Glucocorticoid-induced adrenal insufficiency and glucocorticoid withdrawal syndrome: Two sides of the same coin.

Diseases of the adrenal glands can lead to primary adrenal insufficiency, and suppression of the hypothalamic-pituitary-adrenal axis can cause secondary adrenal insufficiency (adrenal suppression). The most common cause of adrenal suppression is exogenous steroids, a condition recently termed glucocorticoid-induced adrenal insufficiency (GIAI). Similarly, weaning from high doses of glucocorticoids or giving insufficient glucocorticoid replacement after curative surgery for endogenous hypercortisolism (Cushing syndrome) can lead to glucocorticoid withdrawal syndrome, which overlaps with GIAI.

Monitoring adrenal insufficiency through salivary steroids: a pilot study.

BACKGROUND: Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and exposure lacks adequate biochemical markers. We described the diurnal salivary cortisol (SalF) and cortisone (SalE) rhythm among different GRTs and analysed the associations between saliva-derived parameters and life quality questionnaires. METHODS: Control subjects (CSs, n = 28) and AI patients receiving hydrocortisone (HC, n = 9), cortisone acetate (CA, n = 23), and dual-release hydrocortisone once (DRHC-od, n = 10) and twice a day (DRHC-td, n = 6) collected 9 saliva samples from 07:00 to 23:00. Patients compiled Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Addison disease-specific quality-of-life questionnaires. SalE and SalF were measured by liquid chromatography-mass spectrometry. Exposure was monitored using SalE for HC and DRHC and SalF for CA. Area under the curve (AUC) was computed. Different GRTs were compared by Z-scores calculated from saliva-derived parameters. Questionnaire results predictors were evaluated with multiple regression analysis. RESULTS: Compared with controls, all GRTs resulted in glucocorticoid overexposure in the morning. Hydrocortisone, CA, and DRHC-td caused overexposure also in afternoon and evening. Compared with other treatments, CA determined increased Z-score-07:00 (P < .001), DRHC-td determined increased Z-score-AUC07:00→14:00 (P = .007), and DRHC-od induced lower Z-score-AUC14:00→23:00 (P = .015). Z-scores-AUC14:00→16:00 ≥ .619 best predicted questionnaire scores. CONCLUSIONS: None of the GRTs mimics normal glucocorticoid rhythmicity and exposure. SalE, SalF, and Z-score may be useful markers for monitoring and comparing different GRTs. Excess glucocorticoid in early afternoon best associated with depressive symptoms and worse life and sleep quality.

A case of Empty Sella syndrome with adrenal insufficiency masked by prednisolone after administration of immune checkpoint inhibitors.

INTRODUCTION: The use of immune checkpoint inhibitors (ICIs) is gradually increasing; ICIs produce a variety of immune-related adverse events (irAEs), especially ICI-induced hypoadrenocorticism, which can be a lethal complication if treatment is delayed. PATIENT CONCERNS: A 63-year-old man received chemotherapy with pembrolizumab for nonsmall cell lung cancer. He developed drug-induced interstitial pneumonia 366 days after receiving pembrolizumab and was treated with prednisolone. Five hundred thirty-seven days later, he developed drug-induced eosinophilic enteritis, and pembrolizumab was discontinued and prednisolone was continued. After discontinuation of prednisolone, general malaise and edema of the lower extremities appeared, and adrenal insufficiency was suspected. DIAGNOSIS: In blood tests on admission adrenocorticotropic hormone (ACTH) was 2.2 pg/mL and cortisol was 15 µg/dL, with no apparent cortisol deficiency. However, the cortisol circadian rhythm disappeared and remained low throughout the day; a corticotropin-releasing hormone stimulation test showed decreased reactive secretion of ACTH. Pituitary magnetic resonance imaging showed pituitary emptying, suggesting Empty Sella syndrome. INTERVENTIONS AND OUTCOMES: We started hydrocortisone and his symptoms were improved. CONCLUSIONS: The administration of high-dose steroids after ICI administration may mask the symptoms of hypoadrenocorticism as irAEs. Therefore, we should bear in mind the possibility of hypoadrenocorticism when we stop steroid therapy in patients who are treated with steroids after ICI administration.

