Beyond Skin Deep: The Systemic Impact of Topical Corticosteroids in Dermatology

J Clin Aesthet Dermatol. 2025;18(1–2 Suppl 1):S16–S20.

by Douglas DiRuggiero, DMSc, MHS, PA-C, and Margaret DiRuggiero, BS, MS

Dr. DiRuggiero is with the Skin Cancer and Cosmetic Dermatology Center in Rome, Georgia. Ms. DiRuggiero is with Emory University School of Medicine in Atlanta, Georgia.

Funding: Funding was provided by Arcutis Biotherapeutics, Inc.

Disclosures: Dr. DiRuggiero is an advisory board and/or speaker bureau for following companies: Abbvie, Amgen, Arcutis, Dermavant, Galderma, Incyte, JNJ, Lilly, Novartis, Sanofi/Regeneron, UCB. Ms. DiRuggiero has no conflicts of interest relevant to the content of this article.

ABSTRACT: Corticosteroids are widely prescribed for a variety of dermatologic indications. However, since 2020, regulatory bodies from Canada and the United Kingdom, as well as academic and patient advocacy societies, are increasingly calling for limiting topical corticosteroid use due to safety concerns. This article reviews the variety and extent of both cutaneous adverse effects (i.e., steroid-induced damage) and systemic adverse effects from topical corticosteroids and explores alternative therapies. The risk of adverse effects increases with steroid potency, amount, duration, and frequency of use across indications, routes of administration, and prescribers (i.e., cumulative steroid dose). In order to reduce these safety risks, clinicians should prescribe steroids appropriately and counsel patients on appropriate use and consider combination topical corticosteroid therapy or newer alternative steroid-sparing treatments.

Keywords: Topical corticosteroids, systemic adverse effects, cutaneous adverse effects, topical steroid withdrawal syndrome, steroid-induced damage

Introduction

Corticosteroids are widely prescribed for a variety of dermatologic indications, with approximately 13.8 million prescriptions for topical corticosteroids filled in the United States (US) in 2022.¹ Based on retrospective analyses of claims data between 2005 and 2020, approximately 85 percent of patients with psoriasis received a steroid-containing topical therapy.^2,3 However, since 2020, regulatory bodies from Canada and the United Kingdom (UK), as well as academic and patient advocacy societies, are increasingly calling for limiting topical corticosteroid use due to safety concerns.^4–8 The objective of this article is to review the variety and extent of both cutaneous and systemic side effects from topical corticosteroids and to explore alternative therapies.

History of Corticosteroid Treatment for Inflammatory Dermatoses

Since the initial development of oral corticosteroids by Edward Kendall and Phillip Hench in 1950,⁹ and the subsequent utilization of topical corticosteroids in 1952,¹⁰ corticosteroids have been widely prescribed for a variety of indications (skin dermatoses, respiratory conditions, rheumatologic diseases, and autoimmune diseases), by a number of different medical specialties (primary care, dermatology, allergy, rheumatology, pediatrics, and gastroenterology), and via several distinct routes of administration (oral, topical, ophthalmic, nasal, inhaled, intravenous, intramuscular, intra-articular, and intralesional).

Dermatology specialists initially thought that topical corticosteroid application might avoid the safety concerns seen with oral corticosteroids. However, corticosteroids have a small molecular weight (<500 Daltons) and thus are readily absorbed cutaneously.^11,12 Additionally, various factors such as patient age, body site of application, the amount of topical corticosteroids used, potency of topical corticosteroids, vehicle used to deliver the drug, frequency of application, use of occlusion, and nature of diseased skin can affect systemic absorption of topical corticosteroids.^12,13 Therefore, increasingly, there are calls from regulatory bodies (Canada⁴ and United Kingdom⁵), academic societies (International Eczema Council,⁶ British Dermatological Nursing Group/‌British Association of Dermatologists‌⁷), and patient advocacy groups (National Eczema Society⁷, National Eczema Association⁸) to limit topical corticosteroid use because of safety concerns and risk of steroid-induced side effects with long-term use.

