Exploring the Therapeutic Landscape: A Narrative Review on Topical and Oral Phosphodiesterase-4 Inhibitors in Dermatology

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Phosphodiesterase-4 (PDE4) is involved in the synthesis of inflammatory cytokines that mediate several chronic inflammatory disorders, including psoriasis and atopic dermatitis. In recent years, the therapeutic armamentarium in dermatology has expanded with the introduction of PDE4 inhibitors, both in oral and topical formulations. PDE4 inhibitors have gained increasing interest due to their remarkable safety record and ease of prescription, as evidenced by the recent influx of literature detailing its off-label uses. Apremilast was the first PDE4 inhibitor approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for psoriasis, psoriatic arthritis, and oral ulcers of Behcet’s disease. Off-label use has been reported in diverse dermatological conditions, including aphthous stomatitis, chronic actinic dermatitis, atopic dermatitis, cutaneous sarcoidosis, hidradenitis suppurativa, lichen planus, and discoid lupus erythematosus. Roflumilast is a PDE4 inhibitor that was approved by the FDA and the EMA as an oral treatment of chronic obstructive pulmonary disease. Since patent expiration, several generic formulations of oral roflumilast have become available, and various studies have documented its off-label use in psoriasis and other dermatological conditions such as hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet’s disease. Topical roflumilast has received FDA approval for treatment of plaque psoriasis and seborrheic dermatitis. The favorable safety profile encourages its long-term use as an alternative to corticosteroids, addressing the chronic nature of many dermatological conditions. New oral PDE4 inhibitors are being developed, such as orismilast (LEO-32731), mufemilast (Hemay005), difamilast (OPA-15406) or lotamilast (E6005/RVT-501), among others. This narrative review provides a comprehensive synthesis of the pharmacology, clinical efficacy, safety profile, and practical considerations regarding the oral and topical use of PDE4 inhibitors in dermatology.