While at ENDO 2024 in Boston, the Endocrine Society and European Society of Endocrinology together released the first in a series of guidelines co-authored by the societies. The “European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency” will better prepare endocrinologists to take the lead on a therapy used in virtually every medical discipline.
A wide variety of medical specialties prescribe long-term glucocorticoid therapy for its anti-inflammatory or immunosuppressive benefits, but it inevitably results in suppression of the hypothalamic-pituitary-adrenal (HPA) axis that can lead to adverse effects.
Endocrinologists have now weighed in with guidance on glucocorticoid use with the publication of the “European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency.”
“It was high time for this first joint guideline,” says Felix Beuschlein, chair of the guideline committee and professor in the department of endocrinology at the University of Zurich.
Both societies see this first joint guideline as the initial step in more future collaboration. It was released to an enthusiastic reception in rooms full of interested attendees at an ESE meeting in Stockholm and ENDO 2024 in Boston.
Widespread Use
The literature review done in conjunction with the guideline confirmed that some 1% of the global population use chronic glucocorticoid therapy. This number is enormous, but is “more of a realization than a surprise,” says guideline co-chair, Tobias Else, MD, an endocrinologist at the University of Michigan. “Glucocorticoids are used by many subspecialties, like rheumatology, dermatology, and pulmonology, you name it.”
Yet even low-dose glucocorticoid use is associated with increasing the risks of cardiovascular disease, severe infections, hypertension, diabetes, osteoporosis, and fractures, the guideline notes. The widespread use and accompanying risks reinforce the need for every physician to have the resources to manage these drugs, from primary care to many subspecialities, Else says. “We provide this guidance not only for endocrinologists, but also for other subspecialty colleagues. We provide guidance on how to keep our patients safe, how to get patients off glucocorticoids, and how to recognize the problems that can occur during this process, such as glucocorticoid withdrawal and adrenal insufficiency,” Else says.
Patient Self-Care
In addition to providing a resource for physicians, the guideline emphasizes the need for clinicians to educate patients and provide “up-to-date and appropriate information about different endocrine aspects of glucocorticoid therapy.”
Self-management is a critical skill for patients to learn in order to be active in their own care. Patients who know that they should increase their dosage when they are under stress, for example, when they have a fever or diarrhea, can actively decrease the likelihood of adrenal crisis, Beuschlein says.
“We provide this guidance not only for endocrinologists, but also for other subspecialty colleagues. We provide guidance on how to keep our patients safe, how to get patients off glucocorticoids, and how to recognize the problems that can occur during this process, such as glucocorticoid withdrawal and adrenal insufficiency.”
— Tobias Else, MD, University of Michigan, Ann Arbor, Mich.
To support this effort, the two societies are preparing educational material aimed at patients, with an online brochure already available at the ESE website.
When to Taper
The guideline also recognizes that one of the most important questions clinicians face is how to get patients off glucocorticoids in a way that avoids withdrawal symptoms and adrenal crisis. It suggests that it is not necessary to taper them in patients who have been taking them for less than three to four weeks. These patients can simply stop without a need for laboratory testing of the HPA effects.
For patients treated longer term, the guideline suggests switching from longer-acting glucocorticoids (such as dexamethasone or betamethasone) to short-acting ones (such as hydrocortisone or prednisone) whenever possible because the longer-acting drugs are more likely to cause HPA axis suppression.
In patients who have been on long-term glucocorticoid therapy but no longer need it, the dose should be tapered down until the physiologic daily dose of about 4 – 6 mg of prednisone or equivalent is achieved. As the dose is tapered, patients should be monitored for symptoms of glucocorticoid withdrawal syndrome, including joint or muscle pain, weakness, fatigue, sleep disturbance, and mood changes. Patients with severe cases of glucocorticoid withdrawal syndrome should have their dose temporarily increased to the most recent dose that prevented the withdrawal.
Glucocorticoid withdrawal syndrome can occur when the dose is being reduced but is still within supraphysiologic range. As the dose approaches the physiologic daily dose, clinicians should monitor for clinical signs of glucocorticoid-induced adrenal insufficiency, the symptoms of which are similar to those of withdrawal.
“In most instances, the adrenal cortex will recover and produce adequate levels of cortisol,” the guideline notes, but the time to full recovery of the HPA axis varies greatly among individuals.
Else says that in most cases it is enough to taper the dose and monitor the patient without the need for laboratory tests.
The guideline recommends that “if confirmation of recovery of the HPA axis is desired, we recommend morning cortisol as the first test [with] the value considered as a continuum, with higher values more indicative of HPA axis recovery.”
Different Testing Units
An interesting conundrum of writing a joint European-American guideline is reconciling the different testing units used for cortisol values, Beuschlein says. The guidelines suggest that a cortisol test result greater than 300 nmol/L or 10 mg/dL indicates recovery of the HPA axis, so glucocorticoids can be stopped safely. If the level is below these thresholds, the glucocorticoid dose should be continued and the test repeated in weeks to months, depending on the levels.
Beuschlein says that the committee was aware that these thresholds do not convert to the exact same amounts: “We don’t really have exact numbers. Although the conversion of 300 nmol/L does not equal 10 mg/dL, it is in the correct range, so the committee decided to go with numbers that people remember easily.”
The guideline suggests that patients who do not reach an acceptable level of HPA axis recovery after a year of receiving a physiologic daily dose equivalent should be referred to an endocrinology specialist.
Among these patients whose HPA axis has not rebounded — those with glucocorticoid-induced adrenal insufficiency — treatment should continue with an eye to avoiding adrenal crisis. “Education on stress and emergency dosing can prevent symptoms of adrenal insufficiency and hospitalizations for adrenal crises,” the guideline says. “Oral glucocorticoids should be used in case of minor stress and when there are no signs of hemodynamic instability or prolonged vomiting or diarrhea.”
“Glucocorticoid-induced adrenal insufficiency necessitates careful education and management, and in the rare cases of adrenal crisis, prompt diagnosis and therapy,” the guideline notes. And this joint guideline provides a major step forward in providing the evidence-based advice needed for the many medical specialists prescribing glucocorticoids to achieve these goals.
Members of the guideline-writing committee included: Felix Beuschlein, MD (chair); Tobias Else, MD (co-chair); Irina Bancos, MD; Stefanie Hahner, PhD; Oksana Hamidi, DO; Leonie van Hulsteijn, MD; Eystein S. Husebye, PhD; Niki Karavitaki, MSc, PhD, FRCP; Alessandro Prete, PhD; Anand Vaidya, MD, MMSc; Christine Yedinak, DNP, FNP, MN; and Olaf M. Dekkers, MD, PhD (methodologist).
Seaborg is a freelancer writer living in Charlottesville, Va. In the June issue, he wrote about the “Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline” which was released during ENDO 2024 in Boston.
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