Fluctuations in plasma adrenocorticotropic hormone concentration may predict the onset of immune checkpoint inhibitor-related hypophysitis.

Immune checkpoint inhibitor (ICI)-related hypophysitis (RH) is a common immune-related adverse event. The early detection of ICI-RH prevents life-threatening adrenal insufficiency. However, good predictors of secondary adrenal insufficiency in ICI-RH have not yet been reported. We hypothesized that fluctuations in serum adrenocorticotropic hormone (ACTH) and cortisol levels occur similarly to those in thyroid-stimulating hormone and thyroid hormone (thyroxine and triiodothyronine) levels in ICI-related thyroiditis. Here, we sought to test this hypothesis. Patients who used ICI and had a history of measurement of serum ACTH and cortisol concentrations were retrieved from electronic medical records, and those with a history of glucocorticoid use were excluded from the analysis. We evaluated fluctuations in serum ACTH and cortisol concentrations and the development of ICI-RH. For patients with ICI-RH, data at three points (before ICI administration (pre), maximum ACTH concentration (peak), and onset of ICI-RH) were analyzed to evaluate hormone fluctuations. A total of 202 patients were retrieved from the medical record. Forty-three patients were diagnosed with ICI-RH. Twenty-six out of 43 patients had sufficient data to evaluate fluctuations in serum ACTH and cortisol concentrations and no history of glucocorticoid use. ACTH concentrations changed from 37.4 (29.9-48.3) (pre) to 64.4 (46.5-106.2) (peak) pg/mL (1.72-fold increase, p=0.0026) in the patients with ICI-RH before the onset. There were no differences in cortisol concentrations between the pre and peak values in patients with ICI-RH. We also evaluated the fluctuations in serum ACTH and cortisol levels in patients who did not receive ICI-RH (62 cases). However, elevation of serum ACTH levels was not observed in patients without ICI-RH, suggesting that transient elevation of serum ACTH levels is a unique phenomenon in patients with ICI-RH. In conclusion, serum ACTH levels were transiently elevated in some patients with ICI-RH before the onset of secondary adrenal insufficiency. Monitoring the ACTH levels and their fluctuations may help predict the onset of ICI-RH.

Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency: a systematic review.

Background: Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency (IAD) is a rare but potentially fatal disease. Methods: We comprehensively searched the PubMed database and made a systematic review of immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency. If the status of other anterior pituitary hormones was not mentioned, the case was excluded. Results: We identified 123 cases diagnosed as immune checkpoint inhibitor-induced IAD, consisting of 44 female and 79 male patients. The average age of these patients was 64.3 ± 12.6 years old, and 67.5% were 60 years old or above. The majority (78.9%) of these patients received anti-programmed cell death protein-1 (anti-PD-1) antibodies or anti-programmed cell death ligand 1 (anti-PD-L1) antibodies or both, and 19.5% received combined therapy, sequential therapy, or both. A total of 26 patients received anti-cytotoxic T lymphocyte antigen 4 antibodies (anti-CTLA-4). The median ICI treatment cycle before the diagnosis of adrenal insufficiency was 8 (6, 12), and the median ICI treatment duration before the diagnosis of adrenal insufficiency was 6 (4, 8) months. Eleven cases developed IAD 1 to 11 months after discontinuation of ICIs. Fatigue and appetite loss were the most common symptoms, and surprisingly, there were two asymptomatic cases of IAD. Most patients (88 cases) had normal pituitary magnetic resonance imaging, only 14 cases reported mild atrophy or swelling pituitary gland, and 21 cases reported no imaging results. Most diagnoses were made by basal hormone levels, and pituitary stimulation tests were performed in only a part of the cases. No cases had been reported of discontinuation of ICI use due to IAD nor had there been any deaths due to IAD. Conclusion: IAD was predominant in elderly male patients mainly receiving anti-PD-1 or anti-PD-L1 antibodies. It was sometimes difficult to recognize IAD at first glance since non-specific symptoms were common and asymptomatic cases of IAD were also reported. Although IAD can be deadly, it usually does not affect the continued use of ICIs.

