STATE OF THE ART REVIEW

Glucocorticoid induced adrenal insufficiency BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from Alessandro Prete,1 Irina Bancos2

ABSTRACT

1 Synthetic glucocorticoids are widely used for their anti-inflammatory and Institute of Metabolism and Systems Research, University of immunosuppressive actions. A possible unwanted effect of glucocorticoid treatment Birmingham, Birmingham, UK 2Division of Endocrinology, is suppression of the hypothalamic-pituitary-adrenal axis, which can lead to adrenal Metabolism and Nutrition, insufficiency. Factors affecting the risk of glucocorticoid induced adrenal insufficiency Department of Internal Medicine, Mayo Clinic, (GI-AI) include the duration of glucocorticoid therapy, mode of administration, Rochester, MN 55905, USA Correspondence to: I Bancos glucocorticoid dose and potency, concomitant drugs that interfere with [email protected] glucocorticoid metabolism, and individual susceptibility. Patients with exogenous (ORCID 0000-0001-9332-2524) Cite this as: BMJ 2021;374:n1380 glucocorticoid use may develop features of Cushing’s syndrome and, subsequently, http://dx.doi.org/10.1136/bmj.n1380 glucocorticoid withdrawal syndrome when the treatment is tapered down. Symptoms Series explanation: State of the Art Reviews are commissioned of glucocorticoid withdrawal can overlap with those of the underlying disorder, as on the basis of their relevance to academics and specialists well as of GI-AI. A careful approach to the glucocorticoid taper and appropriate in the US and internationally. patient counseling are needed to assure a successful taper. Glucocorticoid therapy For this reason they are written predominantly by US authors. should not be completely stopped until recovery of adrenal function is achieved. In this review, we discuss the factors affecting the risk of GI-AI, propose a regimen for the glucocorticoid taper, and make suggestions for assessment of adrenal function recovery. We also describe current gaps in the management of patients with GI-AI

and make suggestions for an approach to the glucocorticoid withdrawal syndrome, http://www.bmj.com/ chronic management of glucocorticoid therapy, and education on GI-AI for patients and providers.

Introduction the main aspects of GI-AI and discontinuation of Exogenous glucocorticoids can cause adrenal glucocorticoids. insufficiency (glucocorticoid induced adrenal on 28 September 2021 by guest. Protected copyright. insufficiency; GI-AI), which is among the most Epidemiology of glucocorticoid induced adrenal common causes of cortisol deficiency.1 Its true insufficiency prevalence is difficult to ascertain because of the Systemic glucocorticoids are used by 1-3% of the heterogeneity of studies. Moreover, a mismatch general population.3-6 Focusing on the long term use exists between the high prevalence of “biochemical” of oral glucocorticoids, the prevalence is 0.5-1.8%.5-10 GI-AI and the reporting of its “clinical” Oral glucocorticoids are more commonly used by consequences, suggesting potential under-diagnosis women and older people; chronic use is reported in and lack of awareness among clinicians.2 GI-AI 1.4% of patients older than 55 years and in 3% of is one of the most dangerous adverse effects of women over the age of 80.3 7 8 10 A systematic review glucocorticoid therapy and puts patients at risk of and meta-analysis found that the absolute risk of life threatening adrenal crises. Discontinuation of GI-AI induced by oral glucocorticoids was 48.7%, long term glucocorticoid therapy can be difficult; with the highest risk in people with hematologic to stop treatment safely, clinicians must consider malignancies (60%), followed by patients with a both the recovery of normal cortisol secretion history of renal transplant (56.2%), inflammatory and potential withdrawal symptoms. Despite bowel disease (52.2%), and rheumatologic disorders widespread use of glucocorticoids, the evidence (39.4%).11 guiding the management of GI-AI originates from The use of inhaled glucocorticoids has also very heterogeneous studies in terms of design, increased over time in both children and adults,12 13 patient population, sample size, types and regimens and the overall risk of GI-AI in these patients is of glucocorticoids used, and assessment of adrenal 7.8%.11 Adult patients treated with topical or nasal function. Therefore, the level of evidence is low, glucocorticoids were reported to have a lower risk which results in variation in management across of GI-AI of 4.2-4.7%.11 Patients treated with intra- different centers and clinicians. The aim of this articular glucocorticoids had biochemical evidence review is to provide an up-to-date overview of of GI-AI in 52.2% of cases; however, this estimate the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 1 STATE OF THE ART REVIEW

was based on pooled evidence from only four studies extensively. However, it is important to note that high including a total of 69 patients.11 quality evidence is limited. BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from

Sources and selection criteria Systemic glucocorticoid therapy We searched PubMed for studies using the terms Systemic glucocorticoids, especially those with “glucocorticoid-induced adrenal insufficiency”, longer half life and higher potency, are more likely “steroid-induced adrenal insufficiency”, “tertiary to cause GI-AI compared with other administration adrenal insufficiency”, “glucocorticoid withdrawal routes because of the direct negative feedback on the syndrome”, and “glucocorticoid taper.” We HPAA (box 1 and table 2).22 Treatment with bedtime considered all studies published in the English glucocorticoid administration and multiple split language between 1 January 2010 and 15 doses is more likely to affect circadian ACTH release November 2020. Relevant publications outside this and cause GI-AI.23-25 On the other hand, alternate day timeline were selected on the basis of review of the administration, as well as pulse therapy with high bibliography. Unless stated, we report data from dose systemic glucocorticoids, is associated with a studies that assessed adrenal function by dynamic lower risk of GI-AI because the HPAA has more time testing (adrenocorticotropic hormone (ACTH) to recover (box 1).23 26-30 stimulation tests, corticotropin releasing hormone Several studies have suggested a direct relation stimulation test, overnight metyrapone test, insulin between the dose and duration of systemic tolerance test). We predefined the priority of study glucocorticoid therapy and the likelihood of GI-AI, selection for this review according to the level of the although the evidence is limited.2 23 31-33 A recent evidence (systematic reviews and meta-analyses of analysis of medical records from primary and literature and randomized controlled trials, if any), secondary care in England found that the incidence on the basis of the population of interest (studies of GI-AI and iatrogenic Cushing’s syndrome among reporting on GI-AI, with clear description of the type, chronic users of oral glucocorticoids (mainly dose, and duration of glucocorticoid use), the sample prednisolone) increased with higher daily and size (studies with larger sample size were prioritized), cumulative doses.2 Although these data provide and the time of publication (more recent studies were a good population based estimate of the risk of GI- prioritized). AI, establishing this risk at the individual level is difficult.11 32-36

Pathophysiology of hypothalamic-pituitary-adrenal axis Short courses (<2 weeks) of high dose http://www.bmj.com/ suppression and recovery glucocorticoids are usually associated with a swift Glucocorticoids that directly enter the systemic recovery of adrenal function,18 37 38 although cases circulation and those surviving the first pass of GI-AI lasting more than seven to 14 days have metabolism after gastrointestinal absorption exert been described.31 39-44 The possible exception negative feedback on the corticotropin releasing to this is in patients who receive frequent short hormone producing neurons and pituitary glucocorticoid courses, as in the treatment of asthma corticotroph cells. This leads to reduced adrenal or chronic obstructive pulmonary disease and during cortisol production and, after prolonged exposure, emetogenic chemotherapy. Of 37 healthy people on 28 September 2021 by guest. Protected copyright. adrenal cortical hypoplasia and atrophy (fig 1, top given prednisone at doses ranging from 2.5 mg to 60 panel).14-16 After the effect of glucocorticoid therapy mg over seven days on three occasions, separated by on the hypothalamic-pituitary-adrenal axis (HPAA) 14 day washout periods, two developed GI-AI, lasting has worn off, production of ACTH and corticotropin as long as four months in one of them.43 releasing hormone typically recovers first, followed In a prospective study of 311 patients with by that of cortisol, which can remain suppressed in exacerbation of chronic obstructive pulmonary the long term if adrenal atrophy has ensued (fig 1, disease treated with prednisolone for ≤14 days, bottom panel).17-19 9%, 3%, and 2% had biochemical evidence of GI-AI when assessed at one, three, and six months after Factors affecting likelihood of glucocorticoid induced discontinuing glucocorticoids.45 Of note, a substantial adrenal insufficiency number of these patients were exposed to short The risk of developing GI-AI is difficult to predict on an courses of glucocorticoid therapy for exacerbations individual basis. The glucocorticoid formulation used, of chronic obstructive pulmonary disease before and dose, and treatment duration can affect this risk, but during the study.46 In a prospective study of patients a great degree of overlap exists.11 20 21 Nevertheless, with cancer treated with at least three short courses multiple studies have assessed the various factors of high dose dexamethasone (three to four days) that contribute to development of GI-AI (box 1), which every two to four weeks to counteract chemotherapy can help clinicians to establish the risk individualized induced nausea, 15% of patients developed GI- to each patient (table 1). This classification, together AI within three to six months.47 Patients who also with clinical judgment, can be useful in deciding received megestrol acetate had a threefold higher the management of patients exposed to exogenous risk of GI-AI, possibly because of its glucocorticoid glucocorticoids (fig 2 and fig 3); in particular, we activity (box 1).47 48 focused on systemic and inhaled glucocorticoids, as Children also have a significant risk of GI-AI when their effects on the HPAA have been examined more exposed to systemic glucocorticoids, which may be

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A Paraventricular

Negative BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from nucleus of feedback hypothalamus

Gastro- Exogenous GCs Oral intestinal First pass in systemic GCs absorption metabolism circulation CRH

Mouth, Long term exposure to Inhaled pharynx Direct exogenous GCs can GCs absorption lead to atrophy of from lungs Negative pituitary corticotroph cells Anterior feedback IV, IM pituitary ACTH GCs

Topical GCs Adrenal glands Possible systemic absorption Intra- Cortisol Long term exposure to articular exogenous GCs can lead GCs to adrenocortical atrophy Adrenal (atrophy of zona fasciculata androgens and zona reticularis)

Aldosterone secretion is preserved http://www.bmj.com/ Secretion of mineralocorticoids is regulated by renin-angiotensin system

B

Discontinuation of ACTH on 28 September 2021 by guest. Protected copyright. supraphysiological doses of exogenous GCs Cortisol

Normal range Circulating levels

Time

Fig 1 | Pathophysiology of glucocorticoid induced hypothalamic-pituitary-adrenal axis (HPAA) suppression and recovery. Top panel: HPAA suppression by exogenous glucocorticoids. Glucocorticoids that directly enter the systemic circulation and those surviving first pass metabolism after gastrointestinal absorption will exert negative feedback on the HPAA by decreasing hypothalamic corticotropin releasing hormone (CRH) synthesis and secretion and its action on release of ACTH by the anterior pituitary. The acute effect on the pituitary is suppressed synthesis of pro- opiomelanocortin (POMC) (and consequently of adrenocorticotropic hormone (ACTH) and other POMC derived peptides); in the long term, atrophy of corticotroph cells and Crooke’s cells can develop. Crooke’s changes can be found in both endogenous and iatrogenic Cushing’s syndrome and include an intracytoplasmic hyaline ring (keratin filaments), paranuclear vacuoles (lysosomes), and secretory granules. In the absence of ACTH, the adrenal cortex loses the ability to produce cortisol and androgens and, ultimately, can become atrophic. Secretion of aldosterone is preserved. Bottom panel: schematic representation of HPAA recovery following discontinuation of glucocorticoid therapy. After short term treatment with glucocorticoids, ACTH secretion is the first to recover, followed by CRH and eventually cortisol and androgens. After long term exposure, a swift and marked increase of ACTH is observed, and this precedes the recovery of cortisol secretion. Abnormal cortisol secretion can last a very long time if adrenal atrophy has developed. Adrenal androgens can also remain suppressed in the long term. GC=glucocorticoid; IM=intramuscular; IV=intravenous the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 3 STATE OF THE ART REVIEW

Box 1: Factors affecting the risk of glucocorticoid induced adrenal insufficiency (GI-AI) BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from Glucocorticoid mode of administration Systemic administration (including oral, intravenous, intramuscular) Factors increasing the risk of GI-AI: • Daily administration for >2-4 weeks • Multiple daily split doses • Bedtime administration Factors reducing the risk of GI-AI: • Alternate day administration • Pulse systemic therapy (intermittent intravenous administration of very high doses of glucocorticoids over a few days or weeks) Inhaled glucocorticoids Factors increasing the risk of GI-AI: • High daily doses given for >6-12 months • Treatment with fluticasone propionate • Concomitant use of oral glucocorticoids (including intermittent use—eg, in chronic obstructive pulmonary disease) • Lower body mass index (children) • Higher compliance with treatment (children) Intra-articular glucocorticoids • Factors increasing the risk of GI-AI: • Repeated injections with high doses of glucocorticoids • Inflammatory arthropathies Percutaneous glucocorticoids Factors increasing the risk of GI-AI: • Long term and frequent use of large amounts of high potency glucocorticoids • Prolonged use on inflamed skin or with impaired barrier function • Occlusive dressings • Use on mucous membranes, eyelids, and scrotum • Larger body surface area to body weight ratio (children) http://www.bmj.com/ Glucocorticoid half life and potency The use of long acting glucocorticoids (ie, with a longer biological half life) and formulations with higher glucocorticoid potency (ie, stronger binding to the glucocorticoid receptor) predispose to more pronounced adrenal suppression because of the continuous effect on the HPAA. This is particularly relevant for systemic administration. See table 2 for a list of widely used systemic glucocorticoids. Glucocorticoid dose

