thyroid dysfunction is more common under anti-PD1/PD-L1-based treatment than under treatment with ipilimumab (Table). The induction of hypo- and hyperthyroidism and of painless thyroiditis has been described. The incidence of such complications (and others) is higher under combined anti-CTLA4/anti-PD-1 treatment. In the vast majority of cases (96–98%), the clinical manifestations of thyroid dysfunction are only mild (i.e., it is oligosymptomatic or asymptomatic) (26).
Diagnostic evaluation and differential diagnosis
Both the TSH level and the serum fT4 concentration must be measured in order to differentiate primary dysfunction of thyroid metabolism from thyrotropic pituitary insufficiency (Figure 4). If both values are low, or if the TSH level is inappropriately in the low-normal range despite a low fT4 concentration, then secondary hypothyroidism is present; in contrast, primary hypothyroidism is characterized by a high TSH value. Ultrasonography is used as the next step to differentiate the various types of primary thyroid dysfunction. Ultrasonography is especially helpful for patients with hyperthyroidism, in whom it is used to distinguish an organ-destroying thyroiditis from Graves’ disease and from an autonomously hormone-secreting thyroid nodule, particularly after a prior exposure to iodinated contrast media. Destructive thyroiditis is present in most cases of CPI-induced hyperthyroidism (Figure 2b). Rare cases of CPI causing hyperthyroidism by inducing TSH-receptor antibodies (TRAB) have also been described (27, e7); this is a type of autoimmune hyperthyroidism comparable to Graves’ disease. Destructive thyroiditis leads initially to the transient release of preformed thyroid hormone, and later on to hypothyroidism. In case of clinical uncertainty, the diagnosis of destructive hyperthyroidism, rather than CPI-induced autoimmune hyperthyroidism with TRAB, is supported by the absence of detectable TRAB, low perfusion on thyroid Doppler sonography, and low tracer uptake on thyroid scintigraphy. Conversely, the diagnosis CPI-induced autoimmune hyperthyroidism with TRAB is supported by elevated TRAB values, hyperperfusion, symmetrically increased technetium uptake on thyroid scintigraphy, and evidence of endocrine orbitopathy. The diagnosis of contrast-media-induced hyperthyroidism with thyroid autonomy is supported by the presence or a goiter or of thyroid nodules, as well as by a history of prior contrast media exposure.
Thyrostatic drugs (thiamazole, carbimazole, propylthiouracil) are not indicated for the treatment of transient hyperthyroidism due to destructive thyroiditis. Clinically relevant manifestations of hyperthyroidism are treated with beta-blockers, e.g., propranolol 40–120 mg/d. If the destructive process is very severe, with local pain and marked hyperthyroidism, glucocorticoid treatment can be considered as well (prednisolone, 1 mg/kg BW/d for 1–2 weeks). However, this does not affect the long-term course (28). Follow-up at brief intervals is indicated (in 3–6 weeks) in order to detect a potentially rapid transition (3, 29) to hypothyroidism. In some patients, the condition is only diagnosed in the hypothyroid stage. Most patients need long-term thyroid hormone substitution. Interrupting CPI therapy is generally unnecessary.
In patients with hyperthyroidism and elevated TRAB levels indicating an autoimmune process, thyrostatic treatment in combination with beta-blocker administration is indicated; if autoimmune hyperthyroidism persists, thyroid ablation with surgery or radioiodine therapy may be indicated. In such cases, the use of iodinated contrast media should be strictly avoided. In patients with hyperthyroidism of unclear pathophysiology who urgently need contrast studies, the potential adverse effect of contrast medium on the thyroid can be blocked as a pragmatic strategy. Afterward, endocrinological consultation should be obtained for assistance with further treatment.
In patients with a predominantly hypothyroid presentation, thyroid hormones are substituted in case of overt hypothyroidism (low fT4, high TSH) or symptomatic hypothyroidism (e.g., with weight gain, cold intolerance, constipation, and fatigue) (6, 7, 8, 9). TSH values that are only mildly elevated should be rechecked at close intervals (Figure 4). If CPI-induced thyroid dysfunction manifests itself with an elevated concentration of anti-thyroid peroxidase antibodies (TPO-Ab), together with the typical ultrasonographic findings of thyroiditis, substitution therapy may be an appropriate treatment even if the TSH level is only mildly elevated (9). 50–100 µg of levothyroxine per day is the usual starting dose; a lower dose (25–50 µg/d) should be considered for older patients with severe cardiovascular disease (30). The dose is adjusted in the further course of treatment on the basis of the TSH value. Whenever thyroid substitution therapy is to be initiated, other autoimmune endocrinopathies that may be present in parallel must be considered first. Above all, primary or secondary adrenocortical insufficiency must be ruled out, because, in such cases, levothyroxine treatment can be started only after the initiation of hydrocortisone substitution.
Primary adrenocortical insufficiency
The development of primary adrenocortical insufficiency is one of the rarer side effects of CPI (Table) (3, 9). As in secondary corticotropic insufficiency, the typical clinical manifestations are fatigue, hypotension, nausea, vomiting, hyponatremia, and hypoglycemia. The combination of a very low cortisol level and a markedly elevated ACTH level often obviates the need for an ACTH test. Further typical laboratory findings are a high renin concentration and low concentrations of aldosterone and dehydroepiandrosterone sulfate. Antibodies against 21-hydroxylase are present în some cases (e8). Tomographic imaging should be considered in order to rule out adrenal metastases of the underlying malignancy (Figure 3), but the initiation of potentially life-saving hydrocortisone substitution must not be delayed while physicians wait for the diagnostic studies to be completed. The procedure in such cases is the same as in the treatment of acute pituitary insufficiency. In further treatment, mineralocorticoid substitution
should be initiated (fludrocortisone, ca.
