The Perils of Prednisone

AUTHOR:
Samuel Louie, MD

AFFILIATION:
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, UC Davis Medical Center, Sacramento, California

CITATION:
Louie S. The perils of prednisone. Consultant. 2020;60(9):5, 12-16. doi:10.25270/con.2020.09.00001

DISCLOSURES:
The author reports serving as a speaker and consultant for AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Regeneron, and Sanofi Genzyme.

CORRESPONDENCE:
Samuel Louie, MD, UC Davis Medical Center, 4150 V St, Ste 3400, Sacramento, CA 95817 (sylouie@ucdavis.edu)

“No one ever died from acute Cushing syndrome.”

My mentor, Glen Lillington, MD, whispered these reassuring words to me at a pulmonology symposium in 1990, when I looked incredulous after the renowned pulmonologist Tom Petty, MD, recommended that patients with asthma and chronic obstructive pulmonary disease (COPD) “take a handful of prednisone” to treat an acute exacerbation. But is this approach correct? Is it safe? What have patients taught us about prednisone?

In short:

Prednisone is a prodrug.

Prednisone is a glucocorticoid.

Prednisone is a mineralocorticoid.

But is prednisone a poison?

OVERVIEW

Prednisone and other glucocorticoids regulate the metabolic and inflammatory function of many cells, tissues, and organs by directly modulating DNA transcription. Decreasing transcription (transrepression) can decrease the production of inflammatory cytokines, chemokines, adhesion molecules, and receptors. Alternatively, increasing transcription (transactivation) of selected DNA genes can increase inflammatory cytokine production or anti-inflammatory proteins, such as annexin A1 (also known as lipocortin).

Prednisone is often prescribed as an oral anti-inflammatory drug for myriad medical diseases and disorders in an attempt to attenuate systemic inflammatory response and restore a dynamic physiological homeostasis in patients—for example, in patients who have significant inflammatory response with sepsis and respiratory failure from community-acquired pneumonia.

The common chronic diseases treated with prednisone range from asthma, COPD, and inflammatory bowel disease to rheumatoid arthritis, sarcoidosis, and granulomatosis with polyangiitis. Prednisone has not cured any of these conditions, but it can induce temporary remission of symptoms and cause adverse effects (AEs) in patients who try to live normally between exacerbations of their underlying ailment.

Prednisone was the 22nd most commonly prescribed drug in the United States in 2017, with more than 25 million prescriptions written.¹

MECHANISM OF ACTION

Three stages must occur for successful signal transduction by prednisone and other oral corticosteroids (CSs) into target tissues and cells: extracellular, cytoplasmic and nuclear (Table 1). In stage 1, prednisone must be converted in the liver by 11β-hydroxysteroid dehydrogenase (11β-HSD) into prednisolone, which is biologically active (Figure).

Next, in stage 2, prednisolone diffuses across cell membranes into the cytoplasm and binds to a glucocorticoid receptor (GR) to form a prednisolone-plus-GR complex (abbreviated GR+CS), discarding chaperone heat-shock proteins into the cytoplasm. Then, in stage 3, the GR activated by prednisolone is able to translocate through nuclear pores and bind to glucocorticoid response elements (GREs) on glucocorticoid-sensitive DNA genes.^2-4

Two GR+CS monomers bind to one GRE, which can then increase or decrease transcription of glucocorticoid-sensitive DNA genes by RNA polymerase into messenger RNA (mRNA). Because mRNA acts as template for protein synthesis or translation, corticosteroids can either stimulate or inhibit the synthesis of specific proteins.

Transcription of DNA is tightly regulated by the acetylation of core histones, which keep DNA coiled tightly, forming chromatin, which cannot be transcribed by RNA polymerase. Acetylation of selected core histones allows a portion of DNA to uncoil, permitting transcription by RNA polymerase encoding in mRNA the instructions for ribosomes to synthesize inflammatory proteins (eg, cytokines). Deacetylation of histones causes DNA to coil again and inhibits transcription.