Higher doses of glucocorticoids correlate with increased inhibition of corticotropin releasing hormone secretion, especially when given daily over on 28 September 2021 by guest. Protected copyright. a prolonged period. The evidence for the effect of the dose of systemic glucocorticoids on manifestations of GI-AI is, however, limited. A stronger relation between the risk of GI-AI and administered doses has been described for inhaled glucocorticoids and can inform the risk of adrenal suppression (table 1 and table 3). Drug interactions CYP3A4 inhibitors CYP3A4 is the major pathway for the inactivation of most prescribed glucocorticoids. CYP3A4 inhibitors are expected to increase the systemic exposure to synthetic glucocorticoids (ie, higher risk of GI-AI): • Strong inhibitors include boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, mifepristone, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole • Moderate inhibitors include amiodarone, aprepitant, cimetidine, conivaptan, crizotinib, ciclosporin, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, fosaprepitant, grapefruit juice, imatinib, isavuconazole, netupitant, nilotinib, ribociclib, schisandra, and verapamil CYP3A4 inducers CYP3A4 inducers are expected to decrease the systemic exposure to synthetic glucocorticoids. Therefore, patients who have underlying GI-AI may develop signs and symptoms of cortisol deficiency: • Strong inducers include apalutamide, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, lumacaftor-ivacaftor, mitotane, phenobarbital, phenytoin, primidone, and rifampicin • Moderate inducers include bexarotene, bosentan, cenobamate, dabrafenib, efavirenz, elagolix/estradiol/norethindrone acetate combination, eslicarbazepine, etravirine, lorlatinib, modafinil, nafcillin, pexidartinib, rifabutin,​ rifapentine, and St John’s wort (Hypericum perforatum) Concomitant use of other drugs • Megestrol acetate potentially increases the risk of adrenal suppression because of its glucocorticoid activity. • High dose medroxyprogesterone acetate can inhibit release of adrenocorticotropic hormone and exerts weak glucocorticoid activity

CYP3A4=cytochrome P450 3A4; HPAA=hypothalamic-pituitary-adrenal axis

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Table 1 | Likelihood of clinically relevant adrenal suppression by exogenous glucocorticoids (GCs). Doses are reported as prednisolone equivalent BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from doses (PED) Systemic GCs (including oral, intravenous, and Risk Any administration route intramuscular administration) Inhaled GCs Intra-articular GCs Very high risk of Patients with history of exogenous GC use presenting with adrenal crisis GI-AI Patients with history of exogenous GC use presenting with cushingoid appearance High risk of Patients with current or recent history of Daily treatment with PED ≥5 mg for >4 weeks Use of high doses (regardless of Robust evidence GI-AI exogenous GC use presenting with signs and (adults) treatment duration). Fluticasone is lacking. HPAA symptoms suggestive of adrenal insufficiency propionate carries particularly suppression is (excluding adrenal crisis and cushingoid high risk common up to appearance) Daily treatment with PED ≥2-3 mg/m2 Continuous treatment for >12 2 months after (=hydrocortisone 8-10 mg/m2) for >4 weeks months (regardless of dose used) injections† (children) Concomitant use of strong CYP3A4 inhibitors Long term bedtime administration* Concomitant use of other GCs Moderate risk of Patients without symptoms who have Daily treatment with PED ≥5 mg for 2-4 weeks Use of low/intermediate doses for GI-AI discontinued long term GC therapy for <1 year (adults) 6-12 months (especially if further short courses of GCs are Daily treatment with PED ≥2-3 (=hydrocortisone prescribed) 8-12 mg/m2) for 2-4 weeks (children) Daily treatment with PED <5 mg (adults) Daily treatment with PED <2-3 mg/m2 (children) Multiple courses with daily administration, each lasting <2 weeks Long term treatment on alternate days Low risk of GI-AI Patients without symptoms who have Single course with daily administration lasting <2 Use of low/intermediate doses for discontinued long term GC therapy for >1 year weeks (any dose) less than 6 months Pulse therapy (any dose) CYP3A4=cytochrome P450 3A4; HED=hydrocortisone equivalent dose; HPAA=hypothalamic-pituitary-adrenal axis; GI-AI=glucocorticoid induced adrenal insufficiency. *Excluding modified release formulations (eg, modified release prednisone). †Clinical discretion should be used to determine risk on individual basis. Patients receiving multiple or simultaneous injections have higher risk of GI-AI. Patients should be monitored for signs and symptoms of adrenal insufficiency, especially during first 2 months after injection. Low threshold for testing advised if clinical suspicion of adrenal insufficiency exists.

higher in those aged under 5 years.49 A retrospective the cumulative dose of inhaled glucocorticoids, the study of 103 children receiving supraphysiological concomitant use of nasal glucocorticoids, higher

doses of glucocorticoids for prolonged periods of adherence to treatment, and low body mass index in http://www.bmj.com/ time (median >1 year) did not find an association children increase the likelihood of GI-AI.57-60 between the duration of treatment, the cumulative Most cases of GI-AI in patients using inhaled glucocorticoid dose, and the risk of GI-AI.50 A glucocorticoids have been linked to fluticasone systematic review of 10 studies that included 298 propionate.61-64 This drug has a long half life children with acute lymphoblastic leukemia showed (14.4 hours) and a strong binding affinity for that GI-AI occurred in nearly all cases treated with the glucocorticoid receptor (18 times that of high dose systemic glucocorticoids for less than two dexamethasone), which may lead to pronounced months.51 Most children recovered adrenal function negative feedback on the HPAA.22 Fluticasone furoate on 28 September 2021 by guest. Protected copyright. within a few weeks, but GI-AI persisted in 11% of has the same steroidal backbone as fluticasone patients retested at 12-34 weeks.51 propionate but a different ester substituent and has a longer retention time in respiratory tissues.65 This Inhaled glucocorticoid therapy may explain the lower levels of systemic absorption Inhaled glucocorticoids can be absorbed directly and the low impact on the HPAA observed in both from the lungs or from the gastrointestinal tract. The children and adults (box 1),66-69 although East Asian drug that does not reach the lungs is deposited into people may have a higher risk of systemic exposure the mouth and pharynx, where it can be swallowed to the drug.69 Ciclesonide and its active metabolite and absorbed. The portion of the drug that survives desisobutyryl-ciclesonide have high concentrations the first pass metabolism in the liver exerts systemic of plasma protein binding (that is, reduced biological effects (box 1, table 3, and fig 1, top panel).52-54 activity) and high clearance rate (that is, reduced A systematic review and meta-analysis found systemic exposure)52 70; this might explain the low that patients with asthma or chronic obstructive degree of HPAA suppression observed with this pulmonary disease who used only inhaled compound.71-73 Therefore, inhaled ciclesonide may glucocorticoids had a 6.8% risk of GI-AI.11 This be a safer alternative than fluticasone propionate,52 74 risk had a positive correlation with both the although cases of GI-AI have been associated with its glucocorticoid dose (up to 18.5% risk in those using use.55 75 76 high doses) and the treatment duration (risk up In children and adults with asthma, most studies to 20.3% if used for longer than one year).11 This did not find GI-AI when inhaled glucocorticoids were dose-response relation was also observed in other used at fluticasone equivalent doses below 400 µg/ large cohorts.55 56 Several studies have also shown day and 500 µg/day, respectively.52 77-80 However, that patients treated with inhaled glucocorticoids long term users of inhaled glucocorticoids (>6-12 who also use oral glucocorticoids are much more months) can develop GI-AI even at intermediate and likely to develop GI-AI (up to 43.7%).11 56 Moreover, low doses.68 7 581 A study in 70 children with asthma the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 5 STATE OF THE ART REVIEW

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treated with inhaled glucocorticoids for at least six osteoarthritis and inflammatory arthropathies. months found GI-AI in 24% of cases, with most They are favored over oral glucocorticoids because being treated for more than 24 months at fluticasone of the much lower systemic absorption and risk of equivalent doses above 400 µg/day.82 adverse effects. However, a proportion of injected Patients with cystic fibrosis often need inhaled glucocorticoid reaches the systemic circulation glucocorticoids if they develop symptoms of asthma and can affect the HPAA (box 1). Exogenous or in the setting of allergic bronchopulmonary glucocorticoids can be detected in the urine for aspergillosis. Limited evidence suggests that they may months after the injection, pointing to possible be at particularly high risk of GI-AI.11 83 Patients who prolonged systemic absorption.84 85 Repeated need prolonged courses of systemic glucocorticoids injections and higher doses of glucocorticoids and antifungal drugs (strong inhibitors of CYP3A4) increase the risk of GI-AI.86-90 Moreover, patients for acute allergic bronchopulmonary aspergillosis with inflammatory arthropathies have a higher are more susceptible to HPAA suppression.83 risk of systemic glucocorticoid absorption because of its injection into a highly vascularized area Intra-articular and epidural glucocorticoid therapy (box 1).89 This is particularly relevant in the Intra-articular glucocorticoid injections are pediatric population, as inflammatory (rather than commonly used for symptom relief in patients with degenerative) arthropathies are more common.86

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Fig 3 | Approach to patients with different risks of glucocorticoid (GC) induced adrenal insufficiency. Schematic approach to the management of GC therapy according to the likelihood of hypothalamic-pituitary-adrenal axis (HPAA) suppression. This is a guide only—management must be tailored on an individual basis. ACTH=adrenocorticotropic hormone; GI-AI=glucocorticoid induced adrenal insufficiency; PED=prednisolone equivalent dose. *If the patient is taking long acting GCs (eg, dexamethasone), switch to a replacement dose of hydrocortisone (eg, 15 mg am + 5 mg early pm) before testing serum cortisol. This would otherwise be affected by the long half life of the GCs. †Patients should also be tested to see if they can stop the inhaled GCs, reduce the dose, or switch to a different formulation. ‡Patients should be tested 24 h after the last dose of exogenous GCs. Predniso(lo)ne can interfere with immunoassays and cause falsely elevated cortisol values. §Hydrocortisone has a short half life and should be favored in case of delayed recovery of the HPAA. ¶If taking hydrocortisone: stop immediately. If taking prednisolone: taper down and stop. **If ACTH is low or suppressed, the HPAA is very unlikely to have recovered. ††Dynamic testing options include: (1) 250 μg ACTH stimulation test—cortisol is measured after injection of synthetic ACTH (cosyntropin). Examples of normal responses: 30 minute cortisol >350-550 nmol/L (12.7-20 µg/dL); 60 minute cortisol >380-500 nmol/L (13.8-18.1 µg/dL). Cut-offs vary according to the cortisol assay used and local practices. The cut-offs proposed here should be seen as a guide only. (2) Overnight metyrapone stimulation test: a normal response consists of early morning serum 11-deoxycortisol concentration of 200-635 nmol/L. (3) Insulin tolerance test: a normal response is achieved if serum cortisol increases to >350-550 nmol/L (12.7-19.9 µg/dL, depending on the cortisol assay used) and if the serum glucose falls to <2.8 mmol/L (50 mg/dL) the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 7 STATE OF THE ART REVIEW

Table 2 | Commonly prescribed systemic glucocorticoids also observed after injections of methylprednisolone 96 97 BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from Prednisolone equivalent doses acetate, with patients receiving higher doses (80 97 (using 5 mg prednisolone as mg) being at higher risk of GI-AI. Drug type Drug reference)* Short acting glucocorticoids with lower Hydrocortisone 20 mg Topical and rectal glucocorticoid therapy potency (biological half life <12 h) Cortisone acetate 25 mg The evidence of an effect of topical glucocorticoids Deflazacort 6 mg Intermediate acting glucocorticoids with Prednisone 5 mg on the HPAA is mostly anecdotal. Cases of GI- intermediate potency (biological half life Prednisolone 5 mg AI have been reported after exposure to nasal, 62 98-102 12-36 h) Methylprednisolone 4 mg intradermal, and cutaneous glucocorticoids. Triamcinolone 4 mg The pharmacokinetic and pharmacodynamic Long acting glucocorticoids with higher Dexamethasone 0.50 mg characteristics of the glucocorticoid used can potency (biological half life 36-54 h) Betamethasone 0.50 mg influence its effect on adrenal function; however, *Glucocorticoid potency equivalences apply to oral and/or intravenous administration and take no account of mineralocorticoid effects. Potency and conversion reported are estimates and should be seen as guide only. short term administration at the recommended dosages is safe.103 104 Skin inflammation, impaired barrier function due to damage, use of occlusive In patients treated for osteoarthritis of the knee, dressings, and the site of application affect the rate of biochemical evidence of GI-AI was observed two systemic absorption in case of topical glucocorticoid to four weeks after the injection of intra-articular use.101 105 For example, percutaneous absorption is methylprednisolone acetate and betamethasone higher through mucous membranes, eyelids, and acetate/betamethasone sodium phosphate in 25% scrotum.101 The risk of GI-AI may be higher in infants and 5% of people, respectively.91 92 Asymptomatic because of a larger body surface area to body weight GI-AI was observed in 60% of patients receiving ratio (box 1).22 simultaneous bilateral knee injections of Rectal glucocorticoids are often used to limit methylprednisolone acetate and persisted for eight systemic exposure in patients with inflammatory weeks in 10% of cases.93 Interestingly, a minority bowel diseases affecting the lower part of the colon of these patients had intermittent abnormalities and rectum. Although short term use is safe, systemic in cortisol secretion over time, suggesting possible glucocorticoid absorption is possible.106 GI-AI has variation in systemic absorption of the glucocorticoid been described in users of prednisolone enemas.107 from the knee joint.93 Rectal budesonide and beclometasone dipropionate 108-111

The effects of epidural glucocorticoids on the may be safer than other glucocorticoids ; http://www.bmj.com/ HPAA have been assessed in a few small studies. however, most of the evidence is based on single Eight people receiving a single epidural injection of serum cortisol measurements. triamcinolone had a significant reduction in 24 hour urinary cortisol after 12 weeks, as well as a blunted Oral budesonide response of ACTH and cortisol to corticotropin Oral budesonide, frequently used to treat 94 releasing hormone stimulation. Another study inflammatory bowel disease, undergoes extensive showed that 35% of patients receiving multiple inactivation during first pass metabolism. However, epidural injections of triamcinolone acetate had GI- the drug can be absorbed systemically and cases of on 28 September 2021 by guest. Protected copyright. 95 AI, which resolved within three months. This was adrenal crisis and Cushing’s syndrome have been

Table 3 | Commonly prescribed inhaled glucocorticoids Dose* Adults ≥17 years Children 5-11 years Low doses Fluticasone propionate <300 µg/day Fluticasone propionate <150 µg/day Beclometasone dipropionate (standard particle inhalers) <600 µg/day Beclometasone dipropionate (standard particle inhalers) <300 µg/day Beclometasone dipropionate (extra fine particle inhalers) <300 µg/day Beclometasone dipropionate (extra fine particle inhalers) <150 µg/day Budesonide <600 µg/day Budesonide <300 µg/day Ciclesonide <240 µg/day Ciclesonide <160 µg/day Mometasone furoate <400 µg/day Intermediate doses Fluticasone propionate 300-500 µg/day Fluticasone propionate 150-20 0µg/day Beclometasone dipropionate (standard particle inhalers) 600-1000 µg/day Beclometasone dipropionate (standard particle inhalers) 300-400 µg/day Beclometasone dipropionate (extra fine particle inhalers) 300-400 µg/day Beclometasone dipropionate (extra fine particle inhalers) 150-200 µg/day Budesonide 600-800 µg/day Budesonide 300-400 µg/day Ciclesonide 240-320 µg/day Ciclesonide 160 µg/day Fluticasone furoate 100 µg/day Mometasone furoate 400 µg/day High doses Fluticasone propionate >500 µg/day Fluticasone propionate >200 µg/day Beclometasone dipropionate (standard particle inhalers) >1000 µg/day Beclometasone dipropionate (standard particle inhalers) >400 µg/day Beclometasone dipropionate (extra fine particle inhalers) >400 µg/day Beclometasone dipropionate (extra fine particle inhalers) >200 µg/day Budesonide >800 µg/day Budesonide >400 µg/day Ciclesonide >320 µg/day Ciclesonide >160 µg/day Fluticasone furoate >100 µg/day Mometasone furoate >400 µg/day *Doses should be seen as a guide only. Doses are based on information from manufactures’ summaries of product characteristics, Global Initiative for Asthma (2018), British National Formulary, and British National Formulary for Children. London Respiratory Network has proposed different cut-offs to define low, intermediate, or high doses for some inhaled glucocorticoids in adults.

