Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurred in polyglandular endocrinopathies

doi:10.21203/rs.3.rs-2604581/v1

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Research Article

Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurred in polyglandular endocrinopathies

https://doi.org/10.21203/rs.3.rs-2604581/v1

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Journal Publication

published 06 Jul, 2023

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Background: With the increasing application of immune checkpoint inhibitors (ICI) in tumor therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as one of its adverse effects, is on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events.

Methods: A retrospective study was conducted in patients with ICI-induced endocrinopathies in Endocrinology Department from January 2019 to August 2022. Clinical features, laboratory findings and therapy information were collected. All patients underwent 3-6-month follow-up.

Results: 28 patients with IAD were enrolled. All of them were treated with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 weeks after starting ICI treatment.Over half of patients (53.5%) also had primary hypothyroidism or fulminant type 1 diabetes mellitus (FT1DM). Other types of endocrinopathy were not found. The interval between two gland damages was 4-21 weeks or at the same time. In the 28patients, primary hypothyroidism (46.4%) was more common than FT1DM (7.1%). Fatigue and nausea were the chief manifestation. Hyponatremia was also easily to be detected. All patients continued oral cortisol during follow-up.

Conclusions: IAD induced by ICI could occur independently, and more often in combination with hypothyroidism or FT1DM. This damage could happen at any stage of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy.

immune checkpoint inhibitors

isolated adrenocorticotropic hormone deficiency

primary hypothyroidism

fulminant type 1 diabetes mellitus

Immune checkpoint inhibitors (ICI) are monoclonal antibodies for advanced tumor therapy by blocking cytotoxic-T cell lymphocyte antigen-4 (CTLA4) or programmed cell death receptor-1 (PD-1) and its ligand (PD-L1) [1]. Apart from anti-tumor effects, ICI can also cause unpredictable immune-related adverse events (irAEs), including various endocrine disorders through overactivated immune cells [2]. Although some studies suggested endocrine irAEs predict positive prognosis for some type of cancer [3–5], some endocrine damages, such as adrenocorticotropic deficiency, can be fatal and recovery is often impossible.

The occurrence of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been growing as a result of the prevalence of ICI. IAD is characterized by secondary adrenal insufficiency with low or no cortisol production and normal secretion of pituitary hormones other than ACTH[6]. Sometimes, it can be challenging to recognize IAD, as its presentation is quite similar to the symptoms during cancer therapy, such as fatigue, appetite loss, and weight loss [7, 8]. Furthermore, IAD could also occur with other endocrine damages simultaneously or sequentially during ICI treatment or even after ICI cessation [9]. Therefore, IAD could be overlooked when pituitary hormones are not measured routinely. Hence, it is essential to identify IAD patients and provide them with appropriate treatment.

To gain a better insight into IAD caused by ICI, we retrospectively reviewed patients with IAD induced by ICI in our department. We summarized their clinical features to improve our apprehension and awareness of this disorder, particularly from an endocrine perspective.

2.1 Participants and Study Design.

A retrospective study was conducted in Department of Endocrinology of Zhongshan Hospital from January 2019 to August 2022, to investigate patients with ICI-induced endocrinopathies. Patients were referred to our department due to suspected or confirmed diagnosis of endocrine irAE. Information was extracted from history record, including the type of cancer, ICI used, clinical presentation, biochemical results, pituitary magnetic resonance imaging (MRI), and initial and follow-up treatment. All hormone and biochemistry measurements were performed at the central lab of Zhongshan hospital. Patients were followed up of 3–6 months after discharge. Those with endocrine gland disorders prior to ICI were excluded from the study. All methods were carried out in accordance with declaration of Helsinki. This study was approved by the Ethics Committee of Zhongshan Hospital of Fudan university.

2.2 Diagnostic Criteria.

Briefly, IAD was defined as following the established biochemical diagnostic criteria of this clinical entity, i.e., the association of low cortisol level with inappropriately normal/low ACTH levels [6]. Pituitary MRI was also performed, when possible, to rule out other potential disorders particularly metastasis.

Overt primary hypothyroidism (HT) was defined by a thyroid stimulating hormone (TSH) level above the upper reference limit, with a concomitant free thyroxine (FT4) level below the lower reference interval or by TSH > 10.0 mIU/L regardless of FT4. Subclinical hypothyroidism was defined as normal FT4 level in the presence of TSH elevation above the upper limit of the normal reference range and < 10.0 mIU/L. Thyroid autoantibodies were examined as well, including thyroid peroxidase antibody (TPO-Ab), thyroglobulin antibody (TG-Ab) and TSH-receptor antibody (TR-Ab).

