Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus, recurrent eczematous lesions, and a significant impact on quality of life. In recent years, Janus kinase (JAK) inhibitors have emerged as an important systemic treatment option for patients with moderate-to-severe atopic dermatitis. However, not all JAK inhibitors are the same. Differences in selectivity, efficacy, safety profiles, and real-world applicability make it essential for clinicians to understand how these agents compare and how to choose the most appropriate therapy for individual patients.

This CME activity explores the key distinctions among systemic JAK inhibitors used in atopic dermatitis and provides guidance on translating the latest clinical evidence into real-world treatment decisions.

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Understanding the JAK-STAT Pathway in Atopic Dermatitis

The JAK-STAT signaling pathway plays a central role in immune regulation and inflammatory responses. In atopic dermatitis, cytokines such as interleukin (IL)-4, IL-13, IL-31, and interferon-γ drive inflammation, skin barrier dysfunction, and pruritus. These cytokines signal through different JAK enzymes—primarily JAK1, JAK2, JAK3, and TYK2.

Systemic JAK inhibitors work by blocking one or more of these enzymes, thereby reducing downstream inflammatory signaling. However, the degree of selectivity for specific JAK enzymes varies among agents, which directly influences both therapeutic benefits and safety risks.

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Key Differences in Efficacy Among Systemic JAK Inhibitors

Clinical trials have demonstrated that systemic JAK inhibitors can provide rapid and meaningful improvements in atopic dermatitis, often with faster itch relief compared to some biologic therapies. However, efficacy is not uniform across agents.

• JAK1-selective inhibitors tend to show strong efficacy in reducing pruritus and skin inflammation, reflecting the central role of JAK1-mediated cytokines in AD pathophysiology.

• Less selective JAK inhibitors may offer broad immunomodulation but do not necessarily translate to superior clinical outcomes in atopic dermatitis.

Differences in trial endpoints—such as EASI-75, EASI-90, Investigator’s Global Assessment (IGA) response, and time to itch relief—highlight that some agents achieve higher response rates or faster symptom control. Understanding these nuances helps clinicians align treatment choice with patient priorities, such as rapid itch reduction or long-term disease control.

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Safety Profiles: Why Selectivity Matters

Safety considerations are critical when prescribing systemic JAK inhibitors. While all agents in this class share certain warnings, the risk profile can differ based on JAK selectivity, dosage, and patient characteristics.

Key safety considerations include:

• Infections: Herpes zoster and other opportunistic infections have been reported, with risk varying by agent and patient age.

• Laboratory abnormalities: Changes in lipid levels, liver enzymes, and blood counts may occur and require monitoring.

• Cardiovascular and thromboembolic risk: These risks appear to be influenced by patient-specific factors such as age, smoking status, and comorbidities, as well as by the degree of JAK inhibition beyond JAK1.

• Long-term safety: Ongoing real-world data and post-marketing surveillance continue to refine our understanding of long-term risk.

A more selective JAK1 inhibitor may reduce off-target effects associated with JAK2 or JAK3 inhibition, potentially improving the benefit–risk balance for certain patients.

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Applying Evidence to Real-World Treatment Decisions

Choosing the right systemic JAK inhibitor for atopic dermatitis requires an individualized approach. Clinicians should consider:

• Disease severity and symptom burden, particularly the impact of itch on sleep and daily functioning

• Patient age and comorbidities, including cardiovascular risk factors and history of infections

• Previous treatment response, including biologics and conventional systemic therapies

• Need for rapid symptom control versus long-term maintenance therapy

• Patient preferences, such as oral versus injectable treatments and monitoring requirements

Shared decision-making is essential. Discussing both the potential benefits and risks allows patients to make informed choices aligned with their treatment goals.

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Conclusion

Systemic JAK inhibitors have transformed the treatment landscape for moderate-to-severe atopic dermatitis, but they are not interchangeable. Differences in JAK selectivity lead to meaningful variations in efficacy, speed of response, and safety profiles. By understanding these distinctions and applying the latest clinical evidence, clinicians can make more precise, patient-centered treatment decisions.

As real-world data continue to emerge, ongoing education remains essential to optimize outcomes and ensure the safe, effective use of JAK inhibitors in atopic dermatitis.