Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol

Woods, C. G.; Argese, Nicola; Chapman, Matthew; Boot, Christopher; Webster, Rachel; Dabhi, Vijay; Grossman, Ashley; Toogood, Andrew; Arlt, Wiebke; Stewart, Paul M.; Crowley, Rachel; Tomlinson, Jeremy W.

doi:10.1530/eje-15-0608

Cited by 129 publications

(134 citation statements)

References 43 publications

Supporting

Mentioning

122

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, three patients did not even meet the cortisol cut offs recently suggested by Tomlinson et al as sufficient to justify avoiding an SST (<35 and >348 nmol/L in patients taking inhaled glucocorticoids). 14 Just over half of patients were co-managed with the endocrine team; this was unevenly distributed across the centres and may reflect the availability of local referral pathways. Pharmacological management was also very varied, with some clinicians stopping/switching the steroid alone, others switching the ARVs and stopping the steroid and some opting to switch ARVs only.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9][10][11] Although glucocorticoid treatment courses of less than 3 weeks duration often will not lead to HPA axis suppression, at relatively high doses, significant HPA suppression can occur in as little as 5 days. 13,14 Longer-acting glucocorticoid formulations are associated with a higher risk of SAI. 15,16 …”

Section: Features and Timing Of Ics And Saimentioning

confidence: 99%

“…13 Of note, many use a lower threshold of greater than 450 nmol/L and greater than 348 nmol/L has been suggested in those on current inhaled glucocorticoids. 14,39 Nevertheless, patients who have 9 am cortisol levels of less than 450 nmol/L should be further investigated. The standard SST is the most frequently used test in this context 40 where 0 minute, 30 minute and 60 minute cortisol levels are measured after a 250 µg tetracosactide injection.…”

Section: Investigation Of Ics/sai and Management Of Highrisk Co-prescmentioning

confidence: 99%

See 2 more Smart Citations

Iatrogenic Cushing’s syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies

et al. 2016

View full text Add to dashboard Cite

Ritonavir and cobicistat, used as pharmacokinetic enhancers in combination with some antiretrovirals (ARVs) for the treatment of HIV, are potent inhibitors of the CYP3A4 isoenzyme. Most glucocorticoids are metabolised via the CYP3A4 pathway and iatrogenic Cushing's syndrome (ICS), with possible secondary adrenal insufficiency (SAI), is a recognised complication following co-administration with ritonavir or cobicistat. A structured approach for identifying and managing potentially affected individuals has not been established. We systematically identified patients with ICS/SAI and found substantial heterogeneity in clinical practice across three large London HIV centres. While this significant drug interaction and its complications are now well-recognised, it is apparent that there is no standardised approach to management or guidance for the general physician. Here we describe the management of ICS/SAI in our current practice, review the available evidence and suggest practice recommendations. KEYWORDS : Adrenal insuffi ciency , cobicistat , Cushing's syndrome , HIV , ritonavir IntroductionRitonavir and cobicistat are pharmacokinetic enhancers used in the treatment of HIV infection. They are extremely potent inhibitors of cytochrome P450 3A4 (CYP3A4) activity. Ritonavir, originally developed as an antiretroviral, is used ABSTRACT Iatrogenic Cushing's syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies at sub-therapeutic doses, in combination with HIV protease inhibitors (PIs), to significantly increase their concentrations and allow less frequent and lower dosing.1 Cobicistat was developed more recently and is similar in structure. It is used in combination with PIs or elvitegravir (an integrase inhibitor) 2 but has no antiretroviral activity itself. 3 The downside of this pharmacokinetic manipulation is the significant potential for interactions with CYP3A4 substrates, leading to side effects. CYP3A4 is the dominant isoenzyme of the hepatic cytochrome P450 system and is the primary metabolic step for the degradation of endogenous and most prescribed corticosteroids. The metabolism of these can therefore be decreased by inhibitors such as ritonavir/cobicistat. 4 Subsequent increases in exogenous corticosteroid plasma concentrations and half-life can lead to iatrogenic Cushing's syndrome (ICS) 5 and, at supraphysiological levels, to suppression of adrenocorticotropic hormone (ACTH) and endogenous corticosteroid secretion, potentially resulting in secondary adrenal insufficiency (SAI). There is abundant evidence highlighting this issue. 1,[6][7][8][9][10][11] However, a structured approach to identify and manage potentially affected individuals has not been established. We aim to summarise the current management of ICS/SAI in three large HIV patient cohorts, review the available literature and develop practice recommendations. Of note, cobicistat became available after the evaluation period covered; however, all advice for ritonavir is applicable to i...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Features and Timing Of Ics And Saimentioning