For example, GR+CS can directly inhibit histone acetyltransferase, allowing increased transcription of DNA for and synthesis of annexin A1, which can diminish leukocyte function and the release of cytokines and other inflammatory proteins. GR+CS, as well as low-dose theophylline (200 mg once or twice daily) can activate histone deacetylase and inhibit gene transcription in asthma but not in COPD. Any interruption of signal transduction can foil the therapeutic effects of CSs. Several polymorphisms in the GR gene, cytokines interleukin 2 and 4, and interference with nuclear translocation of GR+CS can interrupt signal transduction and in part explain the variable response or lack of response (resistance) to CSs.^2-4

CSs can decrease the production of cytokines and decrease activation of key cells, including T lymphocytes, dendritic cells, macrophages, mast cells, basophils, and eosinophils. CSs decrease leukocyte migration, decrease white blood cell phagocytosis by stabilizing lysosomes, and cause lymphopenia to result in general immunosuppression. CSs, through annexin A1, inhibit phospholipase A2, which reduces production of prostaglandins, leukotrienes, and thromboxanes. CSs can increase the protein synthesis of β₂-adrenergic receptors for drugs such as albuterol to bind to and cause bronchial smooth muscles to dilate.²

The potency of CSs (Table 2)⁵ is measured by the degree of skin blanching or vasoconstriction after topical application to the skin of a human, mouse, rat, or guinea pig.⁶

PREDNISONE IN PRACTICE

It has been our experience at UC Davis that patients with difficult-to-control asthma who have an Asthma Control Test (ACT) score lower than 20 despite strict adherence to standard of care—an inhaled corticosteroid (ICS) plus a long-acting β₂-agonist (LABA) with or without an additional controller for 3 or more months—have not received personalized asthma education, have very poor technique with ICS + LABA inhalers, take high daily doses of prednisone (>10 mg/d), have untreated comorbidities, or have the wrong diagnosis.

Understanding why ICSs are failing to control symptoms and prevent exacerbations is at the crux of expert consultation. ICSs remain the most effective first-line daily controller drug therapy, and adherence can reduce the need for prednisone and help prevent death. But is asthma the correct diagnosis? Is the ICS being delivered by the inhaler effectively into the lungs? Is the patient a responder or a nonresponder to ICSs?

The Global Initiative for Asthma (GINA) 2020 recommends that clinicians consider AEs before prescribing daily maintenance oral CSs (OCSs) at low doses (eg, prednisone ≤7.5 mg/d or equivalent), much preferring other add-on treatment options over prednisone, including long-acting muscarinic antagonists (LAMAs) and/or biologics.⁷ However, many clinicians opt to keep their patients on prednisone because of drug costs, convenience of a pill, drug withdrawal symptoms, and unfamiliarity with adding LAMAs and biologics in asthma therapy.

OCS therapy has been a pillar primarily in the treatment of severe asthma exacerbations since the 1950s in outpatient practice (Table 3). Systemic CSs (oral, intravenous, or intramuscular) can prevent death from asthma exacerbations and relapse⁷ and in acute care settings should be administered in all but the mildest exacerbations in adults and adolescents. The individualized written asthma action plan should provide access for reporting to clinicians whenever an exacerbation occurs and include clear instructions on when and how to take OCSs at home. A “handful” of prednisone is not to be recommended.

At UC Davis, we typically prescribe either a short course of prednisone (eg, 40 mg/d for 3 days, 30 mg/d for 3 days, 20 mg/d for 3 days, 10 mg/d for 3 days, and the patient stops, or an even shorter course of 40 mg/d for 5 days for acute moderate to severe exacerbations). Courses lasting 5 to 7 days in adults have been found to be as effective as 10- and 14-day courses, respectively.⁷ According to GINA, failure of resolution from an exacerbation or relapse of symptoms should prompt switching prednisone to prednisolone if impaired conversion by 11β-HSD in the liver is suspected.⁸

Patients should see their primary care health care provider within 1 to 2 weeks to assess asthma control, review the daily controller regimen and inhaler techniques, adjust therapy if necessary, and search diligently for triggers responsible for exacerbation and/or potential risk factors (eg, smoking, gastroesophageal reflux disease [GERD], obstructive sleep apnea).

Any adult or adolescent patient with asthma who reports more than 1 or 2 exacerbations per year despite adherence to GINA step 4 (medium-dose ICS + LABA) or step 5 (high-dose ICS + LABA) therapy should be referred promptly to a specialist center for assessment for additional add-on therapy and to prevent further exacerbations.⁷ There should be zero tolerance for exacerbations. At UC Davis, we recommend any patient with asthma on daily OCSs be referred to our UC Davis Asthma Network clinics for confirmation of asthma diagnosis, phenotyping, endotyping, and consideration for add-on maintenance therapy (eg, LAMA and/or biologics, and bronchial thermoplasty).