Corticosteroids: A Double-Edged Sword?

Detailed reviews of the mechanisms of action of corticosteroids have been published.^14,15 Briefly, corticosteroids have a range of activities relevant to the treatment of inflammatory skin diseases—anti-inflammatory, antiproliferative, and immunosuppressive—some of which can lead to adverse events, especially at high doses/potencies with long-term, chronic use.

Steroid-induced damage. Potential adverse effects of corticosteroids were reported as early as 1951,¹⁶ and by 1960 all of the common toxic effects of chronic corticosteroid treatment were known.⁹ Cutaneous steroid side effects with chronic topical administration include skin barrier damage and atrophic changes (including skin atrophy, telangiectasia, striae, purpura, stellate pseudoscars, ulceration, easy bruising), cataract formation, and less commonly, hyper/hypopigmentation, photosensitization, masking of skin infections, and delayed wound healing (Figure 1).^17–21 However, adverse events with topical administration are not limited to local effects. Topical administration can also lead to perioral dermatitis, acne, disruptions in reproductive endocrinology (abnormal menstruation, lactation disturbances, facial flushing, hirsutism), increased risk of infections, growth suppression, adrenal insufficiency/hypothalamic-pituitary-adrenal axis suppression, Cushing syndrome/cushingoid features (weight gain and redistribution of adiposity [ie, “buffalo hump,” “moon face,” truncal obesity]), ophthalmic effects (ocular hypertension, glaucoma, loss of vision), hyperglycemia/diabetes, and decreased bone density/‌‌‌‌‌​osteoporosis/​increased risk of bone fracture, (Figure 1).^12,19–32

The risk of adrenal insufficiency/hypothalamic-pituitary-adrenal axis suppression with topical corticosteroids was confirmed by a 2014 systematic review of articles assessing adrenal insufficiency in adults using topical corticosteroids. This review identified 74 articles (3,753 patients) and found that, although higher doses and longer durations of use have the highest risk, there was no administration route, dosing regimen, treatment duration, or underlying disease for which the risk of adrenal insufficiency could be eliminated.²⁵ This risk was reconfirmed in a cross-sectional study of 42 adults with adrenal insufficiency who were seen in an outpatient dermatology clinic from June to October 2020 and who used topical corticosteroids for at least one year. The predictive factors for adrenal insufficiency included a higher body surface area affected in ages less than 60 years and a basal serum cortisol less than 7μg/dL; there was no association with underlying disease or topical corticosteroids potency.²⁶ Moreover, at least 43 cases of cushingoid syndrome with topical corticosteroid use have been reported; these occurred mostly in patients with dermatitis or psoriasis following treatment with betamethasone diproprionate or clobetasol (ultra-high/high potency corticosteroids) for as little as 0.3 months (median, children: 2.75 months; adults: 18 months) in children as young as three months (median, children: 8 months; adults: 46 years).²⁷

The risk of cataracts and new-onset diabetes are based on the results of population-based case-control studies. A case-control study based on the General Practice Research Database in the UK found that, among 15,479 people with cataracts and 15,479 matched controls, although lower than the risk with systemic, ocular, or inhaled corticosteroids, the risk of cataracts with topical corticosteroid use (at locations distant from the eye) is elevated (odds ratio, 1.43).²⁸ Case-control studies conducted in adults with new-onset Type 2 diabetes in Denmark from January 1, 2007, to December 31, 2012, (115,218 cases) and the UK from January 1, 2007, to December 31, 2015, (54,944 cases) confirmed the association between topical corticosteroid use and incident Type 2 diabetes (aOR, 1.27), as well as a dose-response relationship with duration of use and corticosteroid potency.²⁹ Interestingly, the risk range for new-onset diabetes with topical corticosteroids and oral corticosteroids overlap.²⁹