8 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj STATE OF THE ART REVIEW

reported following prolonged use.112 113 Patients in the evening is more likely to lead to GI-AI and who are taking higher doses of oral budesonide (eg, glucocorticoid induced side effects as glucocorticoid BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from >6 mg) for more than eight weeks and those on long sensitivity is higher at that time, parallel to the term treatment (regardless of the dose used) should clock gene down-regulation.144 The metabolism of be considered at higher risk of GI-AI.11-117 This is exogenous glucocorticoids (and hence exposure of particularly relevant in patients with recent exposure the HPAA to negative feedback) can also be affected to oral glucocorticoids. by sex, age, body mass index, liver and kidney failure, proinflammatory cytokines, and polymorphisms of CYP Drug interactions enzymes and the cytochrome P450 oxidoreductase.145 Dexamethasone and, to a lesser extent, predniso(lo) ne are metabolized by the hepatic cytochrome Clinical relevance of glucocorticoid induced adrenal P450 3A4 (CYP3A4). Therefore, CYP3A4 inhibitors insufficiency are expected to increase systemic exposure We showed in the previous sections that a biochemical to glucocorticoid (box 1).51 118 For example, diagnosis of GI-AI is common in patients treated with coadministration of ritonavir and prednisone glucocorticoids. However, a fundamental question increased the circulating concentrations of the active needs to be answered—is this just a biochemical metabolite prednisolone by up to 37%.118 The newer abnormality, or is it clinically relevant? A crucial protease inhibitor dolutegravir does not inhibit point to consider is whether GI-AI without apparent CYP3A4 and could be an alternative in patients signs and symptoms of cortisol deficiency is clinically treated with glucocorticoids.119 relevant. A review of the literature found that very few Concomitant treatment with strong CYP3A4 studies assessing the risk of GI-AI in patients treated inhibitors and inhaled, intranasal, and injectable with glucocorticoids also focused on symptoms fluticasone, budesonide, and triamcinolone is of adrenal insufficiency.11 In the pooled analysis, not recommended because of the preferential only 2% of patients reported symptoms consistent metabolism of these drugs by CYP3A4.90 118 120-123 with adrenal insufficiency but, on dynamic testing, Beclometasone and flunisolide may be19% of patients failed to achieve a normal cortisol safer alternatives because of their different response.11 Notably, although symptom assessment metabolism.124 125 Ritonavir has been linked to in this study was not standardized, these data many cases of iatrogenic Cushing’s syndrome and suggest that patients with symptoms are only the

symptomatic GI-AI when used in combination tip of the iceberg. Moreover, patients with GI-AI can http://www.bmj.com/ with inhaled and intranasal glucocorticoids often present with non-specific signs and symptoms (mostly fluticasone propionate).52 103 122 126 This is that can be attributed to other causes. Importantly, particularly relevant because asthma and chronic events such as infections and surgery in a patient obstructive pulmonary disease are more prevalent in with undiagnosed and untreated GI-AI can trigger a HIV infected populations.127 life threatening adrenal crisis because of the inability to mount an adequate stress response.146 Other factors affecting risk of glucocorticoid on 28 September 2021 by guest. Protected copyright. induced adrenal insufficiency Adrenal crisis and symptomatic glucocorticoid Inter-individual variability in the sensitivity of induced adrenal insufficiency the HPAA to exogenous glucocorticoids has been Several cases of adrenal crisis and hospital admission observed.44 128 129 For example, higher cortisol after for GI-AI have been described, including a few administration of dexamethasone was associated deaths.14 35 147-150 Of note, many patients presenting with an inadequate response to the low dose ACTH with adrenal crisis were treated with inhaled stimulation test after a 14 day course of prednisolone glucocorticoids only (mostly high dose fluticasone in healthy volunteers.44 This variation is possibly propionate), emphasizing the potential risks linked—among other factors—to polymorphisms associated with their systemic absorption.14 55 150-153 of the genes encoding the glucocorticoid Symptomatic GI-AI and adrenal crises have also been and mineralocorticoid receptors.14 129-132 described in patients exposed to oral glucocorticoids Glucocorticoid receptor polymorphisms were for less than two months, as well as in patients reported to be associated with increased sensitivity receiving topical, intra-articular, epidural, and rectal to glucocorticoids, leading to a higher prevalence of glucocorticoids.14 85 87 150 154-158 Two studies found features associated with hypercortisolism and efficacy of that patients with GI-AI had a higher incidence of glucocorticoids or, by contrast, a relative glucocorticoid adrenal crisis than did patients with other causes resistance with lower rates of development of features of adrenal insufficiency.159 160 The most common suggestive of iatrogenic Cushing’s syndrome.133-142 triggering factor was infections; of note, several Time of glucocorticoid administration during the day is patients developed an adrenal crisis after reducing or another important factor that likely contributes to the discontinuing the dose of exogenous glucocorticoids, risk of GI-AI. Clock related genes in circulating blood which is a preventable cause of morbidity.160 cells from patients taking exogenous glucocorticoid The tapering down and discontinuation of multiple times a day were found to be abnormal, and glucocorticoids is a crucial time, as an underlying they partially normalized after a switch to once a day GI-AI can become clinically apparent. A Danish administration.143 Administration of glucocorticoid population based study showed that discontinuation the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 9 STATE OF THE ART REVIEW

of long term oral glucocorticoids increased the risk of and unexplained hypoglycemia can be signs of GI- developing hypotension, gastrointestinal symptoms, AI and should prompt an assessment of adrenal BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from hypoglycemia, and hyponatremia.161 These signs, function.76 153 165 Patients with untreated GI-AI may which are suggestive of untreated GI-AI, peaked be more susceptible to infections and recover more up to three months after the glucocorticoids were slowly than those with normal adrenal function; stopped and persisted for several months; older this could be another warning sign in patients with patients taking higher daily doses of glucocorticoids chronic obstructive pulmonary disease and asthma for longer periods of time, as well as those exposed treated with glucocorticoids.153 to infections, had the highest risk of developing Patients presenting with signs and symptoms of symptoms.161 Intriguingly, mortality after cessation cortisol excess due to glucocorticoid use (iatrogenic of chronic oral glucocorticoid therapy markedly Cushing’s syndrome) have had marked systemic increased in the first months after discontinuation, exposure and must be assumed to have a fully raising the suspicion of possible undiagnosed suppressed HPAA (fig 4). Iatrogenic Cushing’s adrenal crises in this population.2 Another syndrome can occur with any formulation of retrospective cohort study showed that 36 adrenal glucocorticoids and can take several months to resolve crises (7.1% of all cases) occurred within 30 days after the dose of glucocorticoid is decreased.87 158 166 of discontinuation of glucocorticoids.152 Adrenal crises have also been reported in patients tapering Approaches to glucocorticoid taper down inhaled glucocorticoids or switching between The goal of glucocorticoid therapy is the shortest different glucocorticoid preparations.153 treatment with the lowest effective dose (box 2). Glucocorticoid taper and eventual discontinuation Risks associated with inhaled glucocorticoid therapy in patients treated with exogenous glucocorticoids Cases of symptomatic GI-AI and iatrogenic require consideration of several aspects of the care Cushing’s syndrome have been linked to inhaled of patients. The first one relates to the original glucocorticoids.52 62 162 Most cases involved patients reason for the exogenous glucocorticoid therapy. treated with fluticasone propionate ≥500 μg/day. A If prescribed for a chronic condition (for example, retrospective cohort study from Canada identified 392 rheumatoid arthritis, asthma, inflammatory bowel hospital admissions due to GI-AI over a 15 year period disease), this may relapse after discontinuation among adults treated with inhaled glucocorticoids.59 of glucocorticoids. A close collaboration with the

Patients using higher daily doses (≥1000 µg/day) and medical team is needed to ensure that the patient http://www.bmj.com/ cumulative doses (>157 000 µg/year) of glucocorticoids is able to discontinue glucocorticoids and the had an almost twofold higher risk of hospital admission underlying disorder is in remission or well controlled than those with lower exposure.59 A study focusing with an alternative, non-glucocorticoid therapy. on the medical records of general practices in the UK Secondly, symptoms related to the glucocorticoid identified only 31 cases of established GI-AI linked withdrawal should be anticipated and necessitate a to inhaled glucocorticoids in a cohort of 2.4 million careful approach. Thirdly, GI-AI should be expected people.56 Considering the widespread use of inhaled and glucocorticoids should not be discontinued until glucocorticoids, the low rates of GI-AI observed in recovery of the HPAA is documented. on 28 September 2021 by guest. Protected copyright. these studies would suggest that this problem is largely unrecognized or under-reported.62 Considerations for glucocorticoid taper The best choice of glucocorticoid to use during Clinical presentation of patients with hypothalamic- glucocorticoid taper has not been explored. However, pituitary-adrenal axis suppression differences in the pharmacokinetics and potency A high degree of clinical suspicion is paramount when of various glucocorticoids likely influence both a history of glucocorticoid exposure exists. Patients glucocorticoid withdrawal syndrome (GWS) and with GI-AI may have no symptoms, present with the rapidity of HPAA recovery.167 Glucocorticoid varying degrees of symptoms of cortisol deficiency, dose and taper are not standardized, leading to or present with life threatening adrenal crisis (fig 4). significant differences in practice. Reported tapering Clinical diagnosis of GI-AI seems to be difficult, with regimens are based on very low quality evidence.168 most patients reporting multiple symptoms at the In several studies investigating the effect of different time of diagnosis and 66% of patients needing to see types and dosage of glucocorticoid therapy on the more than one physician to make the diagnosis of GI- duration of HPAA recovery and/or GWS, evidence AI.159 GI-AI generally has a less dramatic presentation was inconclusive.169-171 than primary adrenal insufficiency; acute circulatory Approaches to the glucocorticoid taper collapse and electrolyte abnormalities are infrequent should include consideration of the duration of because the secretion of mineralocorticoids is supraphysiological glucocorticoid use, the average preserved (fig 1, top panel).114 Symptoms such dose used over this period, clinical manifestations as fatigue and abdominal pain are non-specific, of iatrogenic Cushing’s syndrome, overall functional and their onset may be insidious and mistakenly status, and the risk of relapse of the underlying attributed to other causes or to the disease for disorder that was treated with glucocorticoids which glucocorticoids were prescribed.14 162-164 (box 3). Rapid taper protocols were found to be In children, stunted growth, reduced final height, less effective than a standard taper in maintaining

10 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj STATE OF THE ART REVIEW

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Fig 4 | Glucocorticoid induced adrenal insufficiency and adrenal crisis

remission.172 The patient’s previous experience glucocorticoid taper, an individualized approach is with glucocorticoid taper and GWS can also guide needed for each patient. As most patients are treated the aggressiveness of taper. In the absence of with either predniso(lo)ne or dexamethasone, we well designed studies evaluating approaches to suggest conversion to predniso(lo)ne therapy taken the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 11 STATE OF THE ART REVIEW

Box 2: Recommendations to reduce the risk of glucocorticoid induced adrenal insufficiency BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from Systemic glucocorticoid administration (including oral) • Whenever possible, use the lowest effective dose of glucocorticoids for the shortest period of time • Whenever possible, favor once daily dosing when using intermediate and long acting glucocorticoids (eg, prednisone, prednisolone, dexamethasone) • Whenever possible, avoid bedtime administration of glucocorticoids* • Do not taper down glucocorticoids if the treatment course is <2 weeks. The risk of HPAA axis suppression in such cases is low, and glucocorticoids can be discontinued abruptly. If treatment is prolonged beyond 2 weeks, the risk of HPAA suppression increases Inhaled glucocorticoids • Whenever possible, use the lowest effective dose of glucocorticoids for the shortest period of time • Use spacers and mouth rinsing to reduce systemic absorption through the gastrointestinal tract Intra-articular glucocorticoids • Whenever possible, reduce the number of injections and space out the administration of intra-articular glucocorticoids† • Whenever possible, avoid simultaneous injections of multiple joints • Use the lowest effective dose of glucocorticoids • Favor triamcinolone hexacetonide over triamcinolone acetonide because of its higher residence time in the joint (lower risk of systemic absorption)