GINA 2020 reflects the best available evidence at the time the recommendations were prepared. Adherence to guidelines will not ensure successful treatment in every patient. Guidelines should not be setting a standard of care or exclude other evidence-based effective asthma treatments.

The final decision to embark on a specific asthma treatment must be made jointly by the patient with the clinician in view of the personal circumstances presented by each patient, and the realization that response to treatments, even ICS + LABA, can be highly variable. One of our most important goals in managing asthma is always to reduce and eliminate the need and use of OCSs at every opportunity by improving asthma control within the framework of GINA 2020.

However, strict adherence to best-practice reports or guidelines may leave a patient with asthma who does not respond to ICSs to require escalating dosages of ICSs and even daily OCSs. Look for a meaningful change in the ACT score (≥3 points) or a greater than 5% improvement in forced expiratory volume in the first second of expiration (FEV₁) after 4 weeks of ICS or ICS + LABA therapy.⁹

If a patient’s asthma control significantly improves with adding an OCS to ICS + LABA therapy, consider an upper-airway obstruction from obese habitus, a large tongue, faulty inhaler techniques, a need to change to a different inhaler device or a nebulizer, and/or nonadherence.

Finally, strict adherence to guidelines may leave patients who have been misdiagnosed with asthma to continue treatment for a disease they do not have. The risks of complications and danger is never greater than when patients are prescribed daily prednisone or methylprednisolone.

IS PREDNISONE POISON?

A common pitfall is to prescribe prednisone for its therapeutic benefits while distancing concern for AEs and the risk of causing a concurrent condition to occur. Prednisone is an iatrogenic poison whenever clinicians lose awareness of these dangers or when it is prescribed inappropriately or for too long. It is imperative to realize that even short courses of prednisone (5 to 14 days) can be associated with AEs and risks of developing new conditions or exacerbating underlying conditions that require immediate diagnosis and treatment (Table 4). Iatrogenic Cushing syndrome is the most common cause of Cushing syndrome.^10,11 Prednisone and other CSs are absolutely contraindicated in systemic fungal infections and in patients with known hypersensitivity to prednisone and/or its components.

The AEs of prednisone can cause nonspecific signs and symptoms that patients can mistake for ordinary daily aches and pains (Table 5).¹² The most commonly reported AEs associated with prednisone include fluid retention, alteration in glucose tolerance, hypertension, behavior and mood changes, increased appetite, and weight gain. The occurrence of these effects is often associated with dose and duration of therapy. Long-term effects are more familiar to clinicians and include a cushingoid appearance, cataracts and increased intraocular pressure/glaucoma, osteoporosis, and vertebral compression fractures.

Serious and often life-threatening complications can occur from even short-term use of prednisone. OCS-sparing attempts should be made early and frequently but only under medical supervision. OCSs should be tapered slowly to avoid triggering adrenal crisis and even death.¹³

There are other dangers clinicians must be aware of. A retrospective cohort study and self-controlled case series employing a US dataset of private insurance claims linked the frequency of prescriptions for short-term use of OCSs (<30 days duration) with serious AEs.¹⁴ One in 5 adults (18-64 years) in a commercially insured plan were prescribed OCSs for short-term use from 2012 to 2014. Of the more than 1.5 million adults, 327,452 (21.1%) received at least 1 outpatient prescription for short-term use OCSs over the 3-year period. Within 30 days of drug initiation, there was an increase in rates of sepsis, venous thromboembolism (VTE), and fracture, which diminished over the following 31 to 90 days. The increased risk persisted at prednisone-equivalent doses of less than 20 mg/d.¹⁴

A large retrospective cohort study of adults (≥18 years) with asthma from 2000 to 2014 found a significant association between the use of OCSs and AEs based on the number of OCS prescriptions written.¹⁵ A total of 72,063 patients prescribed OCSs were compared with 156,373 patients who were not prescribed OCSs. Patients taking 4 or more OCS prescriptions within a given year had 1.20 times the odds of experiencing an AE or reaction to OCSs within the year. Having 4 or more OCS prescriptions was linked to significantly greater odds of developing osteoporosis, hypertension, obesity, type 2 diabetes, GERD, peptic ulcer disease, gastrointestinal tract bleeding, bone fractures, and cataracts.¹⁵ Each prescription for an OCS can increase a cumulative burden on both current and future health, regardless of the dose and duration. These findings suggest that even OCSs used in bursts for treating acute exacerbations can be harmful to a patient’s health.