The association between topical corticosteroids and decreased bone density/​osteoporosis/​increased risk of bone fracture is based on an analysis of 723,251 Danish adults who filled one or more prescriptions for at least 200g of mometasone furoate (or equivalent) from January 1, 2003, to December 31, 2017, which found a direct association between exposure to potent or very potent topical corticosteroids and the risk of osteoporosis and major osteoporotic fracture.³⁰ This was supported by a subsequent case-control study conducted using data from 2017 to 2020 in the Taiwan National Health Insurance Research Database. Among 129,682 osteoporosis cases and 34,999 major osteoporotic fracture cases matched with 518,728 and 139,996 controls, respectively, also with five or more years of topical corticosteroid exposure, the risk of osteoporosis or fracture was increased for low (adjusted odds ratio [aOR], 2.2), medium (2.6), and high (3.4) potency topical corticosteroids, increasing further for women and those younger 50 years old.³¹ These adverse effects on bone density have been reported in male patients as young as 11 years.³²

Topical steroid withdrawal syndrome. Steroid-induced changes to the epidermal barrier can also lead to topical steroid withdrawal syndrome (TSWS; also known as red skin syndrome and topical steroid addiction; Figure 1), characterized by a shift from skin itching to burning/stinging and a confluent bright red rash that spreads beyond treatment area, followed by skin flaking and peeling.^5,33,34 Recognition of TSWS is limited by the lack of diagnostic criteria and overlap with symptoms of the underlying skin condition. Steroid-induced damage symptoms can even precede steroid withdrawal, indicating that “topical corticosteroid withdrawal syndrome” might be a misnomer or that the patient has developed tachyphylaxis or contact hypersensitivity to the active drug (and related corticosteroids) or vehicle excipients (identification of which is further complicated by lack of consistency in generic formulations). In many cases, symptoms of TSWS, tachyphylaxis, and contact hypersensitivity are misinterpreted as worsening of the underlying disease and the frequency or potency of topical corticosteroid is increased, creating a vicious cycle. Rebound flare after topical corticosteroid cessation or taper can also prompt reinitiation and/or escalation of the precipitating agent. Regulatory agencies in Canada and the UK are updating product labeling to warn of this risk and urging ongoing monitoring of this rare but potentially debilitating and irreversible safety issue.^4,5,35

Risk factors. Although the risk of steroid-induced damage increases with steroid potency (for steroid potencies, see National Psoriasis Foundation³⁶) and duration of use, cases have been reported with low potency varieties and after short periods of use (Figure 1).^5,12,33 In addition, infants and children are thought to be most at risk of developing steroid-induced damage because of their generally higher body surface area and the immaturity of their skin barrier leading to greater permeability.^5,21,33 People who use topical corticosteroids on the face or genital areas and those with atopic dermatitis are at even further risk because of the greater skin permeability associated with thinner skin and the epidermal barrier dysfunction inherent in the condition, respectively.^5,12,33

The potency, amount, duration, and frequency of corticosteroid use across indications, routes of administration, and prescribers all contribute to cumulative steroid dose and risk of adverse events.^24,37,38 In fact, among patients with atopic dermatitis included in a multicenter (n=3) retrospective chart review, greater than 66 percent of patients had at least one additional atopic condition (ie, allergic rhinitis, allergic conjunctivitis, asthma, eosinophilic esophagitis) and approximately 31 percent routinely used two or more non-oral steroid preparations to treat these conditions.³⁹

Strategies to Reduce Exposure and Risk

Appropriate topical corticosteroid use and patient counseling. In order to prevent side effects from topical corticosteroid application, healthcare professionals are advised to prescribe the lowest potency needed, advise patients on the amount and frequency (eg, once or twice a day) of application to the affected area, inform patients on duration of use particularly on sensitive areas (eg, face and genitals), switch to a lower potency TCS if treatment beyond the recommended duration is necessary, taper use or advise periodic breaks in treatment for patients on long-term, continuous, and inform patients to seek medical advice if their skin condition worsens or within two weeks after stopping treatment.⁴ Preferably, utilizing steroid-sparing alternatives with more targeted mechanisms of action and/or advanced vehicle formulations as first-line agents as well as maintenance medications should be considered.

