Scratching the Surface: A Deeper Dive Into Atopic Dermatitis - Episode 5
Other Topical Options to Treat Atopic Dermatitis (AD): Topical JAK Inhibitors and AhR Agonists
A panelist discusses how topical JAK inhibitors and AhR agonists represent emerging therapeutic approaches for atopic dermatitis that target specific inflammatory pathways to provide effective symptom relief with distinct mechanisms of action.
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
