The Diagnosis and Management of Endocrine Side Effects of Immune Checkpoint Inhibitors

Abstract

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 (0.5-2%). 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.

Figures

Figure 1

Diagnostic testing for endocrine side effects of immune checkpoint inhibitor therapy *1 in premenopausal women with regular menstrual cycles, the sex hormones do not need to be measured *2 at least once every four weeks ACTH, adrenocorticotropic hormone; fT4, free tetraiodothyronine; FSH, follicle-stimulating hormone; LH, luteinizing hormone; m, men; TSH, thyroid-stimulating hormone; w, women

Figure 2:

Structural findings of endocrine immune-related adverse events (IRAE) affecting the thyroid and pituitary gland: (a) magnetic resonance imaging (MRI) of ipilimumab-induced hypophysitis (sagittal T1-weighted image with contrast medium), and (b) typical imaging findings of destructive thyroiditis after immune checkpoint inhibitor therapy. The pituitary gland in (a) is enlarged, with convex protrusion into the suprasellar cistern. There is marked contrast enhancement due to hypophysitis, and the pituitary gland is not clearly demarcated.

Figure 3

The diagnosis and management of immune-checkpoint-inhibitor-induced acute hypophysitis *assay-dependent, morning cortisol

Figure 4

The interpretation and management of pathological thyroid hormone parameters under treatment with immune checkpoint inhibitors fT4, free thyroxine; TSH, thyroid-stimulating hormone; RR, reference range