Diagnosis of fulminant type 1 diabetes mellitus (FT1DM) was based on published literature [10]and included all of the following: (1) acute onset of diabetes with rapid progression to ketoacidosis; (2) hyperglycemic symptoms with a duration less than 1 week; (3) high concentrations of plasma glucose (> 16.0 mM) with either normal or mildly elevated glycated hemoglobin (HbA1c) < 8.5% at initial presentation; and (4) severely impaired pancreatic β-cell secretory capacity.

2.3 Severity classification.

Severity of each patient was evaluated based on Common Terminology Criteria for Adverse Events (CTCAE version 5.0). Endocrine-irAEs was graded from asymptomatic (Grade 1) to fatal (Grade 5), with symptoms ranging from mild (Grade 1) to most intense (Grade 3). The severity of IAD was graded based on the criteria of hypopituitarism. Fatigue is a feeling of general weakness with a pronounced inability to summon sufficient energy to accomplish daily activities, grading from relieving by rest (Grade 1) to limiting self-care activity (Grade 3). Nausea is characterized by a queasy sensation and/or the urge to vomit, varying from loss of appetite (Grade 1) to inadequate oral intake (Grade 3). Headache characterized by a sensation of marked discomfort in various parts of the head, not confined to the area of distribution of any nerve.

2.4 Statistical Analysis.

SPSS 26.0 was used for data analysis. Measurement data that conformed to normal distribution were expressed as mean ± standard deviation, and those that did not conform to normal distribution were expressed as median quartile (P25, P75). Enumeration data are expressed as n (%). The Student’s t-test was used for mean comparisons between two groups of subjects for normally distributed data, and the Mann-Whitney test was employed for nonparametric data. P < 0.05 was considered as significant.

3.1 General information of patients with IAD induced by ICI.

In general, total 38 patients with ICI-induced endocrinopathies were admitted to our department from January 2019 to August 2022. Among these patients, 28 patients were diagnosed as IAD. The rest 9 patients were diagnosed with subacute thyroiditis (Grade 1), hypopituitarism (involved at least 2 axes), or type 1 diabetes (Fig. 1). In these 28 patients, 13 patients were diagnosed only with IAD (Grade 3–4), while the other 13 patients with IAD (Grade 3–4) and HT (Grade 1–2), the rest 2 with IAD (Grade 3) and FT1DM (Grade 4). The average ages of patients were 61.2 ± 10.9 years, with a slight majority of males (16 vs 12). The tumor types varied (Table 1). The median time to develop IAD was 24 weeks, and the earliest was 4 weeks (after 2 cycles). Pituitary MRI was performed in 14 patients and all showed no abnormality. For those who received chemotherapy, they have ceased this therapy at least 3 months before hormone testing.

Table 1

General information of patients with IAD.
	IAD (n = 13)	IAD + HT (n = 13)	IAD + FT1DM (n = 2)	Total (n = 28)
Gender (male/female)	8/5	7/6	1/1	16/12
Age, years, mean ± SD	63 ± 9.5	58.8 ± 11.5	65	61.2 ± 10.9
Occurrence time, weeks, [median(range)]
IAD	27(18–40)	24(21–33)	18.5	24(18–39)
HT	-	24(21–42)	-
FT1DM	-	-	18.5
Tumor types, numbers
Cervical cancer	1	1		2
Nasopharyngeal carcinoma	1	1		2
Lung cancer	3	3	1	7
Esophageal cancer	1	2	-	3
Gastric carcinoma	-	1	-	1
Hepatocellular carcinoma	3	4	-	7
Intrahepatic cholangiocarcinoma	3	3	-	6
Renal cell carcinoma	2	2	-	4
Bladder cancer	1	-	-	1
Melanoma		2		2
Breast cancer		1	1	2
Unknown origin	1			2
ICIs (dosage, weeks), numbers
sintilimab (200mg, q3w)	3	6	1	10
pembrolizumab (200mg, q3w)	6	1		7
toripalimab (240mg, q3w)	2	0		2
camrelizumab (200mg, q2w)	2	2		4
tislelizumab (240mg, q2w)	0	1		1
nivolumab (unknown, q2w)	0	1		1
atezolizumab (1200mg, q3w)	0	0	1	1
CS1003 (unknown, q3w)	0	1		1
AK104 (unknown, q2w)	0	1		1
Other combination therapy, numbers
chemotherapy	2	1	1	5
anlotinib	1	2		3
lenvatinib	2	1		3
apatinib	1			1