Primary multiple endocrine insufficiency during immune checkpoint inhibitor treatment: A case report.

RATIONALE: Immunotherapy with immune checkpoint inhibitors (ICI) has shown promising activity against many tumor types. However, they can also induce a wide array of immune-related adverse events, ranging from mild to fatal. Primary 3 endocrine gland insufficiency during treatment with ICI has rarely been reported. PATIENT CONCERNS: We report the case of a 33-year-old man with Ewing sarcoma who was treated with toripalimab as a second-line treatment. Approximately 11 months after initiating treatment, the patient developed subclinical hypothyroidism, which was followed by adrenal insufficiency and hypogonadism 6 months later. Consequently, the decision was made to discontinue ICI therapy and initiate hormone replacement therapy to manage endocrine deficiencies. DIAGNOSES: Serum adrenocorticotropic hormone, thyroid stimulating hormone, and prolactin levels increased significantly, while cortisol, estradiol, and testosterone levels decreased (Table 1). The patient had negative findings on the pituitary MRI. INTERVENTION: As part of the management strategy, ICI therapy was ceased and hormone replacement therapy was commenced to address endocrine deficiencies. OUTCOMES: After hormone replacement therapy, his symptoms improved and follow-up examinations showed normalization of hormone levels. LESSONS: Clinicians should be aware of the potential of immune checkpoint inhibitor therapy to cause endocrine dysfunction. Prompt recognition and management of these adverse events are crucial for patient health and quality of life.

Adrenal Suppression in Children During the Treatment for Acute Lymphoblastic Leukemia Beyond Induction.

BACKGROUND: Adrenal suppression (AS) is an iatrogenic, life-threatening condition that can occur after glucocorticoid exposure. Despite recognition that AS occurs after induction phase treatment in children with acute lymphoblastic leukemia (ALL), the risk of AS in phases beyond induction is unknown. We conducted a pilot study in pediatric patients with ALL to ascertain whether the risk of AS persists in post-induction phases of treatment. PROCEDURE: Patients diagnosed between 12 months to younger than 18 years with B or T-ALL and starting any new phase of treatment were eligible for the study. Relapsed or infant ALL were excluded. Low dose ACTH stimulation testing (LDST), measurement of albumin and cortisol binding globulin were performed in all patients. Screening for symptoms of AS was done. RESULTS: Twenty-four patients enrolled in the study. One was diagnosed with clear AS. Five others had a borderline cortisol peak, representing possible mild AS. Symptoms were nonspecific and did not help distinguish patients with normal LDST from those with borderline or abnormal results. CONCLUSION: Patients on treatment for ALL continue to be at risk of AS beyond induction treatment. Although this risk appears small, physicians must be vigilant as patients may be asymptomatic but could develop adrenal crisis during treatment.

Serum cortisol level to screen for significant hypothalamic-pituitary-adrenal axis suppression in patients receiving multiple steroid injections.

BACKGROUND: Morning serum cortisol level (mSCL) is a practical screening tool for hypothalamic-pituitary-adrenal (HPA) axis suppression and has been used to assess for duration of cortisol deficiency after epidural and peripheral glucocorticoid injections. More evidence is needed to establish the utility of mSCL in patients undergoing repeat injections with increasing cumulative glucocorticoid equivalent dose (CGED) that could place them at higher risk of HPA axis suppression. OBJECTIVES: To estimate the prevalence of spine injection candidates with significant HPA axis suppression (sigAS), to understand the correlation between 12 months of CGED and the presence of sigAS based on the timing of mSCL collection after the most recent glucocorticoid injection (within 6 weeks or between 6 weeks and 12 months), and to investigate demographic and clinical factors relating to sigAS. METHODS: Retrospective chart review of patients scheduled for spine injection who had an associated mSCL and documented histories of prior glucocorticoid injections. The steroid name, dose, type, and procedure location were recorded for each injection that occurred within 12 months before mSCL. CGED was calculated from standard glucocorticoid equivalent conversion factors. RESULTS: SigAS was present in 7.8% to 22% of the analysis cohorts. There was no association found between CGED and sigAS regardless of timing of mSCL. There was a trend toward lower mSCL and sigAS with increasing CGED. There were no significant relationships found between sigAS and overall demographic or clinical factors. CONCLUSIONS: A 3-fold reduction in the rate of sigAS was noted 6 weeks after the most recent steroid injection. Using mSCL provides a template to investigate the impact of CGED and the best timing for mSCL collection in order to define a more practical guideline to identify patients at higher risk of sigAS earlier and plan for future spine injections.