HPAA=hypothalamic-pituitary-adrenal axis. *Excluding modified release formulations (eg, modified release prednisone). †Based on very low quality evidence and personal experience, the risk of sustained glucocorticoid induced adrenal insufficiency is higher in patients receiving multiple glucocorticoid injections, especially if over a short period of time. Patients should be considered to be at moderate to high risk of sustained glucocorticoid induced adrenal insufficiency if they receive >3 injections over the course of a year. Nevertheless, transient adrenal suppression is observed in >50% of patients for up to 2 months after intra-articular glucocorticoid injection. Health professionals should educate patients to report signs and symptoms of adrenal insufficiency, especially during the first 2 months after the injection.

once a day in the morning as soon as possible. adrenal insufficiency and possibly the underlying Initial rapid glucocorticoid taper of 5-10 mg weekly disorder glucocorticoids were initially prescribed increments down to 20 mg daily is usually possible to treat. When physicians and patients do not for patients taking predniso(lo)ne at >20-40 mg per recognize GWS as a separate entity, the recovery day. A much slower taper is subsequently needed process can be difficult and prolonged, especially if

for most patients, which includes a weekly-monthly glucocorticoid doses are increased unnecessarily. In http://www.bmj.com/ predniso(lo)ne decrease of 1-2.5 mg to avoid severe the published evidence so far, very little emphasis GWS (box 3). All patients should be extensively has been placed on assessment of the severity of counseled on the symptoms of GWS and provided GWS during glucocorticoid taper. In a retrospective with a plan on management of severe GWS. The study of patients undergoing curative surgery for management plan includes supportive measures endogenous hypercortisolism, GWS was reported in and a recommendation to incrementally increase 67% of patients and was associated with the severity glucocorticoid to the most recent dose associated of cortisol excess before surgery.170 with symptoms that were tolerable. on 28 September 2021 by guest. Protected copyright. Assessment of hypothalamic-pituitary-adrenal axis Glucocorticoid withdrawal syndrome The recovery of the HPAA should be assessed only GWS is a withdrawal reaction that may occur in patients taking a prednisolone equivalent dose of during the glucocorticoid taper owing to developed no higher than 5 mg a day. HPAA recovery is likely dependence on supraphysiological glucocorticoid to occur more rapidly if the patient is switched to concentrations.173 The pathophysiology of hydrocortisone (short acting glucocorticoid) as GWS is multifactorial and is likely mediated by opposed to predniso(lo)ne (box 1); however, head suppressed corticotropin releasing hormone, to head studies have not been performed. HPAA central noradrenergic and dopaminergic system, recovery is unlikely in patients treated with long decrease in pro-opiomelanocortin related peptides acting glucocorticoids, such as dexamethasone. In a due to chronic suppression of HPAA, and the patient who is undergoing glucocorticoid taper, our increase in cytokines (interleukin 6, tumor necrosis approach is to assess HPAA recovery once the patient factor α) and prostaglandins.173-175 Patients who is treated with prednisolone equivalent doses of 5 mg taper glucocorticoids often feel unwell even when for at least one to four weeks and reassess every three still taking doses that are supraphysiological months until recovery occurs. In patients with GI-AI but lower than their usual glucocorticoid doses. lasting for more than one to two years, reassessment Symptoms may include anorexia, nausea, emesis, can be spanned out to every six to 12 months. Several lethargy, somnolence, arthralgia, myalgia, low approaches to HPAA assessment can be used, all grade fever, postural hypotension, and psychiatric done after 24 hours without any glucocorticoid symptoms (mainly depression, anxiety, and panic therapy other than dexamethasone. These most attacks).173 176 GWS may last months, and patients commonly include measurement of morning cortisol report poor quality of life and wellbeing.170 176 GWS concentrations, synthetic ACTH stimulation tests, is under-recognized as a separate entity, partly and, less commonly, the overnight metyrapone test because of overlap of GWS symptoms with those of and the insulin tolerance test (fig 3).

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Box 3: Approach to glucocorticoid taper and management of glucocorticoid induced adrenal insufficiency BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from Patient education (see fig 2) • Education on symptoms and management of GWS • Education on the symptoms and management of GI-AI Provider education (see fig 2) • Written recommendations in patient’s medical record and letter on the management of glucocorticoid and adrenal insufficiency Considerations for glucocorticoid taper • Duration of glucocorticoid use and average glucocorticoid dose (see box 1 and table 1) • Previous experience with glucocorticoid taper • Functional status • Risk of relapse of the underlying disorder that required glucocorticoid therapy • Avoidance of glucocorticoid administration in the afternoon/evening Initial rapid glucocorticoid taper • For patients on an average daily glucocorticoid dose of: ○○PED >40 mg daily—decrease daily glucocorticoid dose by 5-10 mg weekly increments until PED 20 mg daily ○○PED 20-40 mg daily—decrease daily glucocorticoid dose by 5 mg weekly increments until PED 20 mg daily ○○PED 10-20 mg daily—proceed to the slow glucocorticoid taper recommendations • For patients taking twice a day predniso(lo)ne, or evening doses, switch predniso(lo)ne to once a day, in the morning • For patients taking dexamethasone, switch to predniso(lo)ne equivalent dose Subsequent slow glucocorticoid taper (Note that the decrement and the frequency of glucocorticoid decrease can be adapted according to the severity of the GWS.) • For patients transitioning after the initial rapid glucocorticoid taper or patients taking PED ≤20 mg daily: ○○PED 10-20 mg daily—decrease daily glucocorticoid dose by 1-2.5 mg weekly decrements until 10 mg daily. If severe GWS, consider bi-monthly decrements ○○PED 5-10 mg daily—decrease by 1 mg weekly decrements until 5 mg daily. If severe GWS, consider bi-monthly or even monthly decrements ○○PED 5 mg daily*—do not stop or decrease glucocorticoid until HPAA recovery has been documented. Consider switching to hydrocortisone 20 mg (15 on waking, 5 mg at noon) if HPAA recovery is delayed Assessment of HPAA recovery (see fig 3) Timing of reassessment—should be done only after reaching PED 5 mg or a replacement dose of hydrocortisone (eg, 15 mg in the morning, 5 mg in the afternoon) for 1-4 weeks. Frequency of reassessment—every 2-3 months. If HPAA has not recovered for 1-2 years, consider reassessment every 3-6 months. Testing—assessment should be done in the morning, 24 hours off glucocorticoid therapy with the following tests: http://www.bmj.com/ • Morning serum cortisol • Additional tests to consider (only if indeterminate morning cortisol results) ○○Synthetic ACTH stimulation test ○○Overnight metyrapone test (where available) ○○Insulin tolerance test (very rarely) Management of patients with established GC-AI (see fig 2)

Physician on 28 September 2021 by guest. Protected copyright. • Periodic clinical assessment for symptoms and signs of glucocorticoid over-replacement and under-replacement • Periodic biochemical assessment of HPAA recovery • Assure patient has optimal supplies (oral glucocorticoid, injectables) • Patient counseling on glucocorticoid therapy, special situations (shift work, pregnancy, concomitant diabetes mellitus, excessive physical activity), sick day rules Patient • Chronic glucocorticoid replacement therapy: ○○Hydrocortisone (eg, 15 mg on waking, 5 mg 6-8 hours later), or ○○Predniso(lo)ne 4-5 mg on waking ○○See “Emergent treatments” section for novel preparations • Sick day rules: ○○Sick day rule 1—double or triple daily oral glucocorticoid dose during illness that requires bed rest and/or antibiotics or is associated with high fever (>38°C) until recovery. Double or triple the dose on the day of any minor procedure/surgery that does not require fasting (eg, procedures requiring local anesthesia and tooth extraction) ○○Sick day rule 2†—self-inject glucocorticoid when unable to take oral glucocorticoid (eg, acute gastroenteritis), during severe illness, after major trauma, and if the patient is confused, drowsy, or unconscious. Also, self-inject glucocorticoid in preparation for surgery and procedures requiring general anesthesia, during prolonged fasting (eg, preparation for colonoscopy), and at the onset of adrenal crisis. Examples of recommended injectable doses in adults: hydrocortisone 50 mg every 6 hours, dexamethasone 4 mg/24 hours, methylprednisolone 40 mg/12 hours. If the patient is admitted to hospital, continuous hydrocortisone infusion should be favored over intermittent bolus administration • Wear medical alert bracelet/necklace • Carry steroid card/letter outlining GC-AI management • Become comfortable with GC-AI management • Practice glucocorticoid injections • Communicate with other members of the medical team with regard to GC-AI

ACTH=adrenocorticotropic hormone; HPAA=hypothalamic-pituitary-adrenal axis; GC-AI=glucocorticoid induced adrenal insufficiency; GWS=glucocorticoid withdrawal syndrome; PED=prednisolone equivalent dose. Further decrease of glucocorticoid dose <5 mg PED can be considered in a subset of patients to accelerate the recovery of adrenal function (ie, 4 mg, or even 3 mg, PED). By contrast, a subset of patients may achieve recovery of adrenal function at higher PED (ie, 6-7.5 mg PED). †All patients with GI-AI and their family members/partners should receive appropriate education and a demonstration of glucocorticoid injection. the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 13 STATE OF THE ART REVIEW

In a recent study of patients recovering from discontinuation of supraphysiological glucocorticoid endogenous hypercortisolism, a morning cortisol therapy, and 2-7% of patients may never recover BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from ≥270 nmol/L (10 µg/dL) was associated with no adrenal function.20 189 190 reported symptoms of GWS or instances of adrenal In a recent survey study that included 179 crisis and thus could serve as a simple approach to patients with GI-AI, patients reported a median age HPAA assessment.170 Another large study of patients at diagnosis of 54 years and a median duration of who had synthetic ACTH stimulation testing to GI-AI of three years.159 One in five patients with assess for GI-AI also suggested that morning cortisol GI-AI reported not being aware of the diagnosis. measurements can replace the dynamic testing, with Notably, compared with other causes of adrenal cortisol cut-offs of 221 and 347 nmol/L showing insufficiency, patients with GI-AI were more likely to 86% and 95% sensitivity, respectively.55 report difficulty with management and less likely to Notably, accurate interpretation of cortisol have available injectable glucocorticoid at home or concentrations can be challenging. Morning cortisol to wear medical alert gear. Despite taking a higher concentrations vary according to the individual daily glucocorticoid dose, more patients with GI- circadian rhythm and assays used for measurements. AI reported symptoms due to under-replacement In addition, total cortisol concentrations can be (fatigue, nausea). A higher number of patients with elevated during pregnancy and in patients using GI-AI needed stress dose steroids. When seeking care oral estrogens, owing to higher concentrations in the emergency setting, patients with GI-AI were of cortisol binding globulin.177 By contrast, total around two times less likely to receive proper care cortisol concentrations can be decreased in patients than those with other causes of adrenal insufficiency. with low albumin and cortisol binding globulin, as in Overall, 59% of patients with GI-AI reported poor cirrhosis or critical illness.178 179 In addition, cortisol general health.159 These data reflect the fact that concentrations vary depending on the assays used. patients with GI-AI are less likely to receive adequate For example, in a large study of patients undergoing education on adrenal insufficiency than other synthetic ACTH stimulation testing, basal cortisol that patients, possibly owing to lack of awareness and the excluded adrenal insufficiency varied between 336 belief that the problem is temporary. and 506 nmol/L when measured by three different All patients at risk of or with established GI-AI immunoassays.180 These special circumstances should receive adequate education (fig 2). Special and assay variability need to be considered when attention should be paid to increasing patient

interpreting cortisol cut-offs (fig 3). awareness (including over-the-counter drugs http://www.bmj.com/ The insulin tolerance test is traditionally containing glucocorticoids and intra-articular considered the reference standard dynamic test for glucocorticoid injections), measures targeted secondary adrenal insufficiency but is rarely needed toward prevention of adrenal crisis, and the sick for the diagnosis of GI-AI.181-183 Both high dose and day rules (box 3). This includes counseling on low dose ACTH stimulation testing can be used in glucocorticoid therapy, special situations that may making the diagnosis of adrenal insufficiency.184 require adaptation of glucocorticoid therapy (box However, the performance of both tests is suboptimal 3), use of injectable glucocorticoid therapy, and in secondary adrenal insufficiency, with a high rate signs and symptoms of over-replacement and under- on 28 September 2021 by guest. Protected copyright. of false negative results (sensitivity of 64-83%).185 replacement, including those of adrenal crisis (table The overnight metyrapone stimulation test can also 2). Patients with GI-AI should receive adequate be used to assess the HPAA. Metyrapone inhibits education regardless of the projected duration of the conversion of 11-deoxycortisol to cortisol, with adrenal insufficiency. subsequent stimulation of ACTH and accumulation Chronic glucocorticoid therapy most commonly of 11-deoxycortisol. The overnight metyrapone consists of either twice daily hydrocortisone or stimulation test was reported to have a similar predniso(lo)ne once in the morning. In the absence performance to the insulin tolerance test and a of a reliable biomarker, periodic clinical assessment superior performance to the ACTH stimulation will ensure that the dose is individualized to the tests.186-188 Use of the overnight metyrapone is patient’s needs. Guidelines suggest twice or thrice limited by the availability of metyrapone and daily hydrocortisone as a valid replacement scheme 11-deoxycortisol assays. in patients with adrenal insufficiency to mimic the physiological cortisol rhythm.191 This is also an Management of glucocorticoid induced adrenal appropriate option for GI-AI and should especially be insufficiency considered when patients complain of glucocorticoid HPAA recovery in patients with GI-AI can take months withdrawal symptoms; however, we postulate that to years.20 Patients taking higher glucocorticoid avoiding late afternoon exposure to hydrocortisone doses for a longer duration, those with a lower body by twice daily administration might accelerate the mass index, and those with features of iatrogenic recovery of ACTH secretion by negative feedback. Cushing’s syndrome are likely to take longer to In adult patients with adrenal crisis in a hospital recover.170 A proportion of patients may develop setting, hydrocortisone 100 mg bolus injection chronic or permanent GI-AI. As reported in a followed by the intravenous infusion of 100 mg systematic review of GI-AI, 15% of patients may have hydrocortisone per 24 hours is the preferable persistent GI-AI when reassessed three years after mode of treatment.192 Children with adrenal crisis