3.2 Characteristics of patients with IAD alone.

Among the thirteen patients with IAD, four were treated with sintilimab, four with pembrolizumab, three with camrelizumab, and 2 with toripalimab (Fig. 2). The main symptoms were fatigue (Grade 2–3) and nausea (Grade 2). Head (Grade 1) was very mild in only one patient. Only three patients experienced hypotension (Grade 3). Nine patients showed hyponatremia (seven in Grade 4 and two in Grade 3), and blood potassium was all within the normal range. Six patients used intravenous hydrocortisone, while two developed agitation (Grade 3) after using 100–200 mg of intravenous steroids. Seven people prescribed oral cortisone acetate without using intravenous corticosteroids due to relatively mild symptoms. The average dose of oral cortisone acetate was 43.75 ± 15.5mg at discharge (Table 2).

Table 2

Clinical characteristics of patients with IAD.
	IAD (n = 13)	IAD + HT (n = 13)	IAD + FT1DM(n = 2)	P
Symptoms, n (%)
Fatigue	13(100%)	13(100%)	2(100%)	-
Nausea	11(84.6%)	8(61.5%)	1(50%)	-
Headache	1(7.7%)	2(15.4%)	0	-
Polydipsia	-	-	2(100%)	-
Hypotension, n/n tested (%)	3/13(23.1%)	1/13(7.7%)	0/2	-
Hyponatremia, n/n tested (%)	9/13(69.2%)	8/13(61.5%)	2/2(100%)	-
Laboratory results (unit, normal range)
Morning ACTH (pmol/L, 1.5–13.9)	1.5 ± 1.4	0.7 ± 0.7	1.5	0.22^a
Morning Cortisol (nmol/L, 133–537)	41.1 ± 51.3	34.48 ± 44.4	11.47	0.74^a
TSH (mIU/L, 0.27–4.2)	2.7 ± 1.8	32.63 ± 37.88	24.9 ± 27.9	-
Thyroid autoantibodies, n positive/n tested (%)
TPO-Ab	3/13(23.1%)	2/13(15.4%)	0	-
TG-Ab	1/13(7.7%)	1/13(7.7%)	0	-
TR-Ab	0	0	0	-
GAD/IAA/ICA, n positive	-	-	0	-
Pituitary MRI (numbers)	7	7	-	-
Intravenous glucocorticoid (mg)	283 ± 175.3	308.3 ± 196.0	0	0.00^a
cortisone acetate at discharge (mg)	43.2 ± 14.9	39.4 ± 19.6	37.5	0.56^a
Levothyroxine at discharge (µg)	-	54.5 ± 40.4	-	-

a, comparison between patients with IAD and IAD + HT.

3.3 Characteristics of patients with IAD and HT.

Among the 13 patients with IAD and HT, 5 were treated with sintilimab, and 3 with pembrolizumab, 1 with pembrolizumab, nivolumab, and tislelizumab respectively. Two patients were on AK104 (an anti-PD-1 and anti-CTLA4 bispecific antibody) and CS1003 (nofazinlimab, an anti-PD-1 antibody) respectively, which are still in clinical research (Fig. 2). Five patients showed HT first, and then IAD with interval of 4–20 weeks, while the other 6 were diagnosed at the same time. Only 1 patient who used sintilimab developed HT subsequent to IAD, with an interval of 21 weeks. Fatigue (Grade 2–3), nausea (Grade 2) and headache (Grade 1) were also reported in this group. Eight patients had hyponatremia (five cases in Grade 4, and three in Grade 3). Only two patients were positive for thyroid autoantibodies. Six patients were administered intravenous corticosteroids, with an average dose of 308.3 ± 196.0mg. One of them experienced agitation (Grade 3) and the symptoms were relieved after stopping glucocorticoid temporarily. Five patients with subclinical hypothyroidism did not take levothyroxine. The average dose of levothyroxine taken at discharge was 54.5 ± 40.4 µg (Table 2).

