3d3cb838e9e0c8bfeeeb11a0b40e187a 307577.pdf 1d93e59dadfa9a89b38462b4032d118f6b41b225 307577.pdf 6fbca26291321eba9da9593ff71091a1073f81e23d6098108679a24519064d1d 307577.pdf Title: Exploring the Therapeutic Landscape: A Narrative Review on Topical and Oral Phosphodiesterase-4 Inhibitors in Dermatology Subject: 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. Keywords: phosphodiesterase-4; PDE4; apremilast; roflumilast; orismilast; mufemilast; difamilast; psoriasis; atopic dermatitis; topical therapy; oral therapy; off-label Author: Elena Carmona-Rocha, Lluís Rusiñol and Lluís Puig Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Wed Jan 15 03:42:28 2025 CET ModDate: Wed Jan 15 03:48:26 2025 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 37 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3748722 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SSXPJJ+VnURWPalladioL Type 1 Custom yes yes yes 10 0 HAZQZI+URWPalladioL-Roma Type 1 Custom yes yes yes 16 0 XQBDOW+URWPalladioL-Bold Type 1 Custom yes yes yes 22 0 VKCDBH+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 RRLNOU+EURM10 Type 1 Builtin yes yes yes 56 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722 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-04-10 02:44:19 CEST RepresentationInformation: 307577.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-04-09 12:43:28 CEST Size: 3748722 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 1321 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Methods Destination: section.2 Item: Title: Mechanism of Action of PDE4 Inhibitors Destination: section.3 Item: Title: Oral and Topical Approved Inhibitors of PDE4 Destination: section.4 Children: Item: Title: Apremilast (CC-10004; Otezla®) Destination: subsection.4.1 Children: Item: Title: Apremilast in Psoriasis Destination: subsubsection.4.1.1 Item: Title: Apremilast in Behçet’s Disease Destination: subsubsection.4.1.2 Item: Title: Off-Label Uses of Apremilast Destination: subsubsection.4.1.3 Item: Title: Roflumilast Destination: subsection.4.2 Children: Item: Title: Oral Roflumilast Destination: subsubsection.4.2.1 Item: Title: Topical Roflumilast Destination: subsubsection.4.2.2 Item: Title: Crisaborole (AN2728; Eucrisa®) Destination: subsection.4.3 Children: Item: Title: Crisaborole in Atopic Dermatitis Destination: subsubsection.4.3.1 Item: Title: Off-Label Crisaborole in Psoriasis Destination: subsubsection.4.3.2 Item: Title: Off-Label Crisaborole in Seborrheic Dermatitis Destination: subsubsection.4.3.3 Item: Title: Other Off-Label Uses of Crisaborole Destination: subsubsection.4.3.4 Item: Title: Oral and Topical Inhibitors of PDE4 Under Development Destination: section.5 Children: Item: Title: Orismilast (IBI353) Destination: subsection.5.1 Children: Item: Title: Orismilast in Psoriasis Destination: subsubsection.5.1.1 Item: Title: Orismilast in Hidradenitis Suppurativa Destination: subsubsection.5.1.2 Item: Title: Orismilast in Atopic Dermatitis Destination: subsubsection.5.1.3 Item: Title: Mufemilast (Hemay005) Destination: subsection.5.2 Children: Item: Title: Mufemilast in Psoriasis Destination: subsubsection.5.2.1 Item: Title: Mufemilast in Other Diseases Destination: subsubsection.5.2.2 Item: Title: ME3183 Destination: subsection.5.3 Item: Title: Difamilast (OPA-15406) Destination: subsection.5.4 Item: Title: Lotamilast (E6005/RVT-501) Destination: subsection.5.5 Item: Title: LEO-29102 Destination: subsection.5.6 Item: Title: Pefcalcitol (M5181) Destination: subsection.5.7 Item: Title: PF-07038124 Destination: subsection.5.8 Item: Title: AWD-12-281 (GW842470X) Destination: subsection.5.9 Item: Title: DRM02 Destination: subsection.5.10 Item: Title: HFP034 Destination: subsection.5.11 Item: Title: Discussion Destination: section.6 Item: Title: Conclusions Destination: section.7 Item: Title: Future Directions Destination: section.8 Item: Title: References Destination: section.9 Info: Title: Exploring the Therapeutic Landscape: A Narrative Review on Topical and Oral Phosphodiesterase-4 Inhibitors in Dermatology Author: Elena Carmona-Rocha, Lluís Rusiñol and Lluís Puig Subject: 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. 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