0.5–2.0 μg/d) if hydrocortisone replacement is reduced to less than 50 mg/d; here the treatment differs from that of adrenocortical insufficiency due to impaired pituitary function (21).
CPI-induced diabetes mellitus
The prevalence of autoimmune diabetes mellitus in patients receiving CPI treatment is less than 2%. It typically takes a fulminant course (in 50–86% of patients), presenting with diabetic ketoacidosis (3, 4, 31). Just as in classic type 1 diabetes mellitus, antibodies such as GAD-65-Ab and IA2-Ab and an insulin deficiency are often found over the further course (4, 31). Other characteristic manifestations are rapidly developing, marked hyperglycemia, along with polyuria, polydipsia, weight loss, and nausea (27). The timing of the onset of autoimmune diabetes mellitus is variable; it can arise immediately after the first administration of CPI, but it can also arise 12 months later (4). For this reason, the blood sugar concentration should be regularly checked from the initiation of CPI therapy onward, and rechecked whenever atypical symptoms of any kind are reported (Figure 1). As CPI-induced diabetes mellitus develops rapidly, the hemoglobin-A1c (HbA1c) value is not a suitable marker for screening. The presence of ketoacidosis or low C-peptide concentrations in the setting of hyperglycemia confirm diabetes due to insulin deficiency, necessitating immediate initiation of insulin treatment, fluid and electrolyte replacement, endocrinological consultation, and hospitalization for further monitoring. Insulin requirement is generally irreversible (31), and comprehensive patient education as in classic type 1 diabetes is therefore a key element of treatment. CPI therapy can be continued once the patient has been metabolically stabilized.
The thyroid gland, the pituitary gland, the adrenal gland, and the pancreatic islet cells are the main target organs of the immune-mediated endocrine side effects of treatment with CPI. Because these side effects are common, all patients receiving CPI are given a patient passport (e9) (www.pei.de/DE/arzneimittelsicherheit/schulungsmaterial/schulungsmaterial-node.html) and must be instructed about the risk of endocrine side effects. All patients who are currently under CPI therapy, or who have received CPI therapy in the past, and complain acutely of symptoms of unclear significance should undergo endocrinological evaluation without delay (Figure 3). Many CPI-induced endocrine side effects are characterized by the irreversible loss of one or more hormones and therefore necessitate permanent hormone substitution. With endocrinological consultation for assistance in the diagnostic evaluation and treatment of hormone insufficiency and excess, CPI therapy can usually be continued in these patients, or else restarted after a temporary interruption (32, 33).
Conflict of interest statement
Prof. Mai has received lecture honoraria from BMS and Eisai.
Prof. Fassnacht has received third-party research funding from Enterome.
Prof. Führer-Sakel has received third-party research funding from Novartis and lecture honoraria from Medupdate.
Prof. Honegger has received lecture honoraria from Münchner Akademie für Ärztliche Fortbildung e. V.
Prof. Weber has served as a paid consultant for Novartis, Ipsen, Novo Nordisk, and Lilly. He has received reimbursement of meeting participation fees from Novartis and Ipsen and reimbursement of travel expenses from Novaris, Ipsen, and Novo Nordisk, as well as lecture honoraria from Novartis, Ipsen und Novo Nordisk.
Prof. Kroiss has served as a paid consultant for Lilly, Baye, and Eisai. He has received reimbursement of meeting participation fees from Lilly and Ipsen and reimbursement of travel expenses from Ipsen, as well as lecture honoraria from Ipsen, Bristol Myers Squibb, Lilly, MSD, and Bayer. He has received third-party research funding from Lilly, Loxo Oncology, and Ipsen.
Manuscript submitted on 22 October 2020, revised version accepted on 1 February 2021.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Knut Mai
Medizinische Klinik m. S. Endokrinologie, Diabetes und Stoffwechsel
Charité – Universitätsmedizin, Charitéplatz 1
10117 Berlin, Germany
Cite this as:
Mai K, Fassnacht M, Führer-Sakel D, Honegger JB, Weber MM, Kroiss M:
The diagnosis and management of endocrine side effects of immune checkpoint inhibitors. Dtsch Arztebl Int 2021; 118: 389–96. DOI: 10.3238/arztebl.m2021.0143
Department of Internal Medicine I, Division of Endocrinology and Diabetes, University of Würzburg, University Hospital Würzburg, Würzburg: Prof. Dr. med. Martin Fassnacht, Prof. Dr. med. Dr. rer. nat. Matthias Kroiss
Comprehensive Cancer Center Mainfranken, University Hospital Würzburg: Prof. Dr. med. Martin Fassnacht, Prof. Dr. med. Dr. rer. nat. Matthias Kroiss
Department of Endocrinology, Diabetology and Metabolism, Essen University Hospital, University of Duisburg-Essen: Prof. Dr. med. Dr. rer. nat. Dagmar Führer-Sakel
Department of Neurosurgery, Tübingen University Hospital: Prof. Dr. med. Jürgen B. Honegger
Department of Internal Medicine I, Endocrinology, Johannes Gutenberg University Hospital Mainz: Prof. Dr. med. Matthias M. Weber
Department of Internal Medicine IV, Ludwig-Maximilians-University Munich: Prof. Dr. med.Dr. rer. nat. Matthias Kroiss
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