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should be treated with a lower hydrocortisone dose illness. Guidelines need to be developed to cover depending on their weight, usually 25-50 mg bolus gaps in the management of patients treated with BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from injection followed by infusion of hydrocortisone 50- chronic glucocorticoids to raise awareness of GI-AI 100 mg per 24 hours. When clinical improvement and GWS and provide clear recommendations that is seen, hydrocortisone should be converted to oral can be applied in the interdisciplinary setting. administration at an increased dose (usually double the usual daily dose) and gradually tapered to the RESEARCH QUESTIONS 191 193-195 usual regimen. • What are the best predictors of glucocorticoid induced adrenal insufficiency and its duration? Emerging treatments • What is the best approach to glucocorticoid taper to The HPAA and the peripheral sensitivity to alleviate glucocorticoid withdrawal syndrome while glucocorticoids follow a circadian rhythm, which achieving the quickest recovery of adrenal function? 196 197 can affect the negative feedback response. • What is the best approach to assessing the Novel modified release glucocorticoids have been hypothalamic-pituitary-adrenal axis? designed as either immunosuppressive therapy to • What strategies can be developed to increase mirror the morning cortisol rise and improve clinical awareness of glucocorticoid induced adrenal outcomes (for example, modified release prednisone insufficiency among patients and health in patients with rheumatoid arthritis) or replacement professionals? therapy to reproduce the circadian cortisol rhythm in patients with established adrenal insufficiency (for example, modified release hydrocortisone).197 198 We thank Wiebke Arlt and William Young for their critical review and useful suggestions on tables and figures. Potentially these modified release formulations could Contributors: IB and AP conceptualized and performed the literature reduce the risk of adrenal insufficiency and promote review for this manuscript. AP and IB drafted the manuscript. IB and recovery of adrenal function in patients exposed to AP contributed to the critical revision of the article. AP and IB gave glucocorticoids, but further research in this area is final approval of the version to be published. IB is the guarantor. needed. No interventional trials in patients with GI- Funding: AP is a Diabetes UK Sir George Alberti research training fellow (grant reference number 18/0005782). This research was AI are ongoing. supported by the Catalyst Award for Advancing in Academics from the Mayo Clinic (to IB) and the National Institute of Diabetes and Digestive Guidelines and Kidney Diseases of the NIH under award K23DK121888 (to IB). The views expressed are those of the authors and not necessarily

Clear guidance exists about the prevention and http://www.bmj.com/ those of the NIH. The funders of the study had no role in the emergency management of patients with confirmed conceptualization, writing, and decision to publish the manuscript. All or suspected adrenal insufficiency, including patient researchers were independent from funders. education, sick day rules, and management of adrenal Competing interests: We have read and understood the BMJ policy crisis.21 194 To the best of our knowledge, however, on declaration of interests and declare the following interests: IB is a consultant to CinCor, Corcept, Sparrow Pharmaceutics, Strongbridge, guidelines specifically focusing on GI-AI are lacking. and HRA Pharma, outside this work. IB has received research support Considering the widespread use of glucocorticoids in from HRA Pharma for an investigator initiated study outside this work. different doses and formulations for a vast number of Patient and public involvement: Patients or the public were not conditions across multiple specialties, the fact that involved in the design, conduct, reporting, or dissemination plans for on 28 September 2021 by guest. Protected copyright. the recommendations of several medical societies do this work. not fully cover or differ in terms of who is at risk of GI- Provenance and peer review: Commissioned; externally peer reviewed. AI, when glucocorticoid therapy can be discontinued, 191 194 and how to do so comes as no surprise. 1 Charmandari E, Nicolaides NC, Chrousos GP. Adrenal Although the decision to stop glucocorticoids is insufficiency. Lancet 2014;383:2152-67. doi:10.1016/S0140- 6736(13)61684-0 clearly linked to the underlying disease, the lack of 2 Mebrahtu TF, Morgan AW, Keeley A, Baxter PD, Stewart PM, Pujades- a multidisciplinary consensus on the stratification Rodriguez M. Dose dependency of iatrogenic glucocorticoid excess of patients according to their risk of developing GI- and adrenal insufficiency and mortality: a cohort study in England. J Clin Endocrinol Metab 2019;104:3757-67. doi:10.1210/jc.2019- AI and the management of glucocorticoid taper and 00153 GI-AI is likely associated with suboptimal outcomes. 3 van Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B, Cooper C. Use of oral corticosteroids in the United Kingdom. QJM 2000;93:105-11. doi:10.1093/qjmed/93.2.105 Conclusion 4 Laugesen K, Jørgensen JOL, Sørensen HT, Petersen I. Systemic Patients exposed to exogenous glucocorticoids glucocorticoid use in Denmark: a population-based prevalence study. BMJ Open 2017;7:e015237. doi:10.1136/bmjopen-2016-015237 are at risk of developing GI-AI, which needs to be 5 Overman RA, Yeh JY, Deal CL. Prevalence of oral glucocorticoid usage promptly recognized, anticipated, and optimally in the United States: a general population perspective. Arthritis Care managed. Patients treated with high doses of Res (Hoboken) 2013;65:294-8. doi:10.1002/acr.21796 6 Laugesen K, Jørgensen JOL, Petersen I, Sørensen HT. Fifteen-year glucocorticoids for a longer duration may develop nationwide trends in systemic glucocorticoid drug use in Denmark. severe GWS when the treatment is tapered down. Eur J Endocrinol 2019;181:267-73. doi:10.1530/EJE-19-0305 Individualized glucocorticoid taper can help with 7 Fardet L, Petersen I, Nazareth I. Prevalence of long-term oral glucocorticoid prescriptions in the UK over the past 20 years. symptoms of glucocorticoid withdrawal and a Rheumatology (Oxford) 2011;50:1982-90. doi:10.1093/ quicker eventual recovery of adrenal function. Every rheumatology/ker017 patient with GI-AI should receive optimal education 8 Walsh LJ, Wong CA, Pringle M, Tattersfield AE. Use of oral corticosteroids in the community and the prevention of secondary on management of adrenal insufficiency, including osteoporosis: a cross sectional study. BMJ 1996;313:344-6. management of glucocorticoid therapy during an doi:10.1136/bmj.313.7053.344 the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 15 STATE OF THE ART REVIEW

9 Gudbjornsson B, Juliusson UI, Gudjonsson FV. Prevalence of long 32 Schlaghecke R, Kornely E, Santen RT, Ridderskamp P. The

term steroid treatment and the frequency of decision making to effect of long-term glucocorticoid therapy on pituitary-adrenal BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from prevent steroid induced osteoporosis in daily clinical practice. Ann responses to exogenous corticotropin-releasing hormone. N Engl J Rheum Dis 2002;61:32-6. doi:10.1136/ard.61.1.32 Med 1992;326:226-30. doi:10.1056/NEJM199201233260403 10 Bénard-Laribière A, Pariente A, Pambrun E, Bégaud B, Fardet L, Noize 33 LaRochelle GEJr, LaRochelle AG, Ratner RE, Borenstein DG. Recovery P. Prevalence and prescription patterns of oral glucocorticoids in of the hypothalamic-pituitary-adrenal (HPA) axis in patients adults: a retrospective cross-sectional and cohort analysis in France. with rheumatic diseases receiving low-dose prednisone. Am J BMJ Open 2017;7:e015905. doi:10.1136/bmjopen-2017-015905 Med 1993;95:258-64. doi:10.1016/0002-9343(93)90277-V 11 Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal 34 Karangizi AHK, Al-Shaghana M, Logan S, et al. Glucocorticoid induced Insufficiency in Corticosteroids Use: Systematic Review and Meta- adrenal insufficiency is common in steroid treated glomerular Analysis. J Clin Endocrinol Metab 2015;100:2171-80. doi:10.1210/ diseases - proposed strategy for screening and management. BMC jc.2015-1218 Nephrol 2019;20:154. doi:10.1186/s12882-019-1354-6 12 Bloom CI, Saglani S, Feary J, Jarvis D, Quint JK. Changing 35 Borresen SW, Thorgrimsen TB, Jensen B, et al. Adrenal insufficiency prevalence of current asthma and inhaled corticosteroid treatment in prednisolone-treated patients with polymyalgia rheumatica or in the UK: population-based cohort 2006-2016. Eur Respir giant cell arteritis-prevalence and clinical approach. Rheumatology J 2019;53:1802130. doi:10.1183/13993003.02130-2018 (Oxford) 2020;59:2764-73. doi:10.1093/rheumatology/keaa011 13 van Staa TP, Cooper C, Leufkens HG, Lammers JW, Suissa S. The use of 36 Borresen SW, Klose M, Baslund B, et al. Adrenal insufficiency is inhaled corticosteroids in the United Kingdom and the Netherlands. seen in more than one-third of patients during ongoing low- Respir Med 2003;97:578-85. doi:10.1053/rmed.2002.1453 dose prednisolone treatment for rheumatoid arthritis. Eur J 14 Dinsen S, Baslund B, Klose M, et al. Why glucocorticoid withdrawal Endocrinol 2017;177:287-95. doi:10.1530/EJE-17-0251 may sometimes be as dangerous as the treatment itself. Eur J Intern 37 Lević Z, Micić D, Nikolić J, et al. Short-term high dose steroid therapy Med 2013;24:714-20. doi:10.1016/j.ejim.2013.05.014 does not affect the hypothalamic-pituitary-adrenal axis in relapsing 15 Kannisto S, Korppi M, Remes K, Voutilainen R. Serum multiple sclerosis patients. Clinical assessment by the insulin dehydroepiandrosterone sulfate concentration as an indicator of tolerance test. J Endocrinol Invest 1996;19:30-4. doi:10.1007/ adrenocortical suppression in asthmatic children treated with inhaled BF03347855 steroids. J Clin Endocrinol Metab 2001;86:4908-12. doi:10.1210/ 38 Aljebab F, Choonara I, Conroy S. Systematic review of the jcem.86.10.7975 toxicity of short-course oral corticosteroids in children. Arch Dis 16 Uei Y, Kanzaki M, Ohta T. Immunohistochemical study of crooke’s Child 2016;101:365-70. doi:10.1136/archdischild-2015-309522 hyaline change. Endocr Pathol 1991;2:12-5. doi:10.1007/ 39 Spiegel RJ, Vigersky RA, Oliff AI, Echelberger CK, Bruton J, Poplack BF02915321 DG. Adrenal suppression after short-term corticosteroid therapy. 17 Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, Lancet 1979;1:630-3. doi:10.1016/S0140-6736(79)91077-8 diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, 40 Carella MJ, Srivastava LS, Gossain VV, Rovner DR. Hypothalamic- adrenal insufficiency, and congenital adrenal hyperplasia. Compr pituitary-adrenal function one week after a short burst of steroid Physiol 2014;4:739-69. doi:10.1002/cphy.c130035 therapy. J Clin Endocrinol Metab 1993;76:1188-91. 18 Brigell DF, Fang VS, Rosenfield RL. Recovery of responses to ovine 41 Schuetz P, Christ-Crain M, Schild U, et al. Effect of a 14-day course of corticotropin-releasing hormone after withdrawal of a short course of systemic corticosteroids on the hypothalamic-pituitary-adrenal-axis glucocorticoid. J Clin Endocrinol Metab 1992;74:1036-9. in patients with acute exacerbation of chronic obstructive pulmonary 19 Graber AL, Ney RL, Nicholson WE, Island DP, Liddle GW. disease. BMC Pulm Med 2008;8:1. doi:10.1186/1471-2466-8-1 Natural History of Pituitary-Adrenal Recovery Following Long- 42 Streck WF, Lockwood DH. Pituitary adrenal recovery following short- Term Suppression with Corticosteroids. J Clin Endocrinol term suppression with corticosteroids. Am J Med 1979;66:910-4.

