Differences between immunotherapy-induced and primary hypophysitis—a multicenter retrospective study

Abstract

Objective Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH) Design Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH. Methods All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected. Results Median time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 % of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002). Conclusions Clinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.

Diabetes insipidus: A rare endocrine complication of immune check point inhibitors: A case report and literature review

“…Patients treated with ICIs rarely develop CDI secondary to an autoimmune process involving the hypothalamo-posterior pituitary region. Dysregulation of the posterior pituitary-hypothalamic axis induced by ICI has been reported in 13 case reports that are available in the current literature (summarized in Table II ), ( 1 , 7-16 , 20 , 21 ). Almost all patients developed CDI with a substantial delay from treatment administration, ranging from 28 to 270 days, except in one case where CDI developed immediately after sintilimab, a PD-1 inhibitor ( 14 ).…”

“…Finally, we ended-up to only 13 cases reports reporting data on DI among ICI treated patients (Flow diagram). A total of 14 patients presenting with DI post-immunotherapy with predominance of the male sex (11 males vs. 1 female, in 2 patients sex was not specified) were described (Table V), (1,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)20,21). All patients had been treated with ICIs for solid malignancies except two cases treated for Hodgkin lymphoma and acute myeloid leukaemia.…”

New developments and concepts in the diagnosis and management of diabetes insipidus (AVP‐deficiency and resistance)

“…79,99 PD-1 may be expressed in pituitary cells or lymphocytes, whereas PD-L1 is also expressed in pituitary adenomas. [56][57][58][59]77,78,82,[100][101][102] Because these antibodies are of the IgG4 isotype, the mechanism of IgG4-related hypophysitis may be related to that of anti-PD-1/PD-L1-related hypophysitis 78 (Table 3).…”

“…The mechanistic basis of ICI‐induced CDI remains unclear, but includes type II and type IV hypersensitivity reactions, as well as ectopic pituitary CTLA‐4 expression 79,99 . PD‐1 may be expressed in pituitary cells or lymphocytes, whereas PD‐L1 is also expressed in pituitary adenomas 56–59,77,78,82,100–102 . Because these antibodies are of the IgG4 isotype, the mechanism of IgG4‐related hypophysitis may be related to that of anti‐PD‐1/PD‐L1‐related hypophysitis 78 (Table 3).…”

Immune checkpoint inhibitor-related endocrinopathies

“…The incidence and manifestations of each ICI-related endocrinopathy are listed in Table 2 . [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] ICI-induced APS is even rare. In our previous study, the likelihood of APS in patients on combination therapy of anti-CTLA-4 and anti-PD-1 increased onefold than in patients on PD-1 inhibitors and fourfold than in those on PD-L1 inhibitors.…”