confidence: 99%

Section: Investigation Of Ics/sai and Management Of Highrisk Co-prescmentioning

confidence: 99%

See 1 more Smart Citation

Iatrogenic Cushing’s syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Morning basal cortisol assessment is a simple, inexpensive method with good correlation with serum cortisol after corticotropin-releasing hormone (CRH) stimulus and could be a screening tool in children with asthma at risk of AS after corticosteroid withdrawal. [4][5][6] The study aimed at investigating the integrity of the HPA axis in children with persistent asthma and infants with recurrent wheezing at the beginning of a first inhaled corticosteroids (ICS) trial.…”

Section: Introductionmentioning

confidence: 99%

Oral corticosteroids for asthma exacerbations might be associated with adrenal suppression: Are physicians aware of that?

Barra

Fontes

Cintra

et al. 2017

Rev. Assoc. Med. Bras.

View full text Add to dashboard Cite

show abstract

“…In fact, dose-dependent adrenal insufficiency is common in patients treated with long-term GC therapy as a result of negative-feedback mechanism leading to adrenal suppression 16,68,69. Interestingly, assessment of the plasma cortisol response to ACTH injection in RA patients before and after 12 weeks of treatment with low-dose prednisolone (7.5 mg/day) unveiled a 35% reduction in the mean values of plasma cortisol levels at 60 minutes in the prednisolone group but not in the placebo group 70.…”

Section: Introductionmentioning

confidence: 99%

Chronotherapy with low-dose modified-release prednisone for the management of rheumatoid arthritis: a review

Beltrametti

Ianniello²,

Ricci³

2016

TCRM

View full text Add to dashboard Cite

To date, rheumatoid arthritis (RA) remains a debilitating, life-threatening disease. One major concern is morning symptoms (MS), as they considerably impair the patients’ quality of life and ability to work. MS change in a circadian fashion, resembling the fluctuations of inflammatory cytokines such as interleukin-6, whose levels are higher in RA patients compared to healthy donors. Conversely, serum levels of the potent anti-inflammatory glucocorticoid cortisol are similar to that of healthy subjects, suggesting an imbalance that sustains a pro-inflammatory state. From a therapeutic point of view, administering synthetic glucocorticoids (GCs) to RA patients represents an optimal strategy to provide for the inadequate levels of cortisol. Indeed, due to their high efficacy in RA, GCs remain a cornerstone more than 60 years after their first introduction, and despite the development of a wide range of targeted agents. However, to improve safety, low-dose GCs have been introduced, that have demonstrated high efficacy in reducing disease activity, radiological progression, and improving patients’ signs and symptoms especially in early RA when added to conventional disease-modifying antirheumatic drugs. A further improvement has been provided by the development of modified-release prednisone, which, by taking advantage of the circadian fluctuations of inflammatory cytokines, cortisol and MS, is given at bedtime to be released approximately 4 hours later. Several studies have already demonstrated the efficacy of this agent on disease activity, MS, and quality of life in the setting of established RA. Moreover, preliminary studies have shown that this new formulation not only has no impact on the adrenal function, but likely improves it. This review is a comprehensive, updated summary of the current evidence on the use of GCs in RA, with focus on the efficacy and safety of low-dose prednisone and modified-release prednisone, the latter representing a rational, cost-effective, and tailored approach to maximize the benefit/risk ratio in RA patients.

show abstract

Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol

Cited by 129 publications

References 43 publications

Iatrogenic Cushing’s syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies

Iatrogenic Cushing’s syndrome due to drug interaction between glucocorticoids and the ritonavir or cobicistat containing HIV therapies

Oral corticosteroids for asthma exacerbations might be associated with adrenal suppression: Are physicians aware of that?

Chronotherapy with low-dose modified-release prednisone for the management of rheumatoid arthritis: a review

Contact Info

Product

Resources

About