3.4 Characteristics of patients with IAD and FT1DM.

Two patients who were treated with atezolizumab and toripalimab respectively, developed FT1DM and IAD at 16 weeks and 21 weeks (Fig. 2). Interestingly, both reported mild elevation in blood glucose levels, and then progressed to diabetic ketoacidosis (DKA) within 4 weeks. IAD was diagnosed at the same time. They experienced fatigue (Grade 3), nausea (Grade 2), vomiting, thirsty and polydipsia. HbA_1c levels were 8.4% and 8.0%, respectively. Diabetic autoantibodies, including anti-GAD, insulin autoantibody, and islet cell antibody, were all negative. Fasting insulin and C-peptide were also below the lower limit of detection. Intravenous insulin and fluid resuscitation were started immediately. Both patients were treated with oral cortisol instead of intravenous corticosteroids. They received standard insulin injection regimen with daily doses of 22 and 33 units respectively (Table 2).

3.5 Follow-up.

All patients continued cortisol regimen in the following 3–6 months. Only one patient with poorly differentiated neck adenocarcinoma continued sintilimab. The other 27 patients discontinued ICI in the follow-up. Unfortunately, one patient died of tumor metastasis, while the rest continued to receive other treatments.

In this study, we retrospectively analyzed 28 patients with IAD caused by anti-PD-1/PD-L1. Over half of the patients had an additional endocrinopathy. HT was more common than FT1DM in patients with IAD, but the latter could be more severe. Fatigue and nausea were the chief complaints. Hyponatremia (67.8%) was common laboratory findings. All patients continued oral hydrocortisone regimen during follow-up. To our knowledge, this is the first study to provide a comprehensive overview of IAD patients under ICI therapy.

In our study, IAD was mainly caused by anti-PD1/PD-L1, with the exception of one case induced by a bispecific antibody (AK104). IAD is more common in anti-PD1 therapy, as opposed to whole hypophysitis caused by anti-CTLA4[7, 11]. There is no consensus on whether IAD by ICIs can be classified as hypophysitis, whereas ACTH deficiency was still more commonly affected than thyrotrophs and gonadotrophs in anti-CTLA4-induced hypophysitis [12]. The exact mechanism of IAD by ICI is yet to be determined. However, some studies suggested that it may be associated with the induction of anti-pituitary antibodies by ICI [13, 14]. Additionally, a special phenotype of HLA is also a possible predisposing factor for pituitary irAE [14, 15].

Patients in our research have some similarities with those in prior studies. As suggested previously, ICI-IAD usually occurs several months to over a year [16]. Men at an elder age are more likely to be affected [12]. Hyponatremia tends to be one of the most common presenting findings[7]. Abnormalities in pituitary MRI are seen in 81% of cases due to anti-CTLA-4, while in 18% of patients with hypophysitis caused by anti-PD-1/PD-L1, the initial enlargement of pituitary tends to resolve within weeks [7, 16]. As seen in our patients, no abnormalities in pituitary MRI were indicated, which is in agreement with the previous study [17]. Nevertheless, a normal MRI scan does not exclude hypophysitis, and imaging is still required to diagnose hypophysitis and to exclude other sources of pituitary failure, such as metastatic disease [18]. Although high-dose glucocorticoid is recommended in case of suspected acute adrenal crisis (usually 100 mg hydrocortisone intravenously followed by 50 mg every 6 hour and fluid resuscitation) [19], we noticed that 3 patients in our study developed hyperactivity after 200-300mg hydrocortisone intravenously, and recovered after temporary discontinuation of glucocorticoid. Thus, it is important to be aware of any alterations in patients' symptoms in hormone replacement therapy.

There are also some results different from previous reports. Previous studies have reported that around 38% of patients undergoing anti-PD-1 treatment may experience thyroid dysfunction, including subclinical disease [17, 20], while up to 70% of them may develop thyroid auto-antibodies [21]. However, our research found that almost half of these patients developed HT, and auto-antibodies were negative in most cases. Thyroid dysfunction is common in anti-PD1 induced irAEs [7, 22]. T cells are believed to play a dominant role in destructive thyroiditis by anti-PD-1 [23]. Generally, the symptoms related to HT are mild [4] and treatment can begin when needed [20]. Our study revealed that some patients developed IAD following HT, reminding doctors to be aware of the potential risk of IAD during immunotherapy.