Metab 1965;25:11-6. doi:10.1210/jcem-25-1-11 doi:10.1016/0002-9343(79)90444-3 http://www.bmj.com/ 20 Joseph RM, Hunter AL, Ray DW, Dixon WG. Systemic glucocorticoid 43 Fleishaker DL, Mukherjee A, Whaley FS, Daniel S, Zeiher BG. therapy and adrenal insufficiency in adults: A systematic review. Safety and pharmacodynamic dose response of short-term Semin Arthritis Rheum 2016;46:133-41. doi:10.1016/j. prednisone in healthy adult subjects: a dose ranging, randomized, semarthrit.2016.03.001 placebo-controlled, crossover study. BMC Musculoskelet 21 Simpson H, Tomlinson J, Wass J, Dean J, Arlt W. Guidance for the Disord 2016;17:293. doi:10.1186/s12891-016-1135-3 prevention and emergency management of adult patients with 44 Neidert S, Schuetz P, Mueller B, Christ-Crain M. Dexamethasone adrenal insufficiency. Clin Med (Lond) 2020;20:371-8. doi:10.7861/ suppression test predicts later development of an impaired adrenal clinmed.2019-0324 function after a 14-day course of prednisone in healthy volunteers. 22 Paragliola RM, Papi G, Pontecorvi A, Corsello SM. Treatment with Eur J Endocrinol 2010;162:943-9. doi:10.1530/EJE-09-0930

Synthetic Glucocorticoids and the Hypothalamus-Pituitary-Adrenal 45 Schuetz P, Leuppi JD, Bingisser R, et al. Prospective analysis of on 28 September 2021 by guest. Protected copyright. Axis. Int J Mol Sci 2017;18:2201. doi:10.3390/ijms18102201 adrenal function in patients with acute exacerbations of COPD: 23 Jasani MK, Boyle JA, Greig WR, et al. Corticosteroid-induced the Reduction in the Use of Corticosteroids in Exacerbated COPD suppression of the hypothalamo-pituitary-adrenal axis: observations (REDUCE) trial. Eur J Endocrinol 2015;173:19-27. doi:10.1530/EJE- on patients given oral corticosteroids for rheumatoid arthritis. Q J 15-0182 Med 1967;36:261-76. 46 Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional 24 Nichols T, Nugent CA, Tyler FH. Diurnal Variation in Suppression glucocorticoid therapy in acute exacerbations of chronic obstructive of Adrenal Function by Glucocorticoids. J Clin Endocrinol pulmonary disease: the REDUCE randomized clinical trial. Metab 1965;25:343-9. doi:10.1210/jcem-25-3-343 JAMA 2013;309:2223-31. doi:10.1001/jama.2013.5023 25 Grant SD, Forsham PH, DiRaimondo VC. Suppression of 47 Han HS, Park JC, Park SY, et al. A Prospective Multicenter 17-hydroxycorticosteroids in plasma and urine by single and Study Evaluating Secondary Adrenal Suppression After divided doses of triamcinolone. N Engl J Med 1965;273:1115-8. Antiemetic Dexamethasone Therapy in Cancer Patients doi:10.1056/NEJM196511182732101 Receiving Chemotherapy: A Korean South West Oncology 26 Ackerman GL, Nolsn CM. Adrenocortical responsiveness after Group Study. Oncologist 2015;20:1432-9. doi:10.1634/ alternate-day corticosteroid therapy. N Engl J Med 1968;278:405-9. theoncologist.2015-0211 doi:10.1056/NEJM196802222780801 48 Han HS, Shim YK, Kim JE, et al. A pilot study of adrenal suppression 27 Sturge RA, Beardwell C, Hartog M, Wright D, Ansell BM. Cortisol and after dexamethasone therapy as an antiemetic in cancer patients. growth hormone secretion in relation to linear growth: patients Support Care Cancer 2012;20:1565-72. doi:10.1007/s00520-011- with Still’s disease on different therapeutic regimens. Br Med 1248-z J 1970;3:547-51. doi:10.1136/bmj.3.5722.547 49 Abu Bakar K, Khalil K, Lim YN, et al. Adrenal Insufficiency in Children 28 Carter ME, James VH. Effect of alternate-day, single-dose, With Nephrotic Syndrome on Corticosteroid Treatment. Front corticosteroid therapy on pituitary-adrenal function. Ann Rheum Pediatr 2020;8:164. doi:10.3389/fped.2020.00164 Dis 1972;31:379-83. doi:10.1136/ard.31.5.379 50 Wildi-Runge S, Deladoëy J, Bélanger C, et al. A search for 29 Jespersen S, Nygaard B, Kristensen LO. Methylprednisolone Pulse variables predicting cortisol response to low-dose corticotropin Treatment of Graves’ Ophthalmopathy Is Not Associated with stimulation following supraphysiological doses of glucocorticoids. J Secondary Adrenocortical Insufficiency. Eur Thyroid J 2015;4:222-5. Pediatr 2013;163:484-8. doi:10.1016/j.jpeds.2013.01.011 doi:10.1159/000440834 51 Rensen N, Gemke RJ, van Dalen EC, Rotteveel J, Kaspers 30 Giotaki Z, Fountas A, Tsirouki T, Bargiota A, Tigas S, Tsatsoulis A. GJ. Hypothalamic-pituitary-adrenal (HPA) axis suppression Adrenal reserve following treatment of Graves’ orbitopathy with after treatment with glucocorticoid therapy for childhood intravenous glucocorticoids. Thyroid 2015;25:462-3. doi:10.1089/ acute lymphoblastic leukaemia. Cochrane Database Syst thy.2014.0533 Rev 2017;11:CD008727. doi:10.1002/14651858.CD008727.pub4 31 Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA. 52 Ahmet A, Kim H, Spier S. Adrenal suppression: A practical guide Suppression and recovery of adrenal response after short-term, to the screening and management of this under-recognized high-dose glucocorticoid treatment. Lancet 2000;355:542-5. complication of inhaled corticosteroid therapy. Allergy Asthma Clin doi:10.1016/S0140-6736(99)06290-X Immunol 2011;7:13. doi:10.1186/1710-1492-7-13

16 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj STATE OF THE ART REVIEW

53 National Institute for Health and Care Excellence. Inhaled 75 Cavkaytar O, Vuralli D, Arik Yilmaz E, et al. Evidence of hypothalamic-

corticosteroid doses for NICE’s asthma guideline. 2018 https://www. pituitary-adrenal axis suppression during moderate-to-high-dose BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from nice.org.uk/guidance/ng80/resources/inhaled-corticosteroid-doses- inhaled corticosteroid use. Eur J Pediatr 2015;174:1421-31. pdf-4731528781. doi:10.1007/s00431-015-2610-9 54 London Respiratory Network. Guidance for healthcare professionals 76 Leung JS, Johnson DW, Sperou AJ. A systematic review of adverse on inhaled corticosteroids in adults. https://www.networks.nhs.uk/ drug events associated with administration of common asthma nhs-networks/london-lungs/documents/inhaled-corticosteroids-in- medications in children. PLoS One 2017;12:e0182738. adults. doi:10.1371/journal.pone.0182738 55 Woods CP, Argese N, Chapman M, et al. Adrenal suppression 77 Lipworth BJ, et al. Systemic adverse effects of inhaled corticosteroid in patients taking inhaled glucocorticoids is highly prevalent therapy: A systematic review and meta-analysis. Arch Intern and management can be guided by morning cortisol. Eur J Med 1999;159:941-55. doi:10.1001/archinte.159.9.941 Endocrinol 2015;173:633-42. doi:10.1530/EJE-15-0608 78 Sorkness CA, LaForce C, Storms W, Lincourt WR, Edwards L, Rogenes 56 Mortimer KJ, Tata LJ, Smith CJ, et al. Oral and inhaled corticosteroids PR. Effects of the inhaled corticosteroids fluticasone propionate, and adrenal insufficiency: a case-control study. Thorax 2006;61:405- triamcinolone acetonide, and flunisolide and oral prednisone on the 8. doi:10.1136/thx.2005.052456 hypothalamic-pituitary-adrenal axis in adult patients with asthma. 57 Kapadia CR, Nebesio TD, Myers SE, et al, Drugs and Therapeutics Clin Ther 1999;21:353-67. doi:10.1016/S0149-2918(00)88292-2 Committee of the Pediatric Endocrine Society. Endocrine Effects of 79 Wasserman SI, Gross GN, Schoenwetter WF, et al. A 12- Inhaled Corticosteroids in Children. JAMA Pediatr 2016;170:163-70. week dose-ranging study of fluticasone propionate powder doi:10.1001/jamapediatrics.2015.3526 in the treatment of asthma. J Asthma 1996;33:265-74. 58 Zöllner EW, Lombard C, Galal U, Hough S, Irusen E, Weinberg E. doi:10.3109/02770909609055367 Hypothalamic-pituitary-adrenal axis suppression in asthmatic 80 Masoli M, Weatherall M, Holt S, Shirtcliffe P, Beasley R. Inhaled children on inhaled and nasal corticosteroids--more common fluticasone propionate and adrenal effects in adult asthma: than expected?J Pediatr Endocrinol Metab 2011;24:529-34. systematic review and meta-analysis. Eur Respir J 2006;28:960-7. do doi:10.1515/jpem.2011.198 i:10.1183/09031936.06.00119305 59 Lapi F, Kezouh A, Suissa S, Ernst P. The use of inhaled corticosteroids 81 Choi IS, Sim DW, Kim SH, Wui JW. Adrenal insufficiency associated and the risk of adrenal insufficiency. Eur Respir J 2013;42:79-86. with long-term use of inhaled steroid in asthma. Ann Allergy Asthma doi:10.1183/09031936.00080912 Immunol 2017;118:66-72.e1. doi:10.1016/j.anai.2016.10.002 60 Zöllner EW, Lombard CJ, Galal U, Hough FS, Irusen EM, Weinberg E. 82 Kwda A, Gldc P, Baui B, et al. Effect of long term inhaled corticosteroid Hypothalamic-pituitary-adrenal axis suppression in asthmatic school therapy on adrenal suppression, growth and bone health in children children. Pediatrics 2012;130:e1512-9. doi:10.1542/peds.2012- with asthma. BMC Pediatr 2019;19:411. doi:10.1186/s12887-019- 1147 1760-8 61 Paton J, Jardine E, McNeill E, et al. Adrenal responses to low dose 83 Préville-Ratelle S, Coriati A, Ménard A, Bourdeau I, Tremblay synthetic ACTH (Synacthen) in children receiving high dose inhaled F, Berthiaume Y. Adrenal Insufficiency in Cystic Fibrosis: A fluticasone. Arch Dis Child 2006;91:808-13. doi:10.1136/ Rare Phenomenon?Can Respir J 2018;2018:3629031. adc.2005.087247 doi:10.1155/2018/3629031 62 Molimard M, Girodet PO, Pollet C, et al. Inhaled corticosteroids and 84 Guaraldi F, Gori D, Calderoni P, et al. Comparative assessment of adrenal insufficiency: prevalence and clinical presentation. Drug hypothalamic-pituitary-adrenal axis suppression secondary to Saf 2008;31:769-74. doi:10.2165/00002018-200831090-00005 intrabursal injection of different glucocorticoids: a pilot study. J 63 Boorsma M, Andersson N, Larsson P, Ullman A. Assessment of the Endocrinol Invest 2019;42:1117-24. doi:10.1007/s40618-019- relative systemic potency of inhaled fluticasone and budesonide. Eur 01033-6

Respir J 1996;9:1427-32. doi:10.1183/09031936.96.09071427 85 Lansang MC, Farmer T, Kennedy L. Diagnosing the unrecognized http://www.bmj.com/ 64 Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of systemic absorption of intra-articular and epidural steroid injections. fluticasone propionate compared with budesonide in adult asthmatic Endocr Pract 2009;15:225-8. doi:10.4158/EP.15.3.225 patients. Thorax 1997;52:55-8. doi:10.1136/thx.52.1.55 86 Johnston PC, Lansang MC, Chatterjee S, Kennedy L. Intra-articular 65 Allen A, Bareille PJ, Rousell VM. Fluticasone furoate, a novel glucocorticoid injections and their effect on hypothalamic- inhaled corticosteroid, demonstrates prolonged lung absorption pituitary-adrenal (HPA)-axis function. Endocrine 2015;48:410-6. kinetics in man compared with inhaled fluticasone propionate. Clin doi:10.1007/s12020-014-0409-5 Pharmacokinet 2013;52:37-42. doi:10.1007/s40262-012-0021-x 87 Gondwe JS, Davidson JE, Deeley S, Sills J, Cleary AG. Secondary 66 Salter M, Biggadike K, Matthews JL, et al. Pharmacological properties Cushing’s syndrome in children with juvenile idiopathic arthritis of the enhanced-affinity glucocorticoid fluticasone furoate in vitro following intra-articular triamcinolone acetonide administration.

and in an in vivo model of respiratory inflammatory disease. Am Rheumatology (Oxford) 2005;44:1457-8. doi:10.1093/ on 28 September 2021 by guest. Protected copyright. J Physiol Lung Cell Mol Physiol 2007;293:L660-7. doi:10.1152/ rheumatology/kei154 ajplung.00108.2007 88 Reid DM, Eastmond C, Rennie JA. Hypothalamic-pituitary-adrenal 67 Allen A, Schenkenberger I, Trivedi R, et al. Inhaled fluticasone furoate/ axis suppression after repeated intra-articular steroid injections. Ann vilanterol does not affect hypothalamic-pituitary-adrenal axis function Rheum Dis 1986;45:87. doi:10.1136/ard.45.1.87 in adolescent and adult asthma: randomised, double-blind, placebo- 89 Mader R, Lavi I, Luboshitzky R. Evaluation of the pituitary- controlled study. Clin Respir J 2013;7:397-406. doi:10.1111/ adrenal axis function following single intraarticular injection of crj.12026 methylprednisolone. Arthritis Rheum 2005;52:924-8. doi:10.1002/ 68 Bareille P, Tomkins S, Imber V, et al. A randomized, double-blind, art.20884 placebo-controlled, parallel-group study of once-daily inhaled 90 Hyle EP, Wood BR, Backman ES, et al. High frequency of fluticasone furoate on the hypothalamic-pituitary-adrenocortical axis hypothalamic-pituitary-adrenal axis dysfunction after local of children with asthma. Allergy Asthma Clin Immunol 2020;16:11. corticosteroid injection in HIV-infected patients on protease inhibitor doi:10.1186/s13223-020-0406-6 therapy. J Acquir Immune Defic Syndr 2013;63:602-8. doi:10.1097/ 69 Allen A, Bal J, Cheesbrough A, Hamilton M, Kempsford R. QAI.0b013e31829b662b Pharmacokinetics and pharmacodynamics of intravenous and 91 Habib G, Jabbour A, Artul S, Hakim G. Intra-articular inhaled fluticasone furoate in healthy Caucasian and East Asian methylprednisolone acetate injection at the knee joint and the subjects. Br J Clin Pharmacol 2014;77:808-20. doi:10.1111/ hypothalamic-pituitary-adrenal axis: a randomized controlled study. bcp.12263 Clin Rheumatol 2014;33:99-103. doi:10.1007/s10067-013- 70 Christie P. Ciclesonide: a novel inhaled corticosteroid for 2374-4 asthma. Drugs Today (Barc) 2004;40:569-76. doi:10.1358/ 92 Habib G, Artul S, Chernin M, Hakim G, Jabbour A. The effect of intra- dot.2004.40.7.850475 articular injection of betamethasone acetate/betamethasone sodium 71 Rohatagi S, Arya V, Zech K, et al. Population pharmacokinetics and phosphate at the knee joint on the hypothalamic-pituitary-adrenal pharmacodynamics of ciclesonide. J Clin Pharmacol 2003;43:365- axis: a case-controlled study. J Investig Med 2013;61:1104-7. 78. doi:10.1177/0091270002250998 doi:10.2310/JIM.0b013e3182a67871 72 Xu J, Nave R, Lahu G, Derom E, Derendorf H. Population 93 Habib G, Khazin F, Jabbour A, et al. Simultaneous bilateral knee pharmacokinetics and pharmacodynamics of inhaled ciclesonide injection of methylprednisolone acetate and the hypothalamic- and fluticasone propionate in patients with persistent asthma. J Clin pituitary adrenal axis: a single-blind case-control study. J Investig Pharmacol 2010;50:1118-27. doi:10.1177/0091270009354994 Med 2014;62:621-6. doi:10.2310/JIM.0000000000000048 73 El Baou C, Di Santostefano RL, Alfonso-Cristancho R, et al. Effect of 94 Iranmanesh A, Gullapalli D, Singh R, Veldhuis JD. Hypothalamo- inhaled corticosteroid particle size on asthma efficacy and safety pituitary-adrenal axis after a single epidural triamcinolone injection. outcomes: a systematic literature review and meta-analysis. BMC Endocrine 2017;57:308-13. doi:10.1007/s12020-017-1357-7 Pulm Med 2017;17:31. doi:10.1186/s12890-016-0348-4 95 Kay J, Findling JW, Raff H. Epidural triamcinolone suppresses 74 Heller MK, Laks J, Kovesi TA, Ahmet A. Reversal of adrenal the pituitary-adrenal axis in human subjects. Anesth suppression with ciclesonide. J Asthma 2010;47:337-9. Analg 1994;79:501-5. doi:10.1213/00000539-199409000- doi:10.3109/02770900903509081 00017 the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 17 STATE OF THE ART REVIEW

