Exploring Newer Nonsteroidal Topical Treatments for Atopic Dermatitis: PDE4 Inhibitors

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Newer Nonsteroidal Topical Treatments for Atopic Dermatitis

Overview and Clinical Familiarity: In recent polling, clinical familiarity with newer nonsteroidal topical treatments for atopic dermatitis varies. While some providers actively use these agents in practice, the majority have heard of them but do not currently incorporate them into their management, and a smaller subset are not familiar with these options.

FDA-Approved Nonsteroidal Topical Treatments

Crisaborole (Eucrisa)

• Class: Phosphodiesterase-4 (PDE4) inhibitor
• Indication: FDA approved for patients aged ≥3 months
• Dosing: Twice-daily ointment
• Clinical Trial Data (AD-301 & AD-302):
  • 1522 participants aged 2 to 79 years (mean body surface area [BSA] of approximately 18%)
  • At 4 weeks, 32% to 33% achieved an investigator’s global assessment [IGA] score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement
  • Adverse Effects: Application site pain (burning/stinging) reported in approximately 4%
  • Clinical Tip: Use a moisturizer 15 minutes prior or refrigerate the tube to reduce application discomfort

Roflumilast (Zoryve)

• Class: Next-generation PDE4 inhibitor
• Indication: FDA approved for patients ≥6 years; also approved for psoriasis and seborrheic dermatitis
• Formulation: Foam or once-daily cream
• Clinical Trial Data (INTEGUMENT-1 & -2):
  • 1337 patients, mean BSA of 14%
  • Significant prior inadequate response to topical steroids (61%), calcineurin inhibitors (18%), and crisaborole (7%)
  • At 4 weeks, 29% to 32% achieved an IGA score of 0 or 1 with ≥2-grade improvement
  • Adverse Effects: Mild, including headache, nausea, diarrhea, vomiting, and site irritation (rare)
  • Clinical Insight: High tolerability; elegant vehicle formulation free from propylene glycol. Well-accepted for both efficacy and once-daily use
• Long-Term Data (OLE Study):
  • After initial 4 weeks, patients continued treatment for 52 weeks
  • Maintenance dosing (twice weekly) implemented for patients achieving IGA 0
  • At week 28: 56% maintained IGA 0 to 1; at week 56, 57% maintained response
• Maintenance Role: Demonstrates sustained control and steroid-sparing potential

Ruxolitinib (Opzelura)

• Class: Janus kinase inhibitor
• Indication: Approved for patients ≥12 years
• Dosing: Twice-daily cream
• Mechanism: Targets a broad range of inflammatory cytokines with greater specificity than steroids
• Note: No detailed trial data provided in discussion, but recognized for its targeted, steroid-sparing profile

Tapinarof (Vtama)

• Class: Aryl hydrocarbon receptor agonist
• Indication: Approved for patients ≥2 years
• Dosing: Once-daily cream
• Note: Not extensively discussed but recognized as a novel immunomodulator with additional utility in psoriasis

Additional Clinical Considerations

• Use of Mupirocin:
• Frequently coprescribed during initial evaluation of atopic dermatitis, particularly in cases with signs of impetiginization (oozing, crusting)
• Important clarification: Mupirocin treats secondary bacterial infection, not the underlying dermatitis
• Reinforces the role of microbial dysbiosis and Staphylococcus aureus overgrowth in disease flares

Comparative Summary

• Efficacy: Roflumilast demonstrates slightly higher efficacy and tolerability than crisaborole, possibly due to its significantly stronger PDE4 inhibition (25-300x)
• Tolerability: Roflumilast’s elegant formulation contributes to reduced irritation compared to crisaborole
• Convenience: Roflumilast’s once-daily regimen is favorable for patient adherence
• Steroid-Sparing Role: All agents provide meaningful alternatives to corticosteroids, particularly in sensitive areas or for long-term maintenance