What are the treatment options for patients with moderate to severe dermatological conditions, such as atopic dermatitis, considering the use of Janus Kinase (JAK) inhibitors like upadacitinib (Rinvoq) or abrocitinib?

Treatment Options for Moderate to Severe Atopic Dermatitis with JAK Inhibitors

First-Line Systemic Therapy Recommendation

Dupilumab should be the first-line systemic therapy for moderate-to-severe atopic dermatitis, with JAK inhibitors (upadacitinib or abrocitinib) reserved for patients who have failed other systemic therapies including biologics, or when biologics are inadvisable. 1, 2, 3

The American Academy of Dermatology 2024 guidelines explicitly state that upadacitinib and abrocitinib are approved for moderate-to-severe AD patients who have failed other systemic therapies (immunosuppressants, corticosteroids, antimetabolites, and injectable biologics) or when they are inadvisable—these medications are not considered first-line systemic therapy in most circumstances. 1

When to Choose JAK Inhibitors Over Dupilumab

Select upadacitinib or abrocitinib as preferred agents when:

• Rapid onset of action is critical: JAK inhibitors demonstrate efficacy within 1-2 weeks versus slower onset with dupilumab 1
• Maximum efficacy is needed: High-dose upadacitinib 30 mg daily and abrocitinib 200 mg daily demonstrate the highest efficacy at reducing EASI scores among all available treatments and were superior to dupilumab in head-to-head trials 1, 2
• Severe ocular surface disease exists: Patients who cannot tolerate the 6-26% risk of conjunctivitis with dupilumab should receive JAK inhibitors instead 2
• Dupilumab has failed or is contraindicated 1, 3

JAK Inhibitor Selection and Dosing

For adults with moderate-to-severe AD:

• Upadacitinib: 15 mg or 30 mg orally once daily 1
• Abrocitinib: 100 mg or 200 mg orally once daily 1

The higher doses (upadacitinib 30 mg, abrocitinib 200 mg) achieve superior efficacy with EASI 75 rates of 85-90% at week 140, compared to lower doses. 1, 4

Mandatory Pre-Treatment Screening

Before initiating JAK inhibitors, complete the following:

• Tuberculosis screening: Test for latent TB and treat if positive before starting therapy 1
• Viral hepatitis screening: Check hepatitis B and C status 1
• Pregnancy testing: Required at baseline for women of childbearing potential 1
• Baseline laboratories: Complete blood count with differential, liver enzymes, lipid panel 1
• Vaccination: Administer recombinant zoster vaccine (Shingrix) before initiating treatment, particularly for patients ≥50 years 1
• Complete all live vaccines before starting therapy 1

Laboratory Monitoring Protocol

For abrocitinib:

• CBC with differential and liver enzymes at 4 weeks post-initiation or dose escalation 1
• Lipids at 4 weeks post-initiation 1

For upadacitinib:

• CBC with differential and liver enzymes per routine management after baseline 1
• Lipids at 12 weeks post-initiation 1

Interrupt treatment if:

• Absolute lymphocyte count <500 cells/mm³ 3
• Absolute neutrophil count <1000 cells/mm³ 3
• Hemoglobin <8 g/dL 3

Critical Safety Considerations and Patient Selection

FDA boxed warnings apply to the entire JAK inhibitor class, including increased risk of:

• Serious infections (including tuberculosis and herpes zoster) 1, 3
• Mortality 3
• Malignancy (lymphomas, lung cancers) 1, 3
• Major adverse cardiovascular events (MACE) 1, 3
• Venous thromboembolism (VTE) and arterial thrombosis 1, 3

Exercise extreme caution or avoid JAK inhibitors in:

• Patients ≥50 years with cardiovascular risk factors: The safety signals derive from a tofacitinib trial in rheumatoid arthritis patients aged ≥50 years with ≥1 cardiovascular risk factor, showing increased MACE and malignancies 1
• Current or long-term smokers: Higher malignancy risk, particularly lung cancer 5
• Patients with VTE risk factors: History of thrombosis, prolonged immobilization, malignancy, or inherited thrombophilia 1
• Active serious infections: Absolute contraindication 5
• Severe hepatic impairment: Contraindication 5
• Pregnancy or breastfeeding: Contraindication 5

For high-risk patients where JAK inhibitors are still selected, start with lower doses: abrocitinib 100 mg or upadacitinib 15 mg. 5

Important Contextual Nuances

The FDA warnings are based primarily on tofacitinib data in a substantially different population (rheumatoid arthritis patients aged ≥50 years with cardiovascular risk factors on concomitant methotrexate). 1 Upadacitinib and abrocitinib are more selective JAK-1 inhibitors compared to tofacitinib (JAK-1 and -3 inhibitor), and the baseline risk profile of AD patients differs substantially from this rheumatoid arthritis population. 1 However, serious adverse effects including death and thromboembolic events have occurred in AD clinical trials, warranting appropriate caution. 1

Alternative Systemic Therapies

If JAK inhibitors and dupilumab are both contraindicated or unavailable:

• Cyclosporine: Up to 3-5 mg/kg/day divided twice daily, most effective traditional immunosuppressant but limited to 1-year use 1
• Methotrexate: 10-25 mg weekly, less effective than cyclosporine 1
• Azathioprine: 3-5 mg/kg daily, similar efficacy to methotrexate 1
• Mycophenolate mofetil: 500 mg orally, least evidence among traditional agents 1

Avoid systemic corticosteroids: Conditional recommendation against use due to substantial risk of serious adverse events and rebound flares upon discontinuation. 2

Common Pitfalls to Avoid

• Do not use JAK inhibitors as first-line therapy unless biologics are contraindicated—this violates FDA approval and guideline recommendations 1, 2, 3
• Do not combine JAK inhibitors with other JAK inhibitors, biologics, or potent immunosuppressants (azathioprine, cyclosporine) 3
• Do not neglect herpes zoster prophylaxis: JAK inhibitors increase herpes zoster risk; vaccinate before treatment when feasible 1