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  1. https://doi.org/10.1016/j.amsu.2021.102978Get rights and content Under a Creative Commons license open access Highlights • Cushing syndrome is an abnormality resulting from high level of blood glucocorticoids. • Iatrogenic Cushing syndrome due to the overuse of topical corticosteroids is rarely reported. • This report presents a case of topical corticosteroid induced iatrogenic Cushing syndrome in an infant. Abstract Introduction Cushing syndrome (CS) is an endocrinological abnormality that results from a high level of glucocorticoids in the blood. Iatrogenic CS due to the overuse of topical corticosteroids is rarely reported. The current study aims to present a rare case of topical corticosteroid induced iatrogenic CS in an infant. Case presentation A 4-month-old female infant presented with an insidious onset of face puffiness that progressed over a 2-month period. The mother reported to have used a cream containing Betamethasone corticosteroid 5–8 times a day for a duration of 3 months to treat diaper dermatitis. Laboratory findings revealed low levels of adrenocorticotrophic hormone (ACTH) and serum. Abdominal ultrasound showed normal adrenal glands. The topical corticosteroid was halted and physiologic topical hydrocortisone doses were administered. Clinical discussion Infants are more likely to acquire topical corticosteroid induced iatrogenic CS due to their thin and absorptive skin, higher body surface area, and the high prevalence of conditions that necessitates the use of these medications. Most iatrogenic CS cases following topical steroid application have been reported in infants with diaper dermatitis that are most commonly treated with Clobetasol and Bethamethasone. Conclusion Infants are susceptible to develop CS due to topical corticosteroid overuse. Hence, physicians need to consider this in infantile CS cases, and take appropriate measures to avoid their occurrence. Previous article in issue Next article in issue Keywords Cushing syndrome Infant Iatrogenic Topical corticosteroid 1. Introduction Cushing syndrome (CS) is a reversible endocrinological abnormality that results from high level of cortisol or other glucocorticoids in the blood [1]. It can be caused by either endogenous factors such as excess steroid production and secretion due to adrenal or pituitary tumors, or exogenously through prolonged use of corticosteroid medications resulting in iatrogenic CS [2]. Iatrogenic CS due to the overuse of oral or parenteral corticosteroids is common, however, while topical corticosteroids are one of the most widely prescribed medications by dermatologists, they are less frequently reported to cause iatrogenic CS [3,4]. Even though CS is very rare in the pediatric population with an annual incidence of only 5 cases per million, children of the pediatric age have a higher risk of developing iatrogenic CS, which is likely due to the high prevalence of conditions that necessitates the use of topical corticosteroids and the thinness of their skin that can more easily absorb the steroid [5,6]. The aim of the current study is to present a rare case of topical corticosteroid induced iatrogenic CS in an infant. SCARE guidelines are considered in writing this report [7]. 2. Case presentation 2.1. Patient information A 4-month-old female infant presented with an insidious onset of puffiness of the face; the swelling progressed over a period of 2 months without any other associated symptoms. The infant's prenatal, developmental, and family history were insignificant, and she was born full term to consanguineous parents via caesarian delivery. After delivery she did not require neonatal intense care unit (NICU) and was discharged in good health. She has been given both bottle and breastfeeding every one to two hrs, and she has received all the required vaccinations at their proper times. The mother reported to have used a topical corticosteroid cream (Optizol-B cream; a combination of Clotrimazole and Betamethasone) for a period of 3 months with a dose of 5–8 times a day to treat diaper dermatitis of the infant. 2.2. Clinical findings The infant's physical examination revealed facial puffiness (Moon face) with no body edema, and cutaneous examination showed the diaper rash without any other cutaneous manifestations. The infant was vitally stable with no dysmorphic features and no skeletal deformities. Her growth parameters were within normal limits, and her systemic examination was unremarkable. 2.3. Diagnostic approach Laboratory findings revealed low adrenocorticotropic hormone (ACTH) level in the blood measuring 5.9 p.m./l, a serum cortisol level of 24 nmol/l, and normal serum sodium and potassium levels of 144 mEq/l and 4.8 mmol/l, respectively. Abdominal ultrasonography (US) showed normal adrenal glands. 2.4. Therapeutic intervention The topical corticosteroid cream that contained Bethamethasone was halted and oral hydrocortisone was given (10 mg/m2) tapered over one month. The patient was given a card addressing Cushing syndrome to inform the health care providers in case of emergency situation or unexpected surgical intervention. 2.5. Follow-up and outcome The infant's facial puffiness was significantly improved after 7-month follow-up of the patient. 3. Discussion CS is an endocrinological disorder resulting from high glucocorticoid level in the blood, it is categorized into ACTH dependent (due to pituitary tumors or excess ACTH administration) or ACTH independent CS (due to adrenal neoplasms or excessive glucocorticoid intake) [8,9]. Under normal circumstances, ACTH is secreted by the pituitary gland which in turn stimulates the secretion of cortisol by the adrenal glands [10]. Prolonged exogenous corticosteroid administration can lead to a number of adverse effects based on potency and duration of the treatment, including the suppression of hypothalamic-pituitary-adrenal (HPA) axis and iatrogenic CS, severe infections, and failure to thrive [11]. While iatrogenic CS is frequent with prolonged administration of oral or parenteral corticosteroids, it is occurrence due to topical corticosteroids have rarely been reported [12]. Multiple factors can increase the probability of acquiring the condition, such as corticosteroid potency, amount and frequency of application, age, skin quality, presence of occlusion, and duration of application [4]. In general, infants are more likely to develop topical corticosteroid induced iatrogenic CS, this is due to their thin and absorptive skin, higher body surface area, underdeveloped skin barrier, and the high prevalence of conditions that necessitates the use of these medications [5,6]. Most iatrogenic CS cases following topical steroid application have been reported in infants with diaper dermatitis [8]. This was also the case in this study. This is likely because the diaper area provides occlusion, the perineal skin has intrinsically absorptive properties, the steroid causes local skin atrophy, and percutaneous absorption is even more increased as the result of skin inflammation [13]. The most frequently used corticosteroid for the treatment of diaper dermatitis is reported to be Clobetasol followed by Bethamethasone, with a mean application duration of 2.75 (1–17) months to induce cortisol and ACTH levels suppression [4]. Typical clinical manifestations of CS include facial puffiness (Moon face), generalized body edema and obesity, hirsutism, buffalo hump, hypertension, skin fragility, and purple striae [3,5]. The causative corticosteroid in the current case was Bethamethasone that only resulted in facial puffiness (Moon face) without generalized body edema. A specific and definitive diagnostic approach for iatrogenic CS is currently lacking [5]. However, prolonged exogenously administered glucocorticoids can suppress ACTH secretion which results in dismissing the need for proper endogenous production of cortisol [14]. Hence, almost all iatrogenic CS cases are associated with low ACTH and cortisol levels which can aid in the diagnosis of the condition [8]. Same findings were observed in this case. According to multiple studies, exogenous corticosteroid administration can often lead to HPA axis suppression alongside CS [15,16]. However, topical corticosteroid induced iatrogenic CS has been reported without HPA axis suppression [8]. The management of these cases start with the cessation of the causative corticosteroid medication and administration of physiologic topical hydrocortisone [5]. The same approach was followed in this study. In order to prevent the development of this condition in the first-place; clinicians should avoid prescribing high potency corticosteroids in the treatment of infantile dermatological disorders and instead choose low potency topical steroids, and also parents should be advised not to overuse these medications and only apply a thin layer to the affected area [6]. In conclusion, even though iatrogenic CS in infants is rare, overuse of topical corticosteroids can lead to their occurrence. Hence, physicians need to consider extensive steroid use as a causative agent of infantile CS. Appropriate measures need to be taken to avoid their occurrence by prescribing less potent steroids, limiting the use of high potent steroids, and informing parents about adverse effects of steroid overuse in infants. Source of funding None is found. Author statement Soran Mohammed Ahmed: physician managing the case, follow up the patient, and final approval of the manuscript. Shaho F. Ahmed, Snur Othman, Berwn A. Abdulla, Shvan M.Hussein, Abdulwahid M.Salih, and Fahmi H. Kakamad: literature review, writing the manuscript, final approval of the manuscript. Patient consent Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Provenance and peer review Not commissioned, externally peer-reviewed. Guarantor Fahmi Hussein Kakamad. Declaration of competing interest None to be declared. References [1] A. Tiwari, M. Goel, P. Pal, P. Gohiya Syndrome in the pediatric age group: a rare case report Indian journal of endocrinology and metabolism, 17 (1) (2013), pp. S257-S258 View Record in ScopusGoogle Scholar [2] R.R. Lonser, L. Nieman, E.H. Oldfield Cushing's disease: pathobiology, diagnosis, and management J. Neurosurg., 126 (2) (2017), pp. 404-417 View PDF View Record in ScopusGoogle Scholar [3] A. Ozdemir, V.N. Bas Iatrogenic Cushing's syndrome due to overuse of topical steroid in the diaper area J. Trop. Pediatr., 60 (5) (2014), pp. 404-406 View PDF CrossRefView Record in ScopusGoogle Scholar [4] T. Tempark, V. Phatarakijnirund, S. Chatproedprai, S. Watcharasindhu, V. Supornsilchai, S. Wananukul Exogenous Cushing's syndrome due to topical corticosteroid application: case report and review literature Endocrine, 38 (3) (2010), pp. 328-334 View PDF CrossRefView Record in ScopusGoogle Scholar [5] L. Alkhuder, H. Mawlawi Infantile iatrogenic cushing syndrome due to topical steroids Case reports in pediatrics, 9 (1) (2019), pp. 1-4 View PDF CrossRefView Record in ScopusGoogle Scholar [6] C.W. Ho, K.Y. Loke, Y.Y. Lim, Y.S. Lee Exogenous Cushing syndrome: a lesson of diaper rash cream Hormone research in paediatrics, 82 (6) (2014), pp. 415-418 View PDF CrossRefView Record in ScopusGoogle Scholar [7] R.A. Agha, T. Franchi, C. Sohrabi, G. Mathew, A. Kerwan, A. Thoma, et al. The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg., 84 (2020), pp. 226-230 ArticleDownload PDFView Record in ScopusGoogle Scholar [8] F. Özgüç Çömlek, S. Örüm, S. Aydın, F. Tütüncüler Exogenous Cushing syndrome due to misuse of potent topical steroid Pediatr. Dermatol., 35 (2) (2018), pp. e121-e123 View PDF CrossRefView Record in ScopusGoogle Scholar [9] A. Rustowska, A. Wilkowska, R. Nowicki Iatrogenic Cushing syndrome due to topical glicocorticosteroid therapy Dermatol. Online J., 4 (4) (2013), pp. 503-505 View PDF CrossRefView Record in ScopusGoogle Scholar [10] C.A. Stratakis Diagnosis and clinical genetics of Cushing syndrome in pediatrics Endocrinol. Metabol. Clin, 45 (2) (2016), pp. 311-328 ArticleDownload PDFView Record in ScopusGoogle Scholar [11] M.K. George, A. James, S. Reddy, B. Yasaswini, T.R. Ak, T. Sivakumar Topical steroid induced iatrogenic cushing syndrome in young adult age group: a case report Indian Journal of Pharmacy Practice, 8 (2) (2015), pp. 87-88 View PDF CrossRefView Record in ScopusGoogle Scholar [12] Z. Şiklar, İ. Bostanci, Ö. Atli, Y. Dallar An infantile Cushing syndrome due to misuse of topical steroid Pediatr. Dermatol., 21 (5) (2004), pp. 561-563 View PDF CrossRefView Record in ScopusGoogle Scholar [13] O. Taylor, J.D. Mejia‐Otero, G.M. Tannin, K. Gordon Topical triamcinolone induced Cushing syndrome: a case report Pediatr. Dermatol., 37 (3) (2020), pp. 582-584 View PDF CrossRefView Record in ScopusGoogle Scholar [14] A.W. Root, D.I. Shulman Clinical adrenal disorders Pediatric Endocrinology, Mechanisms, Manifestations, and Management, Lippincott Williams & Wilkins, Philadelphia (2004), pp. 568-600 Google Scholar [15] A. Güven, Ö. Gülümser, T. Özgen Cushing's syndrome and adrenocortical insufficiency caused by topical steroids: misuse or abuse? J. Pediatr. Endocrinol. Metab., 20 (11) (2007), pp. 1173-1182 View Record in ScopusGoogle Scholar [16] F. Tütüncüler, M. Tekin, D. Balci, Ö. Şahaloğlu Iatrogenic Cushing syndrome due to topical steroid administration in an infant Balkan Med. J., 27 (1) (2010), pp. 95-97 View PDF View Record in ScopusGoogle Scholar © 2021 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. From https://www.sciencedirect.com/science/article/pii/S2049080121009286?via%3Dihub
  2. Purpose: This study aimed to identify predictive factors and to develop a predictive model for adrenal insufficiency (AI) related to topical corticosteroids use. Methods: The research was conducted using a cross-sectional design. Adult patients with dermatological conditions who had been prescribed topical steroids for at least 12 months by the dermatology outpatient departments of the Faculty of Medicine, Chiang Mai University from June through October 2020 were included. Data on potential predictors, including baseline characteristics and laboratory investigations, were collected. The diagnoses of AI were based on serum 8AM cortisol and low-dose ACTH stimulation tests. Multivariable logistic regression was used for the derivation of the diagnostic score. Results: Of the 42 patients, 17 (40.5%) had AI. The statistically significant predictive factors for AI were greater body surface area of corticosteroids use, age < 60 years, and basal serum cortisol < 7 μg/dL. In the final predictive model, duration of treatment was added as a factor based on its clinical significance for AI. The four predictive factors with their assigned scores were: body surface area involvement 10– 30% (20), > 30% (25); age < 60 years old (15); basal serum cortisol of < 7 μg/dL (30); and duration of treatment in years. Risk of AI was categorized into three groups, low, intermediate and high risk, with total scores of < 25, 25– 49 and ≥ 50, respectively. The predictive performance for the model was 0.92 based on area under the curve. Conclusion: The predictive model for AI in patients using topical corticosteroids provides guidance on the risk of AI to determine which patients should have dynamic ACTH stimulation tests (high risk) and which need only close follow-up (intermediate and low risk). Future validation of the model is warranted. Keywords: adrenal insufficiency, topical corticosteroids, predictive model, skin diseases Introduction Topical corticosteroids are frequently used for inflammatory skin diseases owing to their anti-inflammatory and immunosuppressive effects. Common indications for use include diseases such as psoriasis, eczema, atopic dermatitis, and vitiligo.1 In clinical practice, a variety of delivery vehicles and potencies of topical corticosteroids are used.1 Prolonged and/or inappropriate use of topical corticosteroids can lead to adverse side effects.2 These adverse side effects can be categorized as cutaneous and systemic side effects. The most common cutaneous side effect is skin atrophy. Systemic side effects include hypothalamic-pituitary-adrenal (HPA) axis suppression, glaucoma, hyperglycemia and hypertension.3 One of the most worrisome adverse side effects from the use of topical corticosteroids is adrenal insufficiency (AI) resulting from HPA axis suppression. Topically applied corticosteroids can be absorbed systemically through the skin and can suppress the HPA axis.4–8 This adverse outcome, the inability to increase cortisol production after stress, can lead to adrenal crisis, which is potentially life-threatening. Tests that are normally used to diagnose or exclude AI include serum morning cortisol and the dynamic ACTH stimulation test.9 Secondary AI from percutaneous absorption of topical corticosteroids is less common than with parenteral or oral administration. The cumulative doses and the durations of oral corticosteroid therapy associated with HPA axis suppression have been well documented.10 Data regarding the dose and duration of oral corticosteroids and HPA axis suppression have similarly been well established. A study by Curtis et al reported that the use of oral prednisolone >7.5 mg/day for an extended period (>3 weeks) was linked to this adverse event, and that the incidence increased with duration.10 However, corresponding data for topical corticosteroids has been limited. The degree of risk of HPA axis suppression from topical corticosteroids use is associated with the level of percutaneous absorption which, in turn, depends on numerous factors including the age of the patient (younger patients are more susceptible), body surface area treated, quantity of topical corticosteroids used, potency of the drug, duration of therapy, body region of application, the associated compounds used, eg, urea or salicylic acid, the characteristics of the diseased skin, the degree of impairment of skin integrity, and the coexistence of hepatic and/or renal disease.11–13 One study reported that HPA axis suppression occurs when high potency steroids are administered at a cumulative dose per week of >50 g.2 Presently, there is a lack of data on predictive factors for AI and no predicative model of the relationship between secondary AI resulting from HPA axis suppression and topical corticosteroids use. A simple predictive model which could help preclude and predict the risk of AI which incorporates both demographic and biochemical data could potentially reduce the number of dynamic ACTH stimulation tests performed. This study aimed to identify potential predictive factors and to design an easy-to-use model for predicting the risk of AI following topical corticosteroids use in dermatological patients. Materials and Methods This cross-sectional study was conducted with 42 patients who were seen at the dermatology outpatient departments at the Faculty of Medicine, Chiang Mai University Hospital over a 5-month period (June – October 2020). The study protocol was approved by the Faculty of Medicine, Chiang Mai University, Ethical Committee (Ethical number: MED-2563-07037). Recruited participants were adult dermatological patients (≥18 years) who had used topical corticosteroids for at least 12 months. Patients with pituitary or adrenal diseases, pregnant women and patients who had been treated with either systemic corticosteroids or other local corticosteroids were excluded. Those who meet all the inclusion criteria gave their informed consent prior to the study. This study was conducted in accordance with the Declaration of Helsinki. Adrenal Function Evaluation Adrenal function was evaluated by serum morning (8 AM) cortisol and the low-dose ACTH stimulation test. Patients were instructed to suspend use of topical corticosteroids for at least 24 hours before serum morning cortisol measurement and ACTH stimulation tests. In those with serum morning cortisol between 3 and 17.9 µg/dL, ACTH stimulation tests were performed on the same day between 9–11AM to either exclude or diagnose AI. Serum cortisol concentrations were measured at 8 AM 0 (basal cortisol) as well as 20 and 40 minutes after 5 µg ACTH was administered intravenously. Data Collection Epidemiological data collected included gender, age, blood pressure, underlying dermatologic diseases, other underlying diseases, body surface area involvement, sensitive area involvement, topical corticosteroid potency, amount and duration of topical corticosteroids use, symptoms of AI and the presence of Cushingoid features. Biochemical data included serum cortisol at 8 AM, 0 (basal cortisol) and at 20 and 40 minutes after ACTH intravenous injection, serum creatinine, electrolytes and albumin. Serum cortisol levels were measured by electrochemiluminescence assay (ECLIA) (Elecsys® Cortisol II assay, Roche Diagnostics GmbH, Mannheim, Germany). Definitions An 8AM cortisol level of ❤️ µg/dL or a peak serum cortisol level of <18 µg/dL at 20 or 40 minutes after an ACTH stimulation test was defined as having AI.14 Sensitive area involvement included the axilla, groin, face and genitalia. Topical corticosteroids are classified by potency based on a skin vasoconstriction assay, and range from ultra-high potency (class I) to low potency (class VII).15 Since some patients had concurrently used more than one class of corticosteroids in one treatment period, the new variable potency·dose·time (summary of corticosteroids potency (I–VII)16 multiplied by total doses (mg) of corticosteroids use and multiplied by duration (months) of corticosteroids use) was created. Symptoms of AI included lethargy, nausea and vomiting, orthostatic hypotension and significant weight loss. Significant weight loss was defined as a loss of 5% of body weight in one month or a loss of 10% over a period of six months.17 Having Cushingoid features was defined as at least one of the excess glucocorticoid features, eg, easy bruising, facial plethora, proximal myopathy, striae, dorsocervical fat pad, facial fullness, obesity, supraclavicular fullness, hirsutism, decreased libido and menstrual abnormalities. Statistical Analysis All statistical analyses were performed using Stata 16 (StataCorp, College Station, Texas, USA). Categorical variables are reported as frequency and percentage, while continuous variables are reported as mean ± standard deviation or median and interquartile range (IQR), according to their distribution. For univariable comparison, Fisher’s exact probability test was used for categorical variables, and the independent t-test or the Mann–Whitney U-test was used for continuous variables. p-values less than 0.05 were considered statistically significant. Multivariable logistic regression was used in the derivation of the prediction model for AI. Predictors with significant p-values in the univariable analysis were included in the multivariable model. We also included age and treatment duration in the model due to the clinical significance of those factors.4,18 The clinical collinearity among the predictors was also evaluated before the selection of the predictors. We generated a weighted score for each predictor by dividing the logit coefficient of the predictor by the lowest coefficient in the model. The discriminative ability of the final multivariable model was assessed using the area under the receiver operating characteristics (ROC) curve. The calibration of the scores was evaluated using the Hosmer-Lemeshow goodness-of-fit test, where a p-value >0.01 was considered a good fit. For clinical applicability, the appropriate cut-off points for the scores were identified based on sensitivity and specificity. We identified one cut-off point with high sensitivity for ruling out AI and another cut-off point with high specificity for ruling in AI. The positive predictive value for each score category with its corresponding confidence interval were presented. A sample size of at least 25 patients with at least 5 patients with AI was estimated to give 80% power at the 5% significance level.4 There was no missing data in this study. Results Baseline characteristics and biochemical investigations are shown in Table 1. Forty-two patients with dermatological diseases were included in this study. Of these, 17 patients (40.5%) had AI of whom 5 (29.4%) were female. The mean age of the group was 56.5 ±15.4 years, the mean duration of treatment was 10.1 ± 6 years, and the majority of patients had psoriasis (n = 14, 82.4%). There was no significant difference in sex, age, duration of treatment, potency dose-time, comorbidities, or underlying skin disease between the AI and non-AI groups. The average body surface area of corticosteroids use was significantly higher in patients with AI than in the non-AI group (27.5 ±18.7 m2 and 10.7 ±11.7 m2, p < 0.001, respectively). Basal serum cortisol levels were significantly lower in the AI group (6.52 ± 4.04 µg/dL) than in the non-AI group (10.48 ± 3.45 µg/dL, p 0.003). Although lower serum morning cortisol levels were observed in the AI group, the difference was not statistically significant (5.24 ± 4.65 µg/dL vs 13.39 ± 15.68 µg/dL, p = 0.069). Three patients were identified as having Cushingoid features. All patients with Cushingoid features had AI. Table 1 Comparison of Clinical Characteristics Between Patients with a History of Topical Corticosteroids Use for at Least 12 Months Who Were Diagnosed with Adrenal Insufficiency and Those without Adrenal Insufficiency (n = 42) Based on the multivariate logistic regression analysis (shown in Table 2), the significant predictive factors for AI in patients who used topical corticosteroids for more than 12 months were body surface area of corticosteroids use of 10–30% and >30% (POR 18.9, p =0.042, and POR 59.2, p = 0.035, respectively), age less than 60 years (POR 13.8, p = 0.04), and basal serum cortisol of <7 µg/dL (POR 131.5, p = 0.003). Only serum basal cortisol was included in the final multivariable model as there was clinical collinearity among serum morning cortisol and basal cortisol as well as 20- and 40-minute cortisol measurements. Table 2 Multivariable Model for Prediction of Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38) Predictive risk score was created to determine the probability of patients having AI using the aforementioned three significant predictive factors from the multivariable analysis (Table 2). As previous studies have demonstrated that duration of treatment is a strong predictive factor for AI in corticosteroid users,4,18 this factor was also incorporated in the model. The transformed score for body surface area, age and basal serum cortisol had a range of 0 to 30. For treatment duration, the transformed score was based on cumulative years of treatment. The total score was categorized into three groups: low, intermediate, and high risk (Table 3). Table 3 Accuracy of the Score to Rule in and Rule Out Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38) The cut-off point of ≥50 suggests high risk for developing AI with a sensitivity of 46.2% and a specificity of 100%, a score of <25 suggests a low risk with a sensitivity of 100% and a specificity of 52%, and a score between 25 and 49 indicates an intermediate risk of having AI. The ROC curve for the model assessing predictive performance which included all significant factors had an AuROC of 0.92 (Figure 1). The Hosmer-Lemeshow goodness-of-fit test revealed non-statistically significant results (p = 0.599), indicating that our newly derived scoring system fits the data well. Figure 1 Model discrimination via receiver operating characteristic curve in patients with a history of topical corticosteroids use for at least 12 months (n = 42). Discussion The present study proposes an easy-to-use predictive model for AI following topical corticosteroids use in dermatological patients based on demographic and biochemical factors. The accuracy of the model shows an excellent diagnostic accuracy of 92% based on AuROC. Currently, the diagnosis of AI in dermatological patients with topical corticosteroids use involves multiple steps including screening for serum morning cortisol followed by dynamic ACTH stimulation testing. The proposed simple predictive model, which requires only three demographic data items (age, body surface area of corticosteroids use, duration of use) and one biochemical test (serum basal cortisol), could potentially reduce the number of dynamic ACTH stimulation tests performed, resulting in cost- and time-saving for both patients and health-care facilities. Based on the proposed cut-off points, we suggest screening of individuals at high risk for having AI, including serum morning cortisol and the ACTH stimulation tests to confirm a diagnosis of AI. If there is evidence of AI, the patient should begin to receive treatment for AI to reduce future complications. For those in the low-risk group, only clinical follow-up should be carried out. In the intermediate-risk group, we recommend regular and close biochemical follow-up including serum morning cortisol and clinical follow-up for signs and symptoms of AI. Signs and symptoms that should raise a high index of suspicion for AI include significant weight loss, nausea and/or vomiting, orthostatic hypotension and lethargy. However, this proposed predictive model was studied in adults and cannot simply be generalized and extrapolated to children or infants. In our study, 40.5% of the patients were determined to have AI. A previous meta-analysis by Broersen et al reported the percentage of patients with AI secondary to all potencies of topical corticosteroids based on a review of 15 studies was 4.7%, 95% CI (1.1–18.5%).19 The higher prevalence of AI in our study could be a result of differences in patients’ baseline characteristics, eg, duration of treatment, corticosteroids potency and body surface area involvement. In the predictive model, we incorporated both clinical and biochemical factors which are easy to obtain in actual clinical practice. Some of those predictive factors have been previously reported to be linked to AI. Body surface area of corticosteroids use larger than 10% found to be significantly related to AI, especially in patients with a lesion area of over 30%. This finding is consistent with a study by Kerner et al which suggests the extent of surface area to which the corticosteroids are applied may influence absorption of the drug.20 Regarding the age of the patients, our study found that individuals over 60 years old tended to be at high risk of AI following topical corticosteroids therapy. The underlying explanation is that the stratum corneum acts as a rate-limiting barrier to percutaneous absorption as the stratum corneum in younger individuals is thinner than in older people. Diminished effectiveness of topical corticosteroid treatment in older people was demonstrated in a study by Malzfeldt et al.21 Even though serum basal cortisol is not recommended as a standard test to diagnose AI, a prior study reported that it can be considered as an alternative choice to diagnose AI when serum morning cortisol results are not available. In fact, it has been reported that there is no difference in diagnostic accuracy between serum morning cortisol and basal cortisol22 which supports our finding that serum basal cortisol <7 µg/dL is one of the significant factors related to AI. The final model found no statistically significant relationship between the incidence of AI and the duration of corticosteroids treatment. However, we decided to include this factor in the final model since previous publications have reported that the duration of treatment is a relevant risk factor for developing AI following continuous topical corticosteroids use. The duration of AI events has been reported to vary between 2 weeks to 18 months.4,18 Additionally, a case report of AI demonstrated that 5 years of topical corticosteroids use can cause AI.6 Together, this suggests that patients with a longer duration of topical corticosteroids use are at increased risk of AI, especially those who also have other risk factors. Although both potency and dosage of topical corticosteroids have been reported to be significantly linked to HPA axis suppression, the present study found only a non-significance link. This could be the result of the small sample size as well as of other factors, eg, body surface area involvement and serum cortisol levels, which could have masked the association between potency and dosage of topical corticosteroids with HPA suppression. To the best of our knowledge, this study is the first to use these novel predictive factors to develop a predictive model for AI in patients using topical corticosteroids. This model has multiple potential implications. First, the model uses clinical and biochemical factors which are obtainable in many institutes. Second, the model’s risk score provides good diagnostic accuracy in terms of both sensitivity and specificity. Finally, each of the predictive factors in the model has an underlying pathophysiological explanation and is not due simply to chance. There are some limitations in this study. First, the sample size is relatively small, although it does offer sufficient statistical power for each of the predictive factors. Second, further external validation is needed to validate the predictive performance of the model. Third, the cut-off level of serum cortisol after ACTH stimulation test was based on the older generation of ECLIA assay. There was a study proposed that the cut-off for serum cortisol in the newer generation of cortisol assay should be lower (~14–15 µg/dL) than the previous one (18 µg/dL).23 However, this proposed cut-off has not yet been established in the current guideline for AI. In the future, if the newer cut-off for serum cortisol will have been employed in the standard guideline, our predictive model may lead to overdiagnosis of AI. Conclusions The proposed predictive model uses both demographic and biochemical factors to determine the risk of AI in dermatological patients following topical corticosteroids use with a high level of diagnostic accuracy. This model has advantages in terms of a reduction in the number of dynamic ACTH stimulation tests needed, thus saving time and resources. Additionally, it can provide guidance to clinical practitioners regarding which patients should be closely followed up for development of AI. Future external validation of this predictive model is warranted. Acknowledgments The authors are grateful to Lamar G. Robert, PhD and Chongchit S. Robert, PhD for editing the manuscript. Disclosure The authors report no conflict of interest in this work. References 1. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79(2):135–140. 2. Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006;54(1):1–15;quiz 16–8. doi:10.1016/j.jaad.2005.01.010 3. Rathi SK, D’Souza P. Rational and ethical use of topical corticosteroids based on safety and efficacy. Indian J Dermatol. 2012;57(4):251–259. doi:10.4103/0019-5154.97655 4. Carruthers JA, August PJ, Staughton RC. Observations on the systemic effect of topical clobetasol propionate (Dermovate). Br Med J. 1975;4(5990):203–204. doi:10.1136/bmj.4.5990.203 5. Staughton RC, August PJ. Cushing’s syndrome and pituitary-adrenal suppression due to clobetasol propionate. Br Med J. 1975;2(5968):419–421. doi:10.1136/bmj.2.5968.419 6. Young CA, Williams IR, MacFarlane IA. Unrecognised Cushing’s syndrome and adrenal suppression due to topical clobetasol propionate. Br J Clin Pract. 1991;45(1):61–62. 7. Abma EM, Blanken R, De Heide LJ. Cushing’s syndrome caused by topical steroid therapy for psoriasis. Neth J Med. 2002;60(3):148–150. 8. Böckle BC, Jara D, Nindl W, Aberer W, Sepp NT. Adrenal insufficiency as a result of long-term misuse of topical corticosteroids. Dermatology. 2014;228(4):289–293. doi:10.1159/000358427 9. Ospina NS, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700 10. Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum. 2006;55(3):420–426. doi:10.1002/art.21984 11. Brazzini B, Pimpinelli N. New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. Am J Clin Dermatol. 2002;3(1):47–58. doi:10.2165/00128071-200203010-00005 12. Dhar S, Seth J, Parikh D. Systemic side-effects of topical corticosteroids. Indian J Dermatol. 2014;59(5):460–464. doi:10.4103/0019-5154.139874 13. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency: clinical implications. Am J Clin Dermatol. 2002;3(3):141–147. doi:10.2165/00128071-200203030-00001 14. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389. doi:10.1210/jc.2015-1710 15. Goa KL. Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review. Drugs. 1988;36(Suppl 5):51–61. doi:10.2165/00003495-198800365-00011 16. Davallow Ghajar L, Wood Heickman LK, Conaway M, Rogol AD. Low risk of adrenal insufficiency after use of low- to moderate-potency topical corticosteroids for children with atopic dermatitis. Clin Pediatr. 2019;58(4):406–412. doi:10.1177/0009922818825154 17. Gaddey HL, Holder K. Unintentional weight loss in older adults. Am Fam Physician. 2014;89(9):718–722. 18. Melian EB, Spencer CM, Jarvis B. Clobetasol propionate foam, 0.05%. Am J Clin Dermatol. 2001;2(2):89–92;discussion 93. doi:10.2165/00128071-200102020-00005 19. Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(6):2171–2180. doi:10.1210/jc.2015-1218 20. Kerner M, Ishay A, Ziv M, Rozenman D, Luboshitzky R. Evaluation of the pituitary-adrenal axis function in patients on topical steroid therapy. J Am Acad Dermatol. 2011;65(1):215–216. doi:10.1016/j.jaad.2010.12.033 21. Malzfeldt E, Lehmann P, Goerz G, Lippold BC. Influence of drug solubility in the vehicle on clinical efficacy of ointments. Arch Dermatol Res. 1989;281(3):193–197. doi:10.1007/bf00456392 22. Manosroi W, Phimphilai M, Khorana J, Atthakomol P. Diagnostic performance of basal cortisol level at 0900-1300h in adrenal insufficiency. PLoS One. 2019;14(11):e0225255. doi:10.1371/journal.pone.0225255 23. Vogeser M, Kratzsch J, Ju Bae Y, et al. Multicenter performance evaluation of a second generation cortisol assay. Clin Chem Lab Med. 2017;55(6):826–835. doi:10.1515/cclm-2016-0400 This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. Download Article [PDF] From https://www.dovepress.com/novel-predictive-model-for-adrenal-insufficiency-in-dermatological-pat-peer-reviewed-fulltext-article-IJGM
  3. By Ed Miseta, Chief Editor, Clinical Leader Follow Me On Twitter @EdClinical Sparrow Pharmaceuticals is an emerging biopharma company on a mission to help patients suffering from an excess of corticosteroids, with a focus on Cushing’s syndrome, autonomous cortisol secretion (ACS), and polymyalgia rheumatica (PMR). Cushing’s and ACS are both caused by an excess of cortisol produced by tumors. Patients with Cushing’s can present physically with a fatty hump between their shoulders, a rounded face, and pink or purple stretch marks on their skin. Cushing’s syndrome and ACS can both result in high blood pressure, bone loss, type 2 diabetes, weight gain, and mood, cognition, and sleep disorders. Any of those symptoms may be side effects for patients with conditions such as PMR who rely on long-term treatment with corticosteroid medications such as prednisone. “Cushing’s syndrome impacts around 20,000 patients in the U.S. alone,” says David Katz, Chief Scientific Officer for Sparrow. “Approximately 50% of those patients can be cured by surgery, but some will develop another tumor years later. ACS is an under-recognized condition, but it may affect up to 3 million patients in the U.S. There are also around 2 million people in the U.S. who rely on long-term use of corticosteroid medications to control autoimmune diseases and other conditions.” The treatments being developed by Sparrow are based on recognition that cortisol and corticosteroid medications are activated in certain tissues such as the liver, bone, fat, and brain, where in excess they act to cause toxicity. The company’s investigational drugs inhibit HSD-1, the enzyme responsible for that activation. Sparrow is about to launch a Phase 2 trial for Cushing’s syndrome. In early 2022 the company will also begin two additional Phase 2 trials for ACS and PMR, a common autoimmune disease in elderly patients. PMR is an arthritic syndrome characterized by a phenomenon known as claudication, which means the more you use a limb, the more it hurts and the harder it is to use. “For example, the more a PMR patient walks, the more painful and stiff their legs will become,” says Katz. “If they're trying to do anything with their arms, the arms will get stiffer and more painful. The disease is pretty debilitating in terms of physical function. The only approved treatment for PMR is steroids, which have side effects such as diabetes, hypertension, osteoporosis, and fractures.” Unknown Clinical Challenges Katz is excited about the clinical trials for ACS and PMR because no sizable interventional trials have been reported in either of those conditions. “We're going into a completely new area, and we don't know what we're going to encounter in terms of patient recruitment and retention,” says Katz. “There is also no strong precedent for how to get approval for a drug in these conditions. The only treatment indicated for PMR is steroids, and that came without any efficacy clinical trials. There are no drugs approved for ACS. It’s hard to anticipate the challenges we will face when we are in an area that is very new.” Patient centricity is a topic that is very important to Katz, and he spends a lot of time thinking about how to make trials a more pleasant experience for patients by limiting the burden placed on them. He notes that can sometimes be a difficult trade-off because of the procedures that must be performed to meet regulatory standards. “In Cushing’s syndrome clinical care and clinical trials, the standard way for someone's cortisol level to be measured is a 24-hour urine collection,” states Katz. “That involves looking at the amount of cortisol in the urine over a 24-hour period. That collection is inconvenient and burdensome, and the patient must then carry it somewhere to be analyzed.” Sparrow hopes to shift that collection to a spot urine sample, like what patients would experience during a physical. The patient would urinate into a cup and hand it off to a clinic employee for analysis. The process would be much simpler and less burdensome for the patient. Sparrow will first need to prove that in a clinical trial the spot sample will work as well or better than the 24-hour collection. Subjects in the initial clinical trials will have to contribute the 24-hour collections so that Sparrow can demonstrate that future patients will not need to do so. The Future of Endocrinology Katz has a positive outlook on the future of endocrinology. Sparrow’s leading drug candidate, SPI-62, is an oral, small-molecule HSD-1 inhibitor. In four clinical trials, it demonstrated potent targeting of HSD-1 in both the brain and liver, and significantly lowered cortisol levels in the liver. The studies also showed a favorable safety and tolerability profile. “If we are successful at developing SPI-62, I believe it will change the field of endocrinology,” says Katz. “We aim to shift the focus in Cushing’s syndrome to intracellular cortisol as the main driver of symptoms. What I mean by that is if we find that SPI-62 substantially reduces symptoms and that the degree of inhibition of our target HSD-1 correlates well with clinical improvement, then we can get to a new standard of care. We can potentially get rid of the 24-hour urine collections, which will be a big relief to patients. Additionally, many of today's drugs have a side effect called adrenal insufficiency, which results when the drugs either reduce cortisol too much or completely block activity. Many of today's drugs also require frequent monitoring and dose titration to prevent adrenal insufficiency. We believe that with HSD-1 inhibition we might avoid adrenal insufficiency as well.” Katz is hopeful patients treated with SPI-62 will not require monitoring and dose titration. That proof will take years and lots of clinical trials. Sparrow may also produce the first targeted therapy for ACS. That could improve the recognition of ACS as a prevalent form of hypercortisolism and a substantial cause of morbidity and mortality. “ACS is probably the most under-recognized condition in endocrinology based on recent epidemiological studies,” adds Katz. “It's possible that as few as 3% of patients who have ACS actually have a diagnosis. That is shocking for a condition that is associated with a lot of cardiometabolic and bone morbidity, negative effects on mood and cognition, sleep, and muscle strength, and is associated with excess mortality. We want to bring attention to this condition by bringing out a targeted therapy to treat a spectrum of symptoms by getting to the root cause of them.” From https://www.clinicalleader.com/doc/sparrow-pharmaceuticals-hopes-to-change-the-future-of-endocrinology-0001
  4. Cushing’s syndrome is a rare disorder that occurs when the body is exposed to too much cortisol. Cortisol is produced by the body and is also used in corticosteroid drugs. Cushing's syndrome can occur either because cortisol is being overproduced by the body or from the use of drugs that contain cortisol (like prednisone). Cortisol is the body’s main stress hormone. Cortisol is secreted by the adrenal glands in response to the secretion of adrenocorticotropic hormone (ACTH) by the pituitary. One form of Cushing’s syndrome may be caused by an oversecretion of ACTH by the pituitary leading to an excess of cortisol. Cortisol has several functions, including the regulation of inflammation and controlling how the body uses carbohydrates, fats, and proteins. Corticosteroids such as prednisone, which are often used to treat inflammatory conditions, mimic the effects of cortisol. Stay tuned for more basic info...
  5. Study Authors: Tsung-Chieh Yao, Ya-Wen Huang, et al.; Beth I. Wallace, Akbar K. Waljee Target Audience and Goal Statement: Primary care physicians, rheumatologists, pulmonologists, dermatologists, gastroenterologists, cardiologists The goal of this study was to examine the associations between oral corticosteroid bursts and severe adverse events among adults in Taiwan. Question Addressed: What were the associations between steroid bursts and severe adverse events, specifically gastrointestinal (GI) bleeding, sepsis, and heart failure? Study Synopsis and Perspective: It has long been known that long-term use of corticosteroids can be both effective and toxic. Long-term use is associated with adverse effects such as infections, GI bleeding/ulcers, cardiovascular disease (CVD), Cushing syndrome, diabetes and metabolic syndromes, cataracts, glaucoma, and osteoporosis. Most clinical practice guidelines caution against long-term steroid use unless medically necessary. Action Points In a retrospective cohort study and self-controlled case series, prescriptions for oral steroid bursts were found to be associated with increased risks for gastrointestinal bleeding, sepsis, and heart failure within the first month after initiation, despite a median exposure of just 3 days. Note that the risks were highest 5 to 30 days after exposure, and attenuated during the subsequent 31 to 90 days. Instead, clinical practice guidelines recommend steroid bursts for inflammatory ailments such as asthma, inflammatory bowel disease, and rheumatoid arthritis. Waljee and colleagues noted in 2017 that they are most commonly used for upper respiratory infections, suggesting that many people are receiving steroids in the real world. In a retrospective cohort study and self-controlled case series, prescriptions for oral steroid bursts -- defined as short courses of oral corticosteroids for 14 or fewer days -- were found to be associated with increased risks for GI bleeding, sepsis, and heart failure within the first month after initiation, despite a median exposure of just 3 days, according to Tsung-Chieh Yao, MD, PhD, of Chang Gung Memorial Hospital in Taoyuan, and colleagues. The risks were highest 5 to 30 days after exposure, and attenuated during the subsequent 31 to 90 days, they reported in Annals of Internal Medicine. The self-controlled case series was based on national medical claims records. Included were adults, ages 20-64, covered by Taiwan's National Health Insurance in 2013-2015. Out of a population of more than 15.8 million, study authors identified 2,623,327 people who received a steroid burst during the study period. These individuals were age 38 on average, and 55.3% were women. About 85% had no baseline comorbid conditions. The most common indications for the steroid burst were skin disorders and respiratory tract infections. The incidence rates among patients prescribed steroid bursts were 27.1 per 1,000 person-years for GI bleeding (incidence rate ratio [IRR] 1.80, 95% CI 1.75-1.84), 1.5 per 1,000 person-years for sepsis (IRR 1.99, 95% CI 1.70-2.32), and 1.3 per 1,000 person-years for heart failure (IRR 2.37, 95% CI 2.13-2.63). Absolute risk elevations were similar in patients with and without comorbid conditions, meaning that the potential for harm was not limited to those at high risk for these adverse events. The study authors acknowledged that they could not adjust for disease severity and major lifestyle factors such as alcohol use, smoking, and body mass index; because these factors were static, the effect could be eliminated using the self-controlled case series design. Their reliance on prescription data also meant they could not tell if patients actually complied with oral corticosteroid therapy. Furthermore, the exclusion of the elderly and younger populations also left room for underestimation of the risks of steroid bursts, they said. Source References: Annals of Internal Medicine 2020; DOI: 10.7326/M20-0432 Editorial: Annals of Internal Medicine 2020; DOI: 10.7326/M20-4234 Study Highlights and Explanation of Findings: Over the 3-year study period, steroid bursts were commonly prescribed to adults. Such prescriptions were written for common conditions, including skin disorders and upper respiratory tract infections. The highest risks for GI bleeding, sepsis, and heart failure occurred within the first month after receipt of the steroid burst, and this risk was attenuated during the subsequent 31 to 90 days. "Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear," the researchers wrote. Notably, one corticosteroid that fits the bill is dexamethasone -- a medication that holds promise for the treatment of critically ill COVID-19 patients, although it is not generally prescribed orally for these patients. Based on preliminary results, the NIH's COVID-19 treatment guidelines panel recommended the use of "dexamethasone (at a dose of 6 mg per day for up to 10 days) in patients with COVID-19 who are mechanically ventilated and in patients with COVID-19 who require supplemental oxygen but who are not mechanically ventilated." In addition, they recommend "against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen." "We are now learning that bursts as short as 3 days may increase risk for serious AEs [adverse events], even in young and healthy people. As providers, we must reflect on how and why we prescribe corticosteroids to develop strategies that prevent avoidable harms," wrote Beth Wallace, MD, and Akbar Waljee, MD, both of the VA Ann Arbor Healthcare System and Michigan Medicine. On the basis of the reported risk differences in the study, Wallace and Waljee calculated that one million patients exposed to corticosteroid bursts experienced 41,200 GI bleeding events, 400 cases of sepsis, and 4,000 cases of new heart failure per year that were directly attributed to this brief treatment. "Although many providers already avoid corticosteroids in elderly patients and those with comorbid conditions, prescribing short bursts to 'low-risk' patients has generally been viewed as innocuous, even in cases where the benefit is unclear. However, Yao and colleagues provide evidence that this practice may risk serious harm, making it difficult to justify in cases where corticosteroid use lacks evidence of meaningful benefit," they wrote in an accompanying editorial. "Medication-related risks for AEs can, of course, be outweighed by major treatment benefit. However, this study and prior work show that corticosteroid bursts are frequently prescribed for self-limited conditions, where evidence of benefit is lacking," Wallace and Waljee noted. "As we reflect on how to respond to these findings, it is useful to note the many parallels between use of corticosteroid bursts and that of other short-term medications, such as antibiotics and opiates. All of these treatments have well-defined indications but can cause net harm when used -- as they frequently are -- when evidence of benefit is low," they emphasized. Last Updated August 07, 2020 Reviewed by Dori F. Zaleznik, MD Associate Clinical Professor of Medicine (Retired), Harvard Medical School, Boston Primary Source Annals of Internal Medicine Source Reference: Yao TC, et al "Association between oral corticosteroid bursts and severe adverse events: a nationwide population-based cohort study" Ann Intern Med 2020; DOI: 10.7326/M20-0432. Secondary Source Annals of Internal Medicine Source Reference: Wallace BI, Waljee AK "Burst case scenario: why shorter may not be any better when it comes to corticosteroids" Ann Intern Med 2020; DOI: 10.7326/M20-4234. Additional Source MedPage Today Source Reference: Lou N "Sobering Data on Risks of Short-Term Oral Corticosteroids" 2020. From https://www.medpagetoday.org/primarycare/generalprimarycare/87959?xid=nl_mpt_DHE_2020-08-08&eun=g1406328d0r&utm_term=NL_Daily_DHE_dual-gmail-definition&vpass=1
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