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Systemic corticosteroids administered orally or by injection were first introduced for the treatment of asthma in the mid-20th century. Although these agents were found to be clinically effective in reducing symptoms and exacerbations, recognition of their many significant adverse effects (AEs) led to the development and introduction of inhaled corticosteroids (ICS) as maintenance therapy for asthma in 1972.1,2 Inhaled corticosteroids, alone or in combination with long-acting β2-agonists (LABAs), are the preferred treatment for asthma today3-5; however, the use of systemic oral corticosteroids (OCS) remains an important component of the therapeutic toolkit for patients experiencing exacerbations or who have severe asthma, despite their association with a wide range of AEs.3,4
An estimated 30% to 40% of patients with severe uncontrolled asthma regularly use OCS on an intermittent or chronic basis to maintain some degree of disease control.6 Patients with uncontrolled severe asthma make up 5% to 10% of the total asthma population7 and compared with patients with milder disease are at greater risk for exacerbations, hospitalizations, and death.8 Although several recently introduced biologic therapies have been demonstrated in clinical trials to reduce the need for OCS, the use of both long- and short-term OCS is still common, particularly in older female patients.9
Adverse events that have been reported with OCS use include bone fractures, osteoporosis, susceptibility to infections, digestive system disorders, type 2 diabetes, cataracts, cardiovascular events, psychiatric disorders, obesity, and adrenal suppression.10-12 According to an analysis of commercial health claims data, patients with asthma and high annual OCS use (≥30 days of OCS use annually) had statistically significantly higher rates of any potential AE compared with nonusers of OCS (83.5% vs 78.1%; P <.001).13 Although adverse corticosteroid-related outcomes have most often been reported at doses >10 mg/d,14 a recent systematic literature review of literature of studies on the dose-response relationship between OCS use and OCS-related complications in patients with asthma evinced a statistically significant linear relationship between increasing doses of these agents and AEs.15
Global Initiative for Asthma guidelines from 2019 state that maintenance OCS are no longer considered “preferred” treatment for patients with uncontrolled asthma because of a high risk for adverse outcomes. Instead, these and other clinical practice guidelines recommend intensifying asthma treatment with inhaled medications (including ICS, LABAs, the long-acting muscarinic antagonist tiotropium, and/or biologic agents) and ensuring that patients have correct inhaler technique and good medication adherence before initiating long-term OCS use3,4; however, evidence suggests that OCS are frequently overprescribed or used inappropriately in patients with asthma.
Results from a study published in Pediatrics showed that the majority of medical records of children with asthma including a pharmacy claim for an OCS such as prednisone, prednisolone, methylprednisolone, or dexamethasone did not contain evidence of other healthcare use that would suggest the presence of poorly controlled asthma, such as excessive short-acting β-agonist medication dispensing, emergency department visits, or hospitalizations.16 Another analysis of pharmacy records from 5002 patients using high-dose ICS (≥500 µg/d) plus LABAs suggested treatment had not been appropriately optimized in accordance with guidelines recommendations.17,18 In that cohort, 29% of patients were exposed to harmful doses of OCS (defined as the cumulative intake of 420 mg of prednisone-equivalent OCS over a 1-year period), yet 47.4% of patients with harmful OCS exposure were nonadherent to their prescribed ICS. Of those persons with adequate adherence, 53.9% were identified as having poor inhaler technique.17,18 In addition, OCS are often prescribed in escalating doses to patients who are resistant or insensitive to their effects.2
To minimize the potential for complications in patients who require OCS, physicians are advised to use the lowest effective dose and the shortest effective duration of treatment. Physicians prescribing long-term OCS should also ensure that patients are monitored for bone mineral density, ocular complications, blood pressure, cardiovascular risk, lipids, blood glucose, and adrenal insufficiency.12 Furthermore, the use of biologic agents targeting the immunoglobulin E or interleukin-5 pathways (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) should be considered as a steroid-sparing alternative for patients with severe allergic or eosinophilic asthma refractory to treatment with ICS or LABAs.2 These monoclonal antibodies have the potential to reduce exacerbations, mitigate the need for rescue medication, improve pulmonary function, and reduce OCS use in eligible patients, with limited AEs.2,14,19
References
1. Anderson SD. Repurposing drugs as inhaled therapies in asthma. Adv Drug Deliv Rev. 2018;133:19-33.
2. Bleecker ER, Menzies-Gow AN, Price DB, et al. Systematic literature review of systemic corticosteroid use for asthma management. Am J Respir Crit Care Med. 2020;201(3):276-293.
3. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma-summary report 2007. J Allergy Clin Immunol. 2007;120(5 suppl):S94-S138. Erratum in J Allergy Clin Immunol. 2008;121(6):1330.
4. Global Strategy for Asthma Management and Prevention. Fontanta, WI: Global Initiative for Asthma; 2019.
5. Buhl R, Heaney LG, Loefroth E, et al. One-year follow up of asthmatic patients newly initiated on treatment with medium- or high-dose inhaled corticosteroid-long-acting β2-agonist in UK primary care settings. Respir Med. 2020;162:105859.
6. Voorham J, Xu X, Price DB, et al. Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma. Allergy. 2019;74(2):273-283.
7. Sullivan PW, Ghushchyan VH, Globe G, Schatz M. Oral corticosteroid exposure and adverse effects in asthmatic patients. J Allergy Clin Immunol. 2018;141(1):110-116.e7.
8. Katial RK. Severe asthma: a heterogeneous disease. Immunol Allergy Clin. 2016;36(3):xv-xvi.
9. Tran T, MacLachlan S, Liu J, Chung Y, Rubino A, Ganz M. Oral corticosteroid treatment patterns for US patients with persistent asthma. Chest. 2019;156(4):A1586-A1587.
10. Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use. Respir Med. 2009;103(7):975-994.
11. Price DB, Trudo F, Voorham J, et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study. J Asthma Allergy. 2018;11:193-204.
12. Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30.
13. Zazzali JL, Broder MS, Omachi TA, Chang E, Sun GH, Raimundo K. Risk of corticosteroid-related adverse events in asthma patients with high oral corticosteroid use. Allergy Asthma Proc. 2015;36(4):268-274.
14. Ramsahai JM, Wark PA. Appropriate use of oral corticosteroids for severe asthma. Med J Aust. 2018;209(S2):S18-S21.
15. Volmer T, Effenberger T, Trautner C, Buhl R. Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature. Eur Respir J. 2018;52(4).
16. Farber HJ, Silveira EA, Vicere DR, Kothari VD, Giardino AP. Oral corticosteroid prescribing for children with asthma in a Medicaid managed care program. Pediatrics. 2017;139(5).
17. Bosworth T. One-third of patients with severe asthma are overusing corticosteroids. CHEST® Physician. Published October 3, 2019. Accessed February 3, 2020.
18. Eger KAB, Amelink M, Hekking PP, Bel E. Late breaking abstract: overuse of oral corticosteroids in asthma – modifiable factors and potential role of biologics. Eur Respir J. 2019:54(suppl 63):OA5334.
19. McGregor MC, Krings JG, Nair P, Castro M. Role of biologics in asthma. Am J Respir Crit Care Med. 2019;199(4):433-445.