In our research, two patients developed IAD and FT1DM after being treated with atezolizumab and sintilimab respectively. The incidence of ICI-T1DM is low, ranging from 0.2–1.4% [24], mainly due to anti-PD-1/PD-L1 [25]. The immune etiology of FT1DM and IAD may be more evident when they co-occur. Destruction of β-cells was more severe in ICI-T1DM in comparison with classic T1DM [26]. In contrast, only 50% of patients with ICI-T1DM have a relevant autoantibody, with anti-GAD65 being the majority [23]. DKA at diagnosis is very frequent, up to 70% [7]. In our study, the C-peptide level was too low to be detected, suggesting severe impairment of islet β cell. ICI-FT1DM combined with IAD is rare and can be fatal, but the treatment in this condition could be conflicting. On one hand, both hormones must be replaced instantly due to profound lack of insulin and glucocorticoid. On the other hand, glucocorticoids will increase serum glucose, potentially worsening hyperglycemia and DKA. In our study, we applied oral glucocorticoid to these patients and obtained remission. This may be an optimal alternative in this condition.

Previous studies have largely focused on the incidence of single endocrine irAEs; however, people with one autoimmune disease are more likely to develop a second autoimmune disease [27]. Growing evidence suggested that polyendocrinopathy is common following ICI treatment, similarly to autoimmune endocrine diseases in general. ICI-induced polyendocrinopathy is usually seen as a combination of thyroid disorder and other endocrinopathy, such as hypophysitis, T1DM, or primary adrenal insufficiency, known as autoimmune polyendocrine syndrome (APS) [28]. It is assumed that ICI-induced APS shares a similar occurrence rate with the classic type [7]. It is possible to classify a combination of IAD and other endocrinopathies as a new type of APS. From this point, the endocrine irAEs can be useful in one respect, as they provide new insights into the pathogenesis of autoimmune endocrinopathy [29].

Our study has several limitations that should be taken into consideration. First, it was a retrospective observational study with a relatively small sample size, thus further research with a larger sample size is needed to gain a better understanding of IAD. Second, only patients admitted to the Department of Endocrinology were included, implicating those with mild symptoms were not enrolled. Third, the follow-up period was short. Therefore, we were unable to determine the relationship between irAEs and treatment effect. Forth, despite similar mechanisms and potential adverse reactions, the prevalence of endocrine irAEs largely depends on the utilization of different ICIs. For instance, some drugs in this study, such as sintilimab, toripalimab, camrelizumab, tislelizumab, are not approved for certain use outside China, thus restricting the clinical application of partial findings in our research.

In conclusion, ICI-induced IAD, especially by anti-PD-1/PD-L1, could be commonly observed in polyendocrinopathy, as the combination of thyroid disease and T1DM. As there have been no reliable biomarkers for predicting IAD at present, dynamic monitoring of cortisol and ACTH should be required in all patients receiving ICI. It is necessary to pay close attention to the patient’s endocrine system irAEs for a long time, even after ending ICI treatment.

ICI, immune checkpoint inhibitor; PD-1, programmed cell death receptor-1; PD-L1, programmed cell death ligand-1;CTLA-4, cytotoxic-T cell lymphocyte antigen-4; irAE, immune related adverse effect; IAD, isolated adrenocorticotropic hormone deficiency; HT, primary hypothyroidism; FT1DM, fulminant type 1 diabetes mellitus; MRI, Magnetic resonance imaging; ACTH, Adrenocorticotropic hormone; TSH, thyroid stimulating hormone; TPO-Ab, thyroid peroxidase antibody; TG-Ab, thyroglobulin antibody; TR-Ab, TSH-receptor antibody; GAD, anti-glutamic acid decarboxylase; IAA, insulin autoantibody; ICA, Islet cell antibody; APS, autoimmune polyendocrine syndrome.

Ethics approval and consent to participate: Written, informed consent was obtained from all of the participants, and the study was approved by the ethics committee of Zhongshan Hospital, Fudan University, China.

Consent for publication: Not Applicable.

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: This work was supported by the National Science Foundation of China (Grant No. 82200896).

Authors' contributions: HC participated in the design of the study and drafted the manuscript. LZ performed the statistical analysis and participated in the data collection. LZ and XL participated in the design of the study and conceived of the study. All authors read and approved the final manuscript.

Acknowledgements: The authors are grateful to all of the subjects who participated in this study.

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No competing interests reported.

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Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurred in polyglandular endocrinopathies

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Journal Publication

Version 1

Abstract

Figures

1 Background

2 Methods

2.1 Participants and Study Design.

2.2 Diagnostic Criteria.

2.3 Severity classification.

2.4 Statistical Analysis.

3 Results

3.1 General information of patients with IAD induced by ICI.

3.2 Characteristics of patients with IAD alone.

3.3 Characteristics of patients with IAD and HT.

3.4 Characteristics of patients with IAD and FT1DM.

3.5 Follow-up.

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1