For patients requiring prednisone daily or who need a prednisone-sparing strategy, monoclonal antibodies offer hope when repeated attempts at withdrawal of prednisone fail. Patients with severe asthma and evidence of type 2 high-inflammation and/or eosinophilic airway inflammation may benefit from a trial of biologics (including benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab) to improve asthma control and reduce or eliminate OCSs.⁷

WITHDRAWAL OF PREDNISONE

Although there are no evidence-based guidelines for tapering of OCSs, gradual tapering is frequently a part of treatment protocols to reduce the risk of severe asthma symptoms and acute exacerbations returning. Time to recovery of endogenous cortisol production in the patient after stopping prednisone can vary considerably. Withdrawal from long-term OCS therapy can result in secondary adrenal insufficiency from adrenal atrophy (from hypothalamic-pituitary-adrenal axis suppression) after discontinuation of prednisone, particularly if the patient has remained on prednisone at a dosage greater than 7.5 mg/d for more than 2 to 3 weeks. If adrenal suppression is suspected, early morning cortisol should be measured when the prednisone dose is reduced to 7.5 mg/d or less prior to the test and no prednisone is given the evening and morning before.¹⁶

Adrenal suppression often occurs following abrupt discontinuation of prednisone. Endogenous cortisol production may be suppressed in a patient taking supraphysiological doses of prednisone (>7.5 mg/d or its equivalent). ICSs may also be absorbed systemically to the degree that they can cause adrenal suppression.¹⁷ It is a pitfall to overlook adrenal suppression in patients prescribed ICSs apart from prednisone.

Table 6 summarizes a number of pitfalls to avoid when treating patients with prednisone and other OCSs.

WARNING AND PRECAUTIONS

The benefits of prednisone outweigh the risks when treating severe exacerbations, and the medication can be life-saving. However, medical treatment for an illness can produce a worse net result than the illness does, notably via AEs. Cardiac arrhythmias, bone fractures, gastrointestinal tract bleeding, mood changes, tuberculosis or fungal pneumonia, sepsis, and venous thromboembolism can be triggered by prednisone but are often considered events separate from asthma and prednisone. Invasive pulmonary aspergillosis has been associated with the use of high-dose ICSs in a patient with asthma.¹⁸ Nasal corticosteroids have been implicated in invasive aspergillosis of the sinuses in an otherwise healthy patient.¹⁹

The report of these complications linked to prednisone should prompt every clinician to assess each patient during the review of systems for underlying heart disease, osteoporosis, GERD, peptic ulcer disease, depression, smoking, cancer, and estrogen replacement. Patient education and regular review of symptoms in the primary care setting are important in early detection of AEs from OCSs or ICSs (eg, Cushing syndrome, diabetes, osteoporosis apart from adrenal suppression during withdrawal of prednisone).

Patients certainly need to be more aware this important safety information as they prepare to take prednisone as directed by their asthma action plan. Prednisone and other OCSs deserve a boxed warning from the Food and Drug Administration. All drugs can be poisons and should be prescribed for their medicinal properties only when appropriate indications exist.

The dose and duration of prednisone treatment should be kept short as possible (5-12 days). All patients should be monitored by email, video visit, or telephone call to assess clinical response. Longer short-term courses or daily prednisone therapy should be used only when absolutely indicated for uncontrolled severe asthma with portents of early death, such as FEV₁ of less than 60%, recent hospitalization, frequent emergency department visits, and intubation with mechanical ventilation.

Referral to an asthmatologist or immediate action by the primary care provider is critical for the patient’s safety. Take time to confirm the asthma diagnosis and consider add-on maintenance drugs to reduce or eliminate the dosage and need for prednisone. Patient safety is a contact sport where the patient and clinician must team up to reduce impairment and risks from asthma and drug therapy. Safety never happens by accident.²⁰

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