96 Jacobs S, Pullan PT, Potter JM, Shenfield GM. Adrenal suppression 119 Cottrell ML, Hadzic T, Kashuba AD. Clinical pharmacokinetic,

following extradural steroids. Anaesthesia 1983;38:953-6. pharmacodynamic and drug-interaction profile of the integrase BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from doi:10.1111/j.1365-2044.1983.tb12025.x inhibitor dolutegravir. Clin Pharmacokinet 2013;52:981-94. 97 Habib G, Jabbour A, Salman J, Hakim G, Haddad H. The effect of doi:10.1007/s40262-013-0093-2 epidural methylprednisolone acetate injection on the hypothalamic- 120 Dort K, Padia S, Wispelwey B, Moore CC. Adrenal suppression due to pituitary-adrenal axis. J Clin Anesth 2013;25:629-33. doi:10.1016/j. an interaction between ritonavir and injected triamcinolone: a case jclinane.2013.07.002 report. AIDS Res Ther 2009;6:10. doi:10.1186/1742-6405-6-10 98 Perry RJ, Findlay CA, Donaldson MD. Cushing’s syndrome, growth 121 Yombi JC, Maiter D, Belkhir L, Nzeusseu A, Vandercam B. Iatrogenic impairment, and occult adrenal suppression associated with intranasal Cushing’s syndrome and secondary adrenal insufficiency after a steroids. Arch Dis Child 2002;87:45-8. doi:10.1136/adc.87.1.45 single intra-articular administration of triamcinolone acetonide 99 Finken MJ, Mul D. Cushing’s syndrome and adrenal insufficiency in HIV-infected patients treated with ritonavir. Clin Rheumatol after intradermal triamcinolone acetonide for keloid scars. Eur J 2008;27(Suppl 2):S79-82. doi:10.1007/s10067-008-1022-x Pediatr 2010;169:1147-9. doi:10.1007/s00431-010-1165-z 122 Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and 100 Sukhumthammarat W, Putthapiban P, Sriphrapradang C. Local Cushing’s syndrome secondary to an interaction between ritonavir Injection of Triamcinolone Acetonide: A Forgotten Aetiology and fluticasone: a review of the literature. HIV Med 2008;9:389-96. of Cushing’s Syndrome. J Clin Diagn Res 2017;11:OR01-02. doi:10.1111/j.1468-1293.2008.00579.x doi:10.7860/JCDR/2017/27238.10091 123 De Wachter E, Vanbesien J, De Schutter I, Malfroot A, De Schepper J. 101 Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of Rapidly developing Cushing syndrome in a 4-year-old patient during topical glucocorticosteroids. J Am Acad Dermatol 2006;54:1-15, quiz combined treatment with itraconazole and inhaled budesonide. Eur J 16-8. doi:10.1016/j.jaad.2005.01.010 Pediatr 2003;162:488-9. doi:10.1007/s00431-003-1233-8 102 Borresen SW, Klose M, Rasmussen AK, Feldt-Rasmussen U. Adrenal 124 Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use Insufficiency Caused by Locally Applied Glucocorticoids-Myth or in HIV-positive individuals taking protease inhibitors: a review of Fact?Curr Med Chem 2015;22:2801-9. doi:10.2174/0929867322 pharmacokinetics, case reports and clinical management. HIV 666150716113003 Med 2013;14:519-29. doi:10.1111/hiv.12039 103 Raveendran AV. Inhalational Steroids and Iatrogenic Cushing’s 125 Boyd SD, Hadigan C, McManus M, et al. Influence of low-dose Syndrome. Open Respir Med J 2014;8:74-84. doi:10.2174/187430 ritonavir with and without darunavir on the pharmacokinetics and 6401408010074 pharmacodynamics of inhaled beclomethasone. J Acquir Immune Defic 104 Bachert C, Lukat KF, Lange B. Effect of intranasal fluticasone Syndr 2013;63:355-61. doi:10.1097/QAI.0b013e31829260d6 propionate and triamcinolone acetonide on basal and dynamic 126 van den Berg SAA, van ’t Veer NE, Emmen JMA, van Beek RHT. measures of hypothalamic-pituitary-adrenal-axis activity in healthy Fluticasone furoate induced iatrogenic Cushing syndrome in a volunteers. Clin Exp Allergy 2004;34:85-90. doi:10.1111/j.1365- pediatric patient receiving anti-retroviral therapy. Endocrinol Diabetes 2222.2004.01843.x Metab Case Rep 2017;2017:16-0158. doi:10.1530/EDM-16-0158 105 Carruthers JA, August PJ, Staughton RC. Observations on the 127 Drummond MB, Kirk GD. HIV-associated obstructive lung systemic effect of topical clobetasol propionate (Dermovate). Br Med diseases: insights and implications for the clinician. Lancet Respir J 1975;4:203-4. doi:10.1136/bmj.4.5990.203 Med 2014;2:583-92. doi:10.1016/S2213-2600(14)70017-7 106 Lee DA, Taylor GM, James VH, Walker G. Plasma prednisolone 128 Vulto A, Minović I, de Vries LV, et al. Endogenous urinary levels and adrenocortical responsiveness after administration glucocorticoid metabolites and mortality in prednisolone-treated of prednisolone-21-phosphate as a retention enema. renal transplant recipients. Clin Transplant 2020;34:e13824. Gut 1979;20:349-55. doi:10.1136/gut.20.5.349 doi:10.1111/ctr.13824 107 Luman W, Gray RS, Pendek R, Palmer KR. Prednisolone 129 de Ruiter RD, Gordijn MS, Gemke RJ, et al. Adrenal insufficiency

metasulphobenzoate foam retention enemas suppress the during treatment for childhood acute lymphoblastic leukemia is http://www.bmj.com/ hypothalamo-pituitary-adrenal axis. Aliment Pharmacol associated with glucocorticoid receptor polymorphisms ER22/23EK Ther 1994;8:255-8. doi:10.1111/j.1365-2036.1994.tb00284.x and BclI. Haematologica 2014;99:e136-7. doi:10.3324/ 108 Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative haematol.2014.105056 treatments in ulcerative colitis: a meta-analysis. Gut 1997;40:775- 130 Manenschijn L, van den Akker EL, Lamberts SW, van Rossum 81. doi:10.1136/gut.40.6.775 EF. Clinical features associated with glucocorticoid receptor 109 Mulder CJ, Endert E, van der Heide H, et al. Comparison of polymorphisms. An overview. Ann N Y Acad Sci 2009;1179:179-98. beclomethasone dipropionate (2 and 3 mg) and prednisolone doi:10.1111/j.1749-6632.2009.05013.x sodium phosphate enemas (30 mg) in the treatment of ulcerative 131 Derijk RH. Single nucleotide polymorphisms related to HPA proctitis. An adrenocortical approach. Neth J Med 1989;35:18-24. axis reactivity. Neuroimmunomodulation 2009;16:340-52.

110 Kumana CR, Seaton T, Meghji M, Castelli M, Benson R, Sivakumaran doi:10.1159/000216192 on 28 September 2021 by guest. Protected copyright. T. Beclomethasone dipropionate enemas for treating inflammatory 132 van Leeuwen N, Kumsta R, Entringer S, et al. Functional bowel disease without producing Cushing’s syndrome or mineralocorticoid receptor (MR) gene variation influences hypothalamic pituitary adrenal suppression. Lancet 1982;1:579-83. the cortisol awakening response after dexamethasone. doi:10.1016/S0140-6736(82)91747-0 Psychoneuroendocrinology 2010;35:339-49. doi:10.1016/j. 111 Gionchetti P, D’Arienzo A, Rizzello F, et al, Italian BDP Study psyneuen.2009.07.006 Group. Topical treatment of distal active ulcerative colitis with 133 Müller LM, Kienitz T, Deutschbein T, et al. Glucocorticoid Receptor beclomethasone dipropionate or mesalamine: a single-blind Polymorphisms Influence Muscle Strength in Cushing’s Syndrome. randomized controlled trial. J Clin Gastroenterol 2005;39:291-7. J Clin Endocrinol Metab 2020;105:dgz052. doi:10.1210/clinem/ doi:10.1097/01.mcg.0000155124.74548.61 dgz052 112 Arntzenius A, van Galen L. Budesonide-related adrenal insufficiency. 134 Akurugu WA, Van Heerden CJ, Mulder N, Zöllner EW. Hypothalamic- BMJ Case Rep 2015;2015:bcr2015212216. doi:10.1136/bcr- pituitary-adrenal axis suppression in asthma: A glucocorticoid 2015-212216 receptor polymorphism may protect. Pediatr Allergy 113 Tripathi K, Dunzendorfer T. Budesonide-Related Iatrogenic Cushing’s Immunol 2021;32:273-9. doi:10.1111/pai.13379 Syndrome in Microscopic Colitis. ACG Case Rep J 2017;4:e5. 135 Bazsó A, Kövesdi A, Rásonyi R, et al. Glucocorticoid receptor doi:10.14309/crj.2017.5 polymorphisms in rheumatoid arthritis: results from a single centre. 114 Kirwan JR, Hickey SH, Hällgren R, et al. The effect of therapeutic Clin Exp Rheumatol 2020;38:858-63. glucocorticoids on the adrenal response in a randomized 136 Huang J, Hu X, Zheng X, et al. Effects of STIP1 and GLCCI1 controlled trial in patients with rheumatoid arthritis. Arthritis polymorphisms on the risk of childhood asthma and inhaled Rheum 2006;54:1415-21. doi:10.1002/art.21747 corticosteroid response in Chinese asthmatic children. BMC Pulm 115 Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG, The Global Med 2020;20:303. doi:10.1186/s12890-020-01332-2 Budesonide Study Group. Oral budesonide is as effective as oral 137 Lou QY, Li Z, Teng Y, et al. Associations of FKBP4 and FKBP5 gene prednisolone in active Crohn’s disease. Gut 1997;41:209-14. polymorphisms with disease susceptibility, glucocorticoid efficacy, doi:10.1136/gut.41.2.209 anxiety, depression, and health-related quality of life in systemic 116 Ferguson A, Campieri M, Doe W, Persson T, Nygård G, Global lupus erythematosus patients. Clin Rheumatol 2021;40:167-79. Budesonide Study Group. Oral budesonide as maintenance therapy doi:10.1007/s10067-020-05195-0 in Crohn’s disease--results of a 12-month study. Aliment Pharmacol 138 Lin RC, Wang XL, Dalziel B, Caterson ID, Morris BJ. Association of Ther 1998;12:175-83. doi:10.1046/j.1365-2036.1998.00285.x obesity, but not diabetes or hypertension, with glucocorticoid 117 Löfberg R, Rutgeerts P, Malchow H, et al. Budesonide prolongs receptor N363S variant. Obes Res 2003;11:802-8. doi:10.1038/ time to relapse in ileal and ileocaecal Crohn’s disease. A placebo oby.2003.111 controlled one year study. Gut 1996;39:82-6. doi:10.1136/ 139 Giordano R, Marzotti S, Berardelli R, et al. BClI polymorphism of gut.39.1.82 the glucocorticoid receptor gene is associated with increased 118 European Medicines Agency. Norvir (ritonavir): Summary of Product obesity, impaired glucose metabolism and dyslipidaemia in patients Characteristics. 2021. https://www.ema.europa.eu/en/documents/ with Addison’s disease. Clin Endocrinol (Oxf) 2012;77:863-70. product-information/norvir-epar-product-information_en.pdf. doi:10.1111/j.1365-2265.2012.04439.x

18 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj STATE OF THE ART REVIEW

140 van Rossum EF, Voorhoeve PG, te Velde SJ, et al. The ER22/23EK the United Kingdom. Arch Dis Child 2002;87:457-61. doi:10.1136/

polymorphism in the glucocorticoid receptor gene is associated with adc.87.6.457 BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from a beneficial body composition and muscle strength in young adults. 163 Spera K, Rubin D, Gupta T, Fantaneanu T, Henderson GV. Clinical J Clin Endocrinol Metab 2004;89:4004-9. doi:10.1210/jc.2003- Reasoning: An 87-year-old man with chronic obstructive pulmonary 031422 disease and acute encephalopathy. Neurology 2016;87:e135-9. 141 van Rossum EF, Koper JW, Huizenga NA, et al. A polymorphism doi:10.1212/WNL.0000000000003149 in the glucocorticoid receptor gene, which decreases sensitivity 164 Da Silva AN, Schiff D. Adrenal insufficiency secondary to to glucocorticoids in vivo, is associated with low insulin and glucocorticoid withdrawal in patients with brain tumor. Surg cholesterol levels. Diabetes 2002;51:3128-34. doi:10.2337/ Neurol 2007;67:508-10. doi:10.1016/j.surneu.2006.07.018 diabetes.51.10.3128 165 Christensson C, Thorén A, Lindberg B. Safety of inhaled budesonide: 142 Trementino L, Appolloni G, Concettoni C, Cardinaletti M, Boscaro clinical manifestations of systemic corticosteroid-related adverse M, Arnaldi G. Association of glucocorticoid receptor polymorphism effects. Drug Saf 2008;31:965-88. doi:10.2165/00002018- A3669G with decreased risk of developing diabetes in patients 200831110-00002 with Cushing’s syndrome. Eur J Endocrinol 2012;166:35-42. 166 Iglesias P, González J, Díez JJ. Acute and persistent iatrogenic doi:10.1530/EJE-11-0722 Cushing’s syndrome after a single dose of triamcinolone acetonide. J 143 Venneri MA, Hasenmajer V, Fiore D, et al. Circadian Rhythm Endocrinol Invest 2005;28:1019-23. doi:10.1007/BF03345342 of Glucocorticoid Administration Entrains Clock Genes in 167 Meikle AW, Tyler FH. Potency and duration of action of Immune Cells: A DREAM Trial Ancillary Study. J Clin Endocrinol glucocorticoids. Effects of hydrocortisone, prednisone and Metab 2018;103:2998-3009. doi:10.1210/jc.2018-00346 dexamethasone on human pituitary-adrenal function. Am J 144 Kino T. Circadian rhythms of glucocorticoid hormone actions in Med 1977;63:200-7. doi:10.1016/0002-9343(77)90233-9 target tissues: potential clinical implications. Sci Signal 2012;5:pt4. 168 Prete A, Paragliola RM, Bottiglieri F, et al. Factors predicting the doi:10.1126/scisignal.2003333 duration of adrenal insufficiency in patients successfully treated 145 Zanger UM, Schwab M. Cytochrome P450 enzymes in drug for Cushing disease and nonmalignant primary adrenal Cushing metabolism: regulation of gene expression, enzyme activities, and syndrome. Endocrine 2017;55:969-80. doi:10.1007/s12020-016- impact of genetic variation. Pharmacol Ther 2013;138:103-41. 1007-5 doi:10.1016/j.pharmthera.2012.12.007 169 Berr CM, Di Dalmazi G, Osswald A, et al. Time to recovery of adrenal 146 Wass JA, Arlt W. How to avoid precipitating an acute adrenal crisis. function after curative surgery for Cushing’s syndrome depends on BMJ 2012;345:e6333. doi:10.1136/bmj.e6333 etiology. J Clin Endocrinol Metab 2015;100:1300-8. doi:10.1210/ 147 Allen G, Mitchell A, Ramirez M, Holsten S, Shah N. A Case of a jc.2014-3632 Post-Operative Addisonian Crisis from HPA Axis Suppression 170 Hurtado MD, Cortes T, Natt N, Young WFJr, Bancos I. Extensive clinical from Inhaled Corticosteroids. Am Surg 2019;85:e483-4. experience: Hypothalamic-pituitary-adrenal axis recovery after doi:10.1177/000313481908500920 adrenalectomy for corticotropin-independent cortisol excess. Clin 148 Moritani K, Tauchi H, Ochi F, et al. Prolonged adrenal insufficiency Endocrinol (Oxf) 2018;89:721-33. doi:10.1111/cen.13803 after high-dose glucocorticoid in infants with leukemia. Pediatr 171 Richter B, Neises G, Clar C. Glucocorticoid withdrawal schemes Hematol Oncol 2018;35:355-61. doi:10.1080/08880018.2018.15 in chronic medical disorders. A systematic review. Endocrinol 39148 Metab Clin North Am 2002;31:751-78. doi:10.1016/S0889- 149 Rushworth RL, Chrisp GL, Torpy DJ. Glucocorticoid-Induced Adrenal 8529(02)00008-7 Insufficiency: A Study of the Incidence in Hospital Patients and a 172 Hellmich B, Agueda A, Monti S, et al. 2018 Update of the Review of Peri-Operative Management. Endocr Pract 2018;24:437- EULAR recommendations for the management of large vessel 45. doi:10.4158/EP-2017-0117 vasculitis. Ann Rheum Dis 2020;79:19-30. doi:10.1136/

150 Goldbloom EB, Mokashi A, Cummings EA, et al. Symptomatic annrheumdis-2019-215672 http://www.bmj.com/ adrenal suppression among children in Canada. Arch Dis 173 Hochberg Z, Pacak K, Chrousos GP. Endocrine withdrawal syndromes. Child 2017;102:338-9. doi:10.1136/archdischild-2016-311223 Endocr Rev 2003;24:523-38. doi:10.1210/er.2001-0014 151 Todd GR, Acerini CL, Buck JJ, et al. Acute adrenal crisis in asthmatics 174 Erkut ZA, Pool C, Swaab DF. Glucocorticoids suppress corticotropin- treated with high-dose fluticasone propionate. Eur Respir releasing hormone and vasopressin expression in human J 2002;19:1207-9. doi:10.1183/09031936.02.00274402 hypothalamic neurons. J Clin Endocrinol Metab 1998;83:2066-73. 152 Iwasaku M, Shinzawa M, Tanaka S, Kimachi K, Kawakami K. Clinical doi:10.1210/jc.83.6.2066 characteristics of adrenal crisis in adult population with and without 175 Papanicolaou DA, Tsigos C, Oldfield EH, Chrousos GP. Acute predisposing chronic adrenal insufficiency: a retrospective cohort glucocorticoid deficiency is associated with plasma elevations of study. BMC Endocr Disord 2017;17:58. doi:10.1186/s12902-017- interleukin-6: does the latter participate in the symptomatology

0208-0 of the steroid withdrawal syndrome and adrenal insufficiency?J on 28 September 2021 by guest. Protected copyright. 153 Sannarangappa V, Jalleh R. Inhaled corticosteroids and secondary Clin Endocrinol Metab 1996;81:2303-6. doi:10.1210/ adrenal insufficiency. Open Respir Med J 2014;8:93-100. doi:10.217 jcem.81.6.8964868 4/1874306401408010093 176 Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW, Chrousos 154 Nathan AW, Rose GL. Fatal iatrogenic Cushing’s syndrome. GP. The longitudinal course of psychopathology in Cushing’s Lancet 1979;1:207. doi:10.1016/S0140-6736(79)90597-X syndrome after correction of hypercortisolism. J Clin Endocrinol 155 Barlow AD, Clarke GA, Kelly MJ. Acute adrenal crisis in a patient Metab 1997;82:912-9. treated with rectal steroids. Colorectal Dis 2004;6:62-4. 177 Bancos I, Erickson D, Bryant S, et al. Performance of Free Versus Total doi:10.1111/j.1463-1318.2004.00540.x Cortisol Following Cosyntropin Stimulation Testing in an Outpatient 156 Jansen TL, Van Roon EN. Four cases of a secondary Cushingoid state Setting. Endocr Pract 2015;21:1353-63. doi:10.4158/EP15820.OR following local triamcinolone acetonide (Kenacort) injection. Neth J 178 Rauschecker M, Abraham SB, Abel BS, et al. Cosyntropin-Stimulated Med 2002;60:151-3. Serum Free Cortisol in Healthy, Adrenally Insufficient, and Mildly 157 Kumar S, Singh RJ, Reed AM, Lteif AN. Cushing’s syndrome after Cirrhotic Populations. J Clin Endocrinol Metab 2016;101:1075-81. intra-articular and intradermal administration of triamcinolone doi:10.1210/jc.2015-2285 acetonide in three pediatric patients. Pediatrics 2004;113:1820-4. 179 Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free doi:10.1542/peds.113.6.1820 cortisol in critically ill patients. N Engl J Med 2004;350:1629-38. 158 Leary J, Swislocki A. Hypothalamic-Pituitary-Adrenal Suppression doi:10.1056/NEJMoa020266 and Iatrogenic Cushing’s Syndrome as a Complication of Epidural 180 Sbardella E, Isidori AM, Woods CP, et al. Baseline morning cortisol Steroid Injections. Case Rep Endocrinol 2013;2013:617042. level as a predictor of pituitary-adrenal reserve: a comparison across doi:10.1155/2013/617042 three assays. Clin Endocrinol (Oxf) 2017;86:177-84. doi:10.1111/ 159 Li D, Genere N, Behnken E, et al. Determinants of Self-reported cen.13232 Health Outcomes in Adrenal Insufficiency: A Multisite Survey Study. J 181 Kane KF, Emery P, Sheppard MC, Stewart PM. Assessing the Clin Endocrinol Metab 2021;106:e1408-19. doi:10.1210/clinem/ hypothalamo-pituitary-adrenal axis in patients on long-term dgaa668 glucocorticoid therapy: the short synacthen versus the insulin 160 Smans LC, Van der Valk ES, Hermus AR, Zelissen PM. Incidence of tolerance test. QJM 1995;88:263-7. adrenal crisis in patients with adrenal insufficiency. Clin Endocrinol 182 Hurel SJ, Thompson CJ, Watson MJ, Harris MM, Baylis PH, (Oxf) 2016;84:17-22. doi:10.1111/cen.12865 Kendall-Taylor P. The short Synacthen and insulin stress tests 161 Laugesen K, Petersen I, Sørensen HT, Jørgensen JOL. Clinical in the assessment of the hypothalamic-pituitary-adrenal axis. indicators of adrenal insufficiency following discontinuation of oral Clin Endocrinol (Oxf) 1996;44:141-6. doi:10.1046/j.1365- glucocorticoid therapy: A Danish population-based self-controlled 2265.1996.555381.x case series analysis. PLoS One 2019;14:e0212259. doi:10.1371/ 183 Hartzband PI, Van Herle AJ, Sorger L, Cope D. Assessment of journal.pone.0212259 hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison 162 Todd GR, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D. of ACTH stimulation, insulin-hypoglycemia and metyrapone. J Survey of adrenal crisis associated with inhaled corticosteroids in Endocrinol Invest 1988;11:769-76. doi:10.1007/BF03350221

the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 19 STATE OF THE ART REVIEW

184 Agha A, Tomlinson JW, Clark PM, Holder G, Stewart PM. The long-term Guideline. J Clin Endocrinol Metab 2016;101:364-89. doi:10.1210/

predictive accuracy of the short synacthen (corticotropin) stimulation jc.2015-1710 BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from test for assessment of the hypothalamic-pituitary-adrenal axis. J Clin 192 Prete A, Taylor AE, Bancos I, et al. Prevention of Adrenal Crisis: Endocrinol Metab 2006;91:43-7. doi:10.1210/jc.2005-1131 Cortisol Responses to Major Stress Compared to Stress Dose 185 Ospina NS, Al Nofal A, Bancos I, et al. ACTH Stimulation Tests for the Hydrocortisone Delivery. J Clin Endocrinol Metab 2020;105:2262- Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis. 74. doi:10.1210/clinem/dgaa133 J Clin Endocrinol Metab 2016;101:427-34. doi:10.1210/jc.2015-1700 193 Arlt W, Baldeweg SE, Pearce SHS, Simpson HL. ENDOCRINOLOGY IN 186 Fiad TM, Kirby JM, Cunningham SK, McKenna TJ. The overnight THE TIME OF COVID-19: Management of adrenal insufficiency. Eur J single-dose metyrapone test is a simple and reliable index Endocrinol 2020;183:G25-32. doi:10.1530/EJE-20-0361 of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol 194 Woodcock T, Barker P, Daniel S, et al. Guidelines for the management (Oxf) 1994;40:603-9. doi:10.1111/j.1365-2265.1994.tb03011.x of glucocorticoids during the peri-operative period for patients 187 Rose SR, Lustig RH, Burstein S, Pitukcheewanont P, Broome DC, with adrenal insufficiency: Guidelines from the Association of Burghen GA. Diagnosis of ACTH deficiency. Comparison of overnight Anaesthetists, the Royal College of Physicians and the Society for metyrapone test to either low-dose or high-dose ACTH test. Horm Endocrinology UK. Anaesthesia 2020;75:654-63. doi:10.1111/ Res 1999;52:73-9. anae.14963 188 Soule S, Van Zyl Smit C, Parolis G, et al. The low dose ACTH 195 Arlt W, Society for Endocrinology Clinical Committee. SOCIETY FOR stimulation test is less sensitive than the overnight metyrapone ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency test for the diagnosis of secondary hypoadrenalism. Clin Endocrinol management of acute adrenal insufficiency (adrenal crisis) in adult (Oxf) 2000;53:221-7. doi:10.1046/j.1365-2265.2000.01057.x patients. Endocr Connect 2016;5:G1-3. doi:10.1530/EC-16-0054 189 Jamilloux Y, Liozon E, Pugnet G, et al. Recovery of adrenal function 196 Nicolaides NC, Charmandari E, Kino T, Chrousos GP. Stress-Related after long-term glucocorticoid therapy for giant cell arteritis: a and Circadian Secretion and Target Tissue Actions of Glucocorticoids: cohort study. PLoS One 2013;8:e68713. doi:10.1371/journal. Impact on Health. Front Endocrinol (Lausanne) 2017;8:70. pone.0068713 doi:10.3389/fendo.2017.00070 190 Di Dalmazi G, Berr CM, Fassnacht M, Beuschlein F, Reincke M. 197 Scherholz ML, Schlesinger N, Androulakis IP. Chronopharmacology Adrenal function after adrenalectomy for subclinical hypercortisolism of glucocorticoids. Adv Drug Deliv Rev 2019;151-152:245-61. and Cushing’s syndrome: a systematic review of the literature. J Clin doi:10.1016/j.addr.2019.02.004 Endocrinol Metab 2014;99:2637-45. doi:10.1210/jc.2014-1401 198 Stewart PM. Modified-Release Hydrocortisone: Is It Time to Change 191 Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Clinical Practice?J Endocr Soc 2019;3:1150-3. doi:10.1210/js.2019- Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice 00046 http://www.bmj.com/ on 28 September 2021 by guest. Protected copyright.

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