ABCs in Dermatology: Topical PDE4 Inhibition in Atopic Dermatitis

Nonsteroidal topicals have reshaped atopic dermatitis care, and phosphodiesterase 4 (PDE4) inhibitors now offer a once-daily option capable of reaching optimal targets for skin and itch.

In this episode of ABCs in Dermatology, hosts Lindsay Ackerman, MD, and Chris Bunick, MD, PhD, examined where topical PDE4 inhibitors fit and how to measure meaningful response.

PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP), a second messenger driving anti-inflammatory programming. Because inhibition acts upstream of the Janus kinase (JAK)-STAT pathway, it dampens Th1, Th2, Th17, and Th22 signaling. Roflumilast (Zoryve) more closely mimics cAMP than crisaborole (Eucrisa) or apremilast (Otezla), with roughly 25-fold to more than 300-fold greater in vitro potency.1

In the phase 3 INTEGUMENT-1 and INTEGUMENT-2 trials, 1337 patients aged 6 years or older applied roflumilast cream 0.15% or vehicle once daily for 4 weeks.1 Validated Investigator Global Assessment success reached 32.0% vs 15.2% and 28.9% vs 12.0%, respectively, with 75.8% entering with moderate disease.1 Itch improved within 24 hours of the first application.1

Application-site pain occurred in 0.9% and 2.1% of roflumilast-treated patients, and none of 47 patients who previously stopped crisaborole for stinging or burning developed application-site adverse events.1 One hypothesis attributes part of crisaborole's irritation to its boron-containing structure. Nausea affected 2.0% or fewer of treated patients,1 and moderate to severe hepatic impairment remains the key contraindication.

In the INTEGUMENT open-label extension, patients reaching clear skin switched to twice-weekly proactive application and maintained clear or almost clear skin for a median of 281 days.2 The regimen mirrors proactive corticosteroid maintenance without cumulative steroid exposure, useful on the face, eyelids, and skin folds. In children aged 2 to 5 years, roflumilast cream 0.05% likewise improved pruritus within 24 hours.3

Unlike ruxolitinib cream (Opzelura), limited to short-term use on 20% or less of body surface area, roflumilast carries no duration or surface area cap. Clinicians increasingly pair it off label with biologics or oral JAK inhibitors for residual disease, often persistent itch.

Treat-to-target goals now define minimal disease activity as clear or almost clear skin plus an itch score of 0 or 1 on a 0-to-10 scale. Reduction of 4 or more points on the Worst Itch Numeric Rating Scale marks a moderate target, signaling response while deeper improvement accrues.

Collectively, once-daily topical PDE4 inhibition positions nonsteroidal therapy as a credible route to minimal disease activity in atopic dermatitis. The data reinforce corticosteroid stewardship for long-term and sensitive-site use.

Relevant disclosures for Bunick include AbbVie, South Beach Symposium, Almirall, Apogee Therapeutics, Arcutis Biotherapeutics, Daiichi Sankyo, Eli Lilly, LEO Pharma, US, Novan, Novartis, Ortho Dermatologics, Palvella Therapeutics, Pfizer Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Timber Pharmaceuticals, and UCB. Relevant disclosures for Ackerman include AbbVie, Alumis, Amgen, Arcutis, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Galderma, L'Oréal, Novartis, Sun Pharmaceutical, and UCB.

References

1. Simpson EL, Eichenfield LF, Alonso-Llamazares J, et al. Roflumilast cream, 0.15%, for atopic dermatitis in adults and children: INTEGUMENT-1 and INTEGUMENT-2 randomized clinical trials. JAMA Dermatol. 2024;160(11):1161-1170. doi:10.1001/jamadermatol.2024.3121

2. Simpson EL, Eichenfield LF, Papp KA, et al. Long-term safety and efficacy with roflumilast cream 0.15% in patients aged ≥6 years with atopic dermatitis: a phase 3 open-label extension trial. Dermatitis. 2026;37(1):75-83. doi:10.1089/derm.2024.0418

3. Eichenfield LF, Serrao R, Prajapati VH, et al. Efficacy and safety of once-daily roflumilast cream 0.05% in pediatric patients aged 2-5 years with mild-to-moderate atopic dermatitis (INTEGUMENT-PED): a phase 3 randomized controlled trial. Pediatr Dermatol. 2025;42(2):296-304. doi:10.1111/pde.15840