Clinical characteristics and outcomes of patients with primary liver cancer and immune checkpoint inhibitor-associated adrenal insufficiency: A retrospective cohort study.

BACKGROUND: Adrenal insufficiency (AI) is a rare, but potentially serious adverse event associated with immune checkpoint inhibitors (ICIs). This study aims to examine the incidence, clinical features and the clinical correlation between occurrence of AI and efficacy in primary liver cancer (PLC) patients treated with ICIs; and to evaluate the significance of the continuation of ICIs treatment in PLC patients who developed AI. METHODS: Between January 2020 and March 2022, 47 PLC patients with ICIs-associated AI (AI cohort) were screened from Zhongshan Hospital, Fudan university, a general hospital in China. Between December 2019 and August 2021, 419 PLC patients who were treated with ICIs were reviewed to identify those without immune- associated adverse events (irAEs) (control cohort). Clinical features and outcomes of the PLC patients from the two cohorts were compared. RESULTS: Totally, 47 PLC patients with AI (AI cohort) and 63 PLC patients without irAEs (control cohort) were included. The incidence of grades 3-4 of AI and all irAEs were 40.4 % and 48.9 %, respectively. The median three-year survival was significantly longer in the AI cohort than that in the control cohort (26.3 months (95 % CI: 18.9--33.5) vs.16.1 months (95 % CI:10.4--21.7); p = 0.021). Multivariable cox proportional hazards regression model showed that the development of AI remained significantly associated with improved overall survival (HR = 0.561; p = 0.033) in the adjusted regression analysis. CONCLUSION: The current study demonstrated that PLC patients undergoing ICIs therapy and developing AI after ICIs treatment had favorable survival outcomes compared to those without irAEs.

Continuing versus tapering low-dose glucocorticoids in patients with rheumatoid arthritis and systemic lupus erythematosus in states of low disease activity or remission: A systematic review and meta-analysis of randomised trials.

OBJECTIVES: To study the benefit and harm associated with continuing versus tapering low-dose glucocorticoids (GCs) in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who have achieved low disease activity/remission. METHODS: A protocolised (PROSPEROCRD42022325175) systematic review and meta-analysis of randomised trials was performed. Trials compared, in patients with low disease activity/remission and GCs at baseline, continued low-dose GCs (≤7.5 mg/d prednisone equivalent) with a taper. Co-primary outcomes were time to flare and adverse events (AEs), accompanied by secondary benefit and harm outcomes. We performed meta-analyses and evaluated risk of bias and quality of evidence (QoE). Subgroup analyses were conducted for patients with RA. RESULTS: Four trials (three: RA; one: SLE; study duration 24-104 weeks) with 472 participants were included. Tapering GCs resulted in a shorter time to flare (hazard ratio 3.41 [95 %-CI 1.96-5.93]; p<0.01; very low QoE). The risks of AEs, serious AEs, and withdrawal due to AEs were similar in both groups (very low to low QoE). There were more withdrawals due to lack of efficacy with tapered GCs (risk ratio 3.02 [1.56-5.87]; low QoE). In RA, the disease activity score-28 was lower with continued GCs (mean difference 0.49 [0.07-0.91]; low QoE). One of 238 patients in the tapering groups experienced adrenal insufficiency. Subgroup analyses yielded consistent results. CONCLUSION: In RA and SLE with low disease activity, continuing low-dose GCs may provide better sustained disease control, but QoE is insufficient. Adrenal insufficiency is very rare when tapering low-dose GCs. Longer-term safety concerns for GCs remain.

Evaluation of psoriasis patients with long-term topical corticosteroids for their risk of developing adrenal insufficiency, Cushing's syndrome and osteoporosis.

PURPOSE: In this study, we will investigate the possible side effects of psoriasis patients using long-term topical corticosteroids (TCS) such as adrenal insufficiency, Cushing's Syndrome (CS) and osteoporosis and determine how these side effects develop. MATERIAL AND METHODS: Forty-nine patients were included in the study. The patients were divided into two groups based on the potency of the topical steroid they took and the patients' ACTH, cortisol and bone densitometer values were evaluated. RESULTS: There was no significant difference between the two groups regarding the development of surrenal insufficiency, CS and osteoporosis. One patient in group 1 and 4 patients in group 2 were evaluated as iatrogenic CS. ACTH stimulation tests of these patients in group 2 showed consistent results with adrenal insufficiency, while no adrenal insufficiency was detected in the patient in Group 1. Patients who used more than 50g of superpotent topical steroids per week compared to patients who used 50g of superpotent topical steroids per week. It was identified that patients who used more than 50g of superpotent topical steroids had significantly lower cortisol levels, with a negatively significant correlation between cortisol level and the amount of topical steroid use (p < .01).Osteoporosis was detected in 3 patients in group 1 and 8 patients in Group 2. Because of the low number of patients between two groups, statistical analysis could not be performed to determine the risk factors. CONCLUSIONS: Our study is the first study that we know of that investigated these three side effects. We have shown that the development of CS, adrenal insufficiency and osteoporosis in patients who use topical steroids for a long time depends on the weekly TCS dosage and the risk increases when it exceeds the threshold of 50 grams per week. therefore, our recommendation would be to avoid long-term use of superpotent steroids and to choose from the medium-potent group if it is to be used.

Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology.

Introduction: Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. Methods: This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. Results: The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. Discussion: In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.

Statin treatment is not associated with an increased risk of adrenal insufficiency in real-world setting.

Introduction: Statins could reduce the synthesis of steroid hormones, thereby could cause adrenal insufficiency. We investigated this risk in a large nationwide database. Methods: We conducted a nested case-control study using a cohort of individuals affiliated to the French health insurance system in 2010, ≥18y and without adrenal insufficiency history. Each case had a first event of adrenal insufficiency between 2015 and 2017 and was matched to up to ten controls on age, sex, and prior treatment with corticosteroids. Statin exposure was measured over the five years preceding the index date, considering a six-month censoring lag-time. Association was estimated using a conditional logistic regression adjusted for confounders included in a disease risk score. Analyses were stratified on age, sex and corticosteroid history of use. Results: 4 492 cases of adrenal insufficiency were compared with 44 798 controls (median age 66y, 58% women), of which 39% vs. 33% were exposed to statins, respectively. No association between statin use and adrenal insufficiency was found when adjusting the model for confounders (adjusted odds ratio 0.98; 95% confidence interval 0.90-1.05). These results were consistent regardless of the exposure definition and stratifications considered. Conclusion: Statin-related adrenal insufficiency risk, if any, seems to be very limited and does not compromise the benefit of statin treatment.

Simultaneous Presentation of Secondary Adrenal Insufficiency and Primary Hypothyroidism due to Pembrolizumab: A Case Report.

Checkpoint inhibitors have gained increased traction in recent years as they have improved prognosis in various malignancies. Pembrolizumab, an anti-programmed cell death protein (PD-1) monoclonal antibody, has become a first-line chemotherapeutic agent for stage II non-small cell lung cancer since 2019. Although much more common with nivolumab, several immune-related adverse effects, particularly endocrinopathies, have been linked with pembrolizumab. We describe a case of a 59-year-old man with a history of unspecified lung cancer who presented with severe hyponatremia later attributed to secondary adrenal insufficiency and accompanying primary hypothyroidism secondary to pembrolizumab. Diagnosing adrenal insufficiency in patients on immune checkpoint inhibitors like pembrolizumab can be challenging due to nonspecific symptoms, making it crucial to rule out other causes of hyponatremia. Immunotherapy is known to cause thyroid immune-related adverse events, and anti-thyroid antibodies may not always be present in the diagnosis of hypothyroidism. Although there are some reported cases of pembrolizumab-induced adrenal insufficiency, the link between immunotherapy and endocrine disorders remains unclear. To our knowledge, no case reports exist that describe both primary hypothyroidism and secondary adrenal insufficiency after taking pembrolizumab, although such cases have been documented with axitinib. Timely diagnosis and treatment of adrenal insufficiency is crucial to prevent adverse effects, especially in patients with cancer receiving immunotherapy, as highlighted in this case.

Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-Risk Resected Melanoma.

Importance: Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. Objective: To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study analyzed patients treated with adjuvant anti-PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation (range, 18.2 to 70.4 months). Main Outcomes and Measures: Incidence, spectrum, and ultimate resolution vs persistence of chronic irAEs (defined as those persisting at least 3 months after therapy cessation). Descriptive statistics were used to analyze categorical and continuous variables. Kaplan-Meier curves assessed survival, and Wilson score intervals were used to calculate CIs for proportions. Results: Among 318 patients, 190 (59.7%) were male (median [IQR] age, 61 [52.3-72.0] years), 270 (84.9%) had a cutaneous primary, and 237 (74.5%) were stage IIIB or IIIC at presentation. Additionally, 226 patients (63.7%) developed acute irAEs arising during treatment, including 44 (13.8%) with grade 3 to 5 irAEs. Chronic irAEs, persisting at least 3 months after therapy cessation, developed in 147 patients (46.2%; 95% CI, 0.41-0.52), of which 74 (50.3%) were grade 2 or more, 6 (4.1%) were grade 3 to 5, and 100 (68.0%) were symptomatic. With long-term follow-up (median [IQR], 1057 [915-1321] days), 54 patients (36.7%) experienced resolution of chronic irAEs (median [IQR] time to resolution of 19.7 [14.4-31.5] months from anti-PD-1 start and 11.2 [8.1-20.7] months from anti-PD-1 cessation). Among patients with persistent irAEs present at last follow-up (93 [29.2%] of original cohort; 95% CI, 0.25-0.34); 55 (59.1%) were grade 2 or more; 41 (44.1%) were symptomatic; 24 (25.8%) were using therapeutic systemic steroids (16 [67%] of whom were on replacement steroids for hypophysitis (8 [50.0%]) and adrenal insufficiency (8 [50.0%]), and 42 (45.2%) were using other management. Among the 54 patients, the most common persistent chronic irAEs were hypothyroid (38 [70.4%]), arthritis (18 [33.3%]), dermatitis (9 [16.7%]), and adrenal insufficiency (8 [14.8%]). Furthermore, 54 [17.0%] patients experienced persistent endocrinopathies, 48 (15.1%) experienced nonendocrinopathies, and 9 (2.8%) experienced both. Of 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) experienced no effect on chronic irAEs whereas 12 (32.4%) experienced a flare in their chronic toxicity. Twenty patients (54.1%) experienced a distinct irAE. Conclusions and Relevance: In this cohort study of 318 patients who received adjuvant anti-PD-1, chronic irAEs were common, affected diverse organ systems, and often persisted with long-term follow-up requiring steroids and additional management. These findings highlight the likelihood of persistent toxic effects when considering adjuvant therapies and need for long-term monitoring and management.

Three-month tapering and discontinuation of long- term, low-dose glucocorticoids in senior patients with rheumatoid arthritis is feasible and safe: placebo-controlled double blind tapering after the GLORIA trial.

OBJECTIVE: The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication. METHODS: Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering. RESULTS: 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency. CONCLUSIONS: Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration.