Moreover, it may lead to over use of these medicines and increase the risk of experiencing adverse reactions, including adrenal suppression. The choice of topical corticosteroid should be determined by the severity of the skin condition and the part of the body to which the product will be applied 3,4.
Topical corticosteroid products are available in a range of potencies Table 1. It is best practice to use the lowest potency corticosteroid needed to control symptoms. A weaker topical corticosteroid should be prescribed if needed, rather than diluting a more potent product in an emollient as this does not actually weaken the effect. Table 1: Potency of topical corticosteroid medicines available on prescription in New Zealand 5.
Serious adverse reactions are rarely seen with appropriate use of topical corticosteroids. The risk of adverse effects is increased by:. New Zealand data sheets for topical corticosteroids include information on the risk of systemic effects, including adrenal suppression www.
Not included in the treatment duration analysis were articles with multiple short courses of corticosteroids spread out over a period of time longer than 1 month. Analysis of the percentage of patients with adrenal insufficiency by treatment dose and by treatment duration was performed in asthma patients only, as opposed to the entire population of corticosteroids users, to provide a homogeneous patient population.
Separate analysis of study groups that performed repeated tests after discontinuation of corticosteroids was performed. Retesting 4 weeks after cessation of corticosteroid therapy was predominantly performed after a short-term, high-dose corticosteroid treatment regimen, whereas retesting 6 months after cessation of corticosteroid therapy predominantly occurred after long-term corticosteroid use in a medium-dose regimen. These two groups were therefore separated in the analysis.
The percentage of patients with adrenal insufficiency at the retest was calculated as the number of patients with adrenal insufficiency at the retest divided by the total number of patients that were measured at time of the first test. All sensitivity analyses were performed in asthma patients only, to minimize patient heterogeneity. No sensitivity analysis for insulin tolerance test use only was performed because there were only three studies using this test, and none of them included asthma patients.
The initial search provided unique articles. By assessment of references of key articles, another 16 articles were found, yielding a total of articles. After screening titles and abstracts, articles remained for detailed review. Reasons for exclusion are shown in Supplemental Figure 1. Finally, 74 articles were included in this meta-analysis, containing a total of study groups. Although in principle articles containing patients below the age of 12 years were excluded, two articles including patients from 9 to 11 years old were included because most the patients in these articles were above the age of One article could not be retrieved even after contacting the first author Study characteristics are shown in Supplemental Table 2.
Included studies were published from to Of the 74 articles, 36 were clinical trials 19 — 54 , 23 were cohort studies 1 , 2 , 8 , 11 , 55 — 73 , and 15 were cross-sectional studies 10 , 74 — The study groups contained a total of participants, of which were healthy volunteers. There were 68 studies on asthma patients, eight studies on rhinitis or rhinosinusitis patients, 12 studies on patients with dermatological conditions psoriasis, atopic dermatitis, and lichen planus , eight studies on patients with rheumatological disorders including rheumatoid arthritis and osteoarthritis , eight studies on renal transplant patients, four studies on patients with hematological malignancies, two studies on patients with nasal polyposis, three studies on patients with cystic fibrosis, two studies on patients with Crohn's disease, and one study each on patients with glaucoma, kidney and pancreas transplantation, bronchiectasis, various carcinomas, and giant cell arteritis, respectively.
There were eight studies on patients with various conditions. The remaining 36 articles did this by the use of a protocol or by retrieving data from medical records. Reported loss to follow-up in these articles was 0 to Details of risk of bias analysis at the level of individual studies are shown in Supplemental Table 3.
Of the participants, were diagnosed with adrenal insufficiency. In seven study groups including patients, use of other corticosteroids was allowed as co-medication. Details of study outcomes and tests used at the level of individual studies are shown in Supplemental Table 4. In only 10 study groups, symptoms of adrenal insufficiency were reported.
In total, 10 of patients reported symptoms of adrenal insufficiency. Symptoms were not scored systematically in either of the articles. After testing, 98 patients appeared to have adrenal insufficiency within these study groups. Consequently, 88 patients would have been missed when only patients with symptoms of adrenal insufficiency had been tested.
Meta-analysis, adrenal insufficiency after corticosteroids use by administration form. The percentage of adrenal insufficiency was The results for other administration forms were: 7. The use of multiple administration forms of corticosteroids resulted in a pooled percentage of adrenal insufficiency of Meta-analysis, adrenal insufficiency after corticosteroids use per condition.
Pooled percentages of adrenal insufficiency per condition are presented in Figure 2 for conditions with at least two studies. Pooled percentages ranged from 6. Asthma patients had an overall percentage adrenal insufficiency of This was lower for patients with asthma using inhaled corticosteroids 6. Meta-analysis, adrenal insufficiency per dose and duration in asthma patients. Analysis per treatment dose and treatment duration was performed in asthmatic patients only for reasons of population homogeneity.
Use of corticosteroids in low, medium, or high doses resulted in a percentage of adrenal insufficiency of 2. Use of corticosteroids for a short, medium, or long term resulted in a percentage of adrenal insufficiency of 1. If performed in asthma patients using inhaled corticosteroids only, the percentages of adrenal insufficiency in low, medium, and high doses were 1. In short-, medium-, and long-term treatment duration groups, percentages of adrenal insufficiency were 1.
Meta-analysis, adrenal insufficiency after corticosteroids use by time of test. Analysis of retests was split into studies that retested after 4 weeks, using mainly short-term, high-dose corticosteroids, and studies that retested after 6 months, using mainly long-term, medium-dose corticosteroids.
Studies retesting after 4 weeks had a percentage of adrenal insufficiency after their first test of After 4 weeks, retesting showed a percentage of adrenal insufficiency of Studies retesting after 6 months had a percentage of adrenal insufficiency after their first test of After 6 months, the percentage of patients with adrenal insufficiency was still For the sensitivity analysis, we combined all studies with asthma patients, which resulted in a percentage of adrenal insufficiency of When only studies were included that explicitly tested for adrenal insufficiency at least 24 hours after the last corticosteroid dose, the percentage of adrenal insufficiency was slightly lower 6.
When performed on studies using RIA only, a percentage of We performed a systematic review and meta-analysis to estimate the percentage of patients that develop adrenal insufficiency after the use of corticosteroids. Depending on administration form, the percentage of patients with adrenal insufficiency varied from 4. According to dose, the percentage of adrenal insufficiency varied from 2. This means that there is no administration form, disease, dose group, or treatment duration for which the risk of adrenal insufficiency can be safely excluded.
Although the percentage of patients with adrenal insufficiency after corticosteroids use declines over time, a substantial number of patients remained adrenal insufficient after 6 months. This is the first meta-analysis providing a broad view on the risk of adrenal insufficiency after use of various types of corticosteroids for several diseases. To the best of our knowledge, only one meta-analysis 88 has been published on appropriately tested adrenal insufficiency in asthma, reporting percentages of adrenal insufficiency ranging from 5.
In the current meta-analysis, we found a percentage of 6. Included studies displayed heterogeneity in the type of corticosteroid used, underlying condition, treatment dose, treatment duration, and route of administration. It is important to consider that this heterogeneity reflects clinical practice. It should also be kept in mind that condition, treatment dose, treatment duration, and route of administration are clearly related. In our stratified analysis, we did not adjust for all mutually dependent factors, mainly because these factors are related in clinical practice as well, but also because meta-regression techniques would fall short in the absence of individual patient level data to disentangle these clearly related factors.
Differences in the percentage of patients with adrenal insufficiency per condition may partly be explained by treatment dose and duration, partly by administration form, and partly by the nature of the disease. Higher treatment dose and longer treatment duration give higher systemic levels of corticosteroids, and therefore higher percentages of adrenal insufficiency This might explain the low risk of adrenal insufficiency in nasal corticosteroids use and the high risk of adrenal insufficiency in rheumatic diseases, after renal transplant, in hematological malignancies, and when multiple administration forms are used.
The use of oral corticosteroids results in higher systemic levels of corticosteroids than in cases of inhalation, topical, and nasal corticosteroids use, and consequently leads to higher percentages of adrenal insufficiency The use of nasal as well as oral and inhalation corticosteroids in rhinitis and rhinosinusitis patients might have contributed to the higher percentage of adrenal insufficiency than in patients using nasal corticosteroids only.
The use of only topical corticosteroids in patients with psoriasis, atopic dermatitis, or lichen planus may explain the low percentage of patients with adrenal insufficiency. The different administration forms in asthma patients may largely explain the low percentage of adrenal insufficiency in patients with asthma using only inhalation corticosteroids and the high percentage of adrenal insufficiency in asthma patients using other administration forms of corticosteroids.
Intra-articular corticosteroids are administered at high doses and are known to suppress serum cortisol levels within 24—48 hours, recovering only after 1—4 weeks This might explain the high percentage of adrenal insufficiency after the use of intra-articular corticosteroids.
The high rate of adrenal insufficiency is probably also a reflection of the fact that these injections are depot formulations. The presence of adrenal insufficiency in such situations may in part be due to the continued presence of corticosteroids in the body, whereas reduction of steroid levels will be gradual rather than abrupt. Most studies did not provide data on treatment adherence, and assessing the impact of non adherence on risk of adrenal insufficiency was therefore not possible.
Because all included studies were observational, the results of our meta-analyses are likely to reflect clinical practice. Included studies also showed heterogeneity in cortisol assay and in the type of cortisol tests performed. Although the diagnostic performance of RIA in the routine evaluation of adrenocortical function is considered superior to other competitive protein-binding analytical methods, like fluorimetry 91 , 92 , the chemiluminescence immunoassay seems to have comparable diagnostic performance and accuracy to RIA It should be kept in mind that test criteria for adrenal insufficiency available in clinical practice have a high sensitivity rather than a high specificity, and therefore the number of false-positive test results is not negligible.
None of the studies retrieved by our literature search used the more modern tandem mass spectrometry Several pathophysiological pathways may be involved in the development of adrenal insufficiency after the use of corticosteroids. It is certainly relevant to disentangle these different pathways and address the question of whether differences in dosage, treatment duration, and type of corticosteroid differentially affect the activity of the hypothalamic-pituitary-adrenal axis.
However, in our review we aimed to evaluate the effect of corticosteroids on adrenal function in clinical practice instead of disentangling the exact mechanisms of adrenal insufficiency. There was no sensitivity analysis performed for low risk of bias articles only, because there was only one article with low risk of bias based on the inclusion of patients and loss to follow-up within the group of studies with asthma patients only.
If only studies with a time gap of at least 24 hours between the last dose of corticosteroids and the test for adrenal insufficiency were included, the percentage of adrenal insufficiency decreased only slightly. In our main analyses, we included articles irrespective of the time between last corticosteroid use and time of test. It is important to keep in mind that the percentage of patients with adrenal insufficiency would have been slightly higher than estimated in this meta-analysis had all articles used a time gap of at least 24 hours between the last dose of corticosteroids and the time of the test.
The risk of developing adrenal insufficiency in these patients is 1. In addition, accurate predictors are not available to distinguish between the patients that will become adrenal insufficient and those that will not. Also there is insufficient evidence to prove any withdrawal scheme after steroid use to be efficient or safe Therefore, we recommend that all patients with unexplained symptoms after steroid withdrawal be tested for possible adrenal insufficiency.
In case of insufficient response, treatment should be initiated with physiological doses of hydrocortisone. In conclusion, this study demonstrates that all patients using corticosteroid therapy are at risk for adrenal insufficiency. This implies that clinicians should: 1 inform patients about the risk and symptoms of adrenal insufficiency; 2 consider testing patients after cessation of high-dose or long-term treatment with corticosteroids; and 3 display a low threshold for testing, especially in those patients with nonspecific symptoms after cessation.
The authors are indebted to Mr J. Schoones for his help in conducting the literature search. The authors did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector. The corresponding author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive license or nonexclusive for government employees on a worldwide basis to the BMJ Publishing Group Ltd to permit this article if accepted to be published in BMJ editions and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our license.
Declaration of Interest: All authors declare: no support from any organization for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.
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