Other Topical Options to Treat Atopic Dermatitis (AD): Topical JAK Inhibitors and AhR Agonists
Topical JAK Inhibitors
Mechanism of Action
- Inhibit Janus kinase signaling pathway, blocking cytokine-mediated inflammatory cascades
- Target specific JAK subtypes (JAK1, JAK2, JAK3, TYK2) involved in AD pathogenesis
- Interrupt IL-4, IL-13, and IL-31 signaling critical to itch and inflammation in AD
Clinical Evidence
- Ruxolitinib 1.5% cream (Opzelura): FDA-approved for mild-to-moderate AD in non-immunocompromised patients ≥12 years
- Delgocitinib ointment: approved in Japan, demonstrates significant efficacy in moderate-to-severe AD
- Rapid improvement in pruritus (often within 12-24 hours)
- Superior efficacy to vehicle in EASI-75 achievement and itch reduction
Safety Considerations
- Local application site reactions generally mild
- Theoretical risk of systemic absorption with potential for:
- Immunosuppression
- Laboratory abnormalities (cytopenias, lipid alterations)
- Increased infection risk
- Boxed warning regarding serious infections, malignancy, and thrombosis
- Long-term safety data still accumulating
Practical Use
- Apply twice daily to affected areas (≤20% BSA for ruxolitinib)
- Not recommended for immunocompromised patients
- Avoid use with biologic therapies or other immunosuppressants
- Consider discontinuation with signs of serious infection
AhR (Aryl Hydrocarbon Receptor) Agonists
Mechanism of Action
- Activate AhR, a ligand-dependent transcription factor
- Modulate skin barrier function and immune response
- Reduce Th2 and Th17 inflammatory pathways
- Promote antimicrobial peptide production
- Support skin microbiome diversity
Clinical Evidence
- Tapinarof 1% cream: promising results in phase 2 trials for AD
- Demonstrated improvement in EASI scores and pruritus
- Effect on transepidermal water loss (TEWL) and barrier function
- Potential for extended remission after treatment discontinuation
Safety Profile
- Generally well-tolerated with favorable safety data
- Main adverse effects include folliculitis and contact dermatitis
- No evidence of immunosuppression
- No significant systemic absorption concerns
- No restrictions on treatment duration or body surface area
Clinical Applications
- Once-daily application
- Potential for maintenance therapy after acute flare control
- May be suitable for patients with recurrent infections
- No rebound effect observed upon discontinuation
Comparative Considerations
- Topical JAK inhibitors show superior efficacy to TCIs and possibly mid-potency TCS
- AhR agonists may offer unique barrier restoration benefits beyond anti-inflammation
- JAKs provide faster itch relief than PDE4 inhibitors
- Cost and access remain significant barriers for newer agents
- Consider specific phenotypic features (barrier dysfunction vs. inflammation predominance)
Future Directions
- Combination regimens with established therapies
- Personalized therapy based on AD endotypes
- Development of more selective JAK inhibitors to improve safety profiles
- Expanded age range indications following additional pediatric studies