Combination topical corticosteroid treatments. In patients with psoriasis, combination treatment with vitamin D analogs can reduce corticosteroid induced skin atrophy by modulating key extracellular matrix components, such as increased lipid synthesis, collagen synthesis and turnover, glycosamine synthesis among other changes in tissue modeling and structure.¹⁵ This combination treatment of topical corticosteroid and vitamin D analogs can reduce the frequency of application to treat skin diseases such as psoriasis and can reduce the adverse events associated with monotherapy application.

Steroid-sparing topical alternatives. To address the growing concerns with topical corticosteroids, novel, more targeted topical therapies have been developed. Between 2000 and 2016, topical calcineurin inhibitors (tacrolimus ointment 0.03% and 0.1% and pimecrolimus cream 1%) as well as a topical phosphodiesterase 4 (PDE4) inhibitor (crisaborole ointment 2%) were approved for the treatment of atopic dermatitis. While the use of topical calcineurin inhibitors has expanded to off-label use in inflammatory skin diseases beyond atopic dermatitis, the use of these topical therapies is limited by their modest efficacy and local tolerability issues upon application. Crisaborole use is also limited by modest efficacy and application site pain.^40,41

Since 2020, promising nonsteroidal targeted topical therapies utilizing new mechanisms of action, higher potency PDE4 inhibitors, and new vehicle formulations have been studied in various inflammatory skin diseases. As the data continue to emerge, these topical treatments provide an opportunity to change the way clinicians treat patients with inflammatory skin diseases. These include twice-daily ruxolitinib cream 1.5% (Opzelura, Incyte Corporation, Wilmington, DE) for atopic dermatitis and vitiligo;⁴² once-daily tapinarof cream 1% (Vtama, Ortho Dermatologics, Bridgewater, NJ) for atopic dermatitis and psoriasis;⁴³ and once-daily roflumilast cream 0.3% (Zoryve, Arcutis Biotherapeutics, Westlake Village, CA) for psoriasis, cream 0.15% for atopic dermatitis, and foam 0.3% for seborrheic dermatitis.⁴⁴ Further development of these new, targeted topical agents are ongoing, and case reports of uses in other inflammatory skin diseases continue to be published. These new developments in steroid-sparing topical therapies for inflammatory skin diseases complements the wealth of data on the safety and efficacy of novel oral and injectable biologic agents, which have made older treatments largely obsolete.

Vehicle considerations. Not only does formulation impact the potency classification of topical corticosteroids,³⁶ vehicles used in topical corticosteroid formulations are also an important consideration in treating patients with inflammatory skin diseases, as vehicles themselves can impact the skin barrier and innate immune response, resulting in improvement or worsening of the disease being treated. Furthermore, in addition to the epidermal barrier damage caused by corticosteroids directly, some commonly used vehicle excipients used to increase drug delivery into the skin can also damage the epidermal barrier^45,46—and patients can develop contact hypersensitivity to both the corticosteroid (and related corticosteroids) and vehicle excipients, some of which are more allergenic than others.⁴⁷ Recent advances in excipient research have led to more elegant vehicle formulations, resulting in good patient satisfaction and low application site irritation in the more recently approved therapies.

Conclusion

Long-term, chronic topical corticosteroid use should be limited because of safety concerns and the risk of both local and systemic side effects. The risk of which increases with steroid potency, amount, duration, and frequency of use across indications, routes of administration, and prescribers (ie, cumulative steroid dose). In order to reduce these safety risks, clinicians should prescribe steroids appropriately and counsel patients on appropriate use and consider combination topical corticosteroid therapy. Going a step further to deliver optimal care, the risk of cutaneous and systemic steroid-induced damage can be eliminated by prescribing a steroid-sparing alternative. The newest steroid-sparing alternatives (ruxolitinib cream,⁴² tapinarof cream,⁴³ and roflumilast cream/foam⁴⁴) each provide advantages over topical corticosteroids—more targeted mechanisms of action, less risk for adverse effects, and updated vehicle formulations—all while delivering efficacy that is, in our experience, at least comparable to moderate-to-high topical corticosteroids with excellent tolerability and high patient satisfaction.

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