MANAGEMENT OF ENDOCRINE DISEASE: Glucocorticoid-induced adrenal insufficiency: replace while we wait for evidence?

Laugesen, Kristina; Broersen, Leonie H A; Hansen, Simon Bøggild; Dekkers, Olaf M.; Sørensen, Henrik Toft; Jørgensen, Jens Otto Lunde

doi:10.1530/eje-20-1199

Cited by 28 publications

(23 citation statements)

References 60 publications

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“…Iatrogenic (ie, glucocorticoid-induced) AI is a well-known potential condition occurring after glucocorticoid withdrawal and one of the most frequent causes of glucocorticoid deficiency ( 14 ). Clinically relevant AI may arise after abrupt or inappropriately managed withdrawal of glucocorticoids, especially in patients taking oral and intra-articular long-acting formulations, high glucocorticoid doses, and long treatment regimens ( 15 , 16 ). Nevertheless, the risk of glucocorticoid-induced AI cannot be safely ruled out even in patients taking topical or inhaled glucocorticoids ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

“…Even though treatment regimens, route of administration, potency, dose, duration of glucocorticoid treatment, as well as individual glucocorticoid sensitivity, have been postulated as potential risk factors for glucocorticoid-induced AI, no clear-cut predictive factors of risk of onset and duration of AI before HPA axis recovery have been identified so far ( 15 , 16 , 20 , 21 ). The main reasons explaining this uncertainty are the lack of reliable data (studies with different design, populations, and treatment regimens) and the absence of guidelines on glucocorticoid-induced AI, leading to heterogeneous glucocorticoid withdrawal plans and different assessment of HPA axis recovery among studies ( 17 , 22 ).…”

Section: Discussionmentioning

confidence: 99%

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The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System

Raschi

Fusaroli

Massari

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Adrenal insufficiency (AI) is a life-threatening condition complicating heterogenous disorders across various disciplines, with challenging diagnosis and notable drug-induced component. Objective To describe the spectrum of drug-induced AI through adverse drug event reports received by the Food and Drug Administration (FDA). Design Retrospective disproportionality analysis. Setting FDA Adverse Event Reporting System (FAERS) (>15,000,000 reports since 2004). Participants Adverse event reports extracted from FAERS over the past 2 decades. Interventions Cases containing any of the preferred terms in the Medical Dictionary for Regulatory Activities describing AI. Signals of disproportionate reporting for drugs recorded in ≥10 cases as primary suspect. Main Outcomes and Measures Reporting trend of drug-induced AI. Results We identified 8,496 cases of AI, 97.5% serious, 41.1% requiring hospitalization. AI showed an exponential increase throughout the years, with 5,282 (62.2%) cases in 2015-2020. We identified 56 compounds associated with significant disproportionality: glucocorticoids (N=1971), monoclonal antibodies (N=1644, of which N=1330 associated with immune checkpoint inhibitors - ICIs), hormone therapy (N=291), anti-infectives (N=252), drugs for hypercortisolism or adrenocortical cancer diagnosis/treatment (N=169), protein kinase inhibitors (N=138). Cases of AI by glucocorticoids were stable in each 5-year period (22-27%), whereas those by monoclonal antibodies, largely ICIs, peaked from 13% in 2010-2015 to 33% in 2015-2020. Conclusions We provided a comprehensive insight into the evolution of drug-induced AI, highlighting the heterogeneous spectrum of culprit drug classes and the emerging increased reporting of ICIs. We claim for urgent identification of predictive factors for drug-induced AI, and establishment of screening and educational protocols for patients and caregivers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System

Raschi

Fusaroli

Massari

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…A much rarer condition, adrenal insufficiency, has been identified in the case of the long-term use of the oral form of budesonide ( 36 ), which in T-ARDIS appears as a potential ARDs associated with the glucocorticoid receptor with a highly significant q -value. Furthermore, the association between glucocorticoids and adrenal insufficiency is an active topic of discussion in the current literature ( 37 ).…”

Section: Resultsmentioning

confidence: 99%

Mining drug–target and drug–adverse drug reaction databases to identify target–adverse drug reaction relationships

2021

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The level of attrition on drug discovery, particularly at advanced stages, is very high due to unexpected adverse drug reactions (ADRs) caused by drug candidates, and thus, being able to predict undesirable responses when modulating certain protein targets would contribute to the development of safer drugs and have important economic implications. On the one hand, there are a number of databases that compile information of drug–target interactions. On the other hand, there are a number of public resources that compile information on drugs and ADR. It is therefore possible to link target and ADRs using drug entities as connecting elements. Here, we present T-ARDIS (Target—Adverse Reaction Database Integrated Search) database, a resource that provides comprehensive information on proteins and associated ADRs. By combining the information from drug–protein and drug–ADR databases, we statistically identify significant associations between proteins and ADRs. Besides describing the relationship between proteins and ADRs, T-ARDIS provides detailed description about proteins along with the drug and adverse reaction information. Currently T-ARDIS contains over 3000 ADR and 248 targets for a total of more 17 000 pairwise interactions. Each entry can be retrieved through multiple search terms including target Uniprot ID, gene name, adverse effect and drug name. Ultimately, the T-ARDIS database has been created in response to the increasing interest in identifying early in the drug development pipeline potentially problematic protein targets whose modulation could result in ADRs. Database URL: http://www.bioinsilico.org/T-ARDIS

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“…Concerns about the use of ACTH stimulation testing for the detection of HPA axis dysfunction have also centred on its susceptibility to false negative results when used in the context of an acute insult to the HPA axis (for example, following pituitary gland surgery or apoplexy). However, despite these recognised limitations, the standard 250-µg test in combination with an unstimulated early morning cortisol test remains the preferred dynamic assessment when screening for secondary/tertiary AI, including glucocorticoid-induced AI [16,17,18], and the assessment protocol utilized in PONENTE mitigated these factors and aligned with clinical practice. The cut-offs chosen to denote normal adrenal function and partial and complete AI were based on the specific assay used and may vary with other clinical immunoassays; a single cut-off value should always be interpreted in the context of the clinical setting.…”

Section: Methodsmentioning

confidence: 99%

Adrenal function recovery after durable oral corticosteroid sparing with benralizumab in the PONENTE study

Menzies‐Gow

Gurnell²,

Heaney³

et al. 2022

Eur Respir J

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Oral corticosteroid dependence among patients with severe eosinophilic asthma can cause adverse outcomes, including adrenal insufficiency. PONENTE's oral corticosteroid-reduction phase showed that, following benralizumab initiation, 91.5% of patients eliminated corticosteroids or achieved a final dosage ≤5 mg·day−1 (median, 0.0 mg [range, 0.0–40.0]).The maintenance phase assessed the durability of corticosteroid reduction and further adrenal function recovery. For approximately 6 months, patients continued benralizumab 30 mg every 8 weeks without corticosteroids or with the final dosage achieved during the reduction phase. Investigators could prescribe corticosteroids for asthma exacerbations or increase daily dosages for asthma control deteriorations.Outcomes included changes in daily oral corticosteroid dosage, Asthma Control Questionnaire 6 (ACQ-6), and St. George's Respiratory Questionnaire (SGRQ), as well as adrenal status, asthma exacerbations, and adverse events.598 patients entered PONENTE; 563 (94.1%) completed the reduction phase and entered the maintenance phase. From the end of reduction to the end of maintenance, the median oral corticosteroid dosage was unchanged (0.0 mg; [range, 0.0–40.0]), 3.2% (n=18/563) of patients experienced daily dosage increases, the mean ACQ-6 score decreased from 1.26 to 1.18, and 84.5% (n=476/563) of patients were exacerbation free. The mean SGRQ improvement (–19.65 points) from baseline to the end of maintenance indicated substantial quality-of-life improvements. Of patients entering the maintenance phase with adrenal insufficiency, 32.4% (n=104/321) demonstrated an improvement in adrenal function. Adverse events were consistent with previous reports.Most patients successfully maintained maximal oral corticosteroid reduction whilst achieving improved asthma control with few exacerbations and maintaining or recovering adrenal function.

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MANAGEMENT OF ENDOCRINE DISEASE: Glucocorticoid-induced adrenal insufficiency: replace while we wait for evidence?

Cited by 28 publications

References 60 publications

The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System

The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System

Mining drug–target and drug–adverse drug reaction databases to identify target–adverse drug reaction relationships

Adrenal function recovery after durable oral corticosteroid sparing with benralizumab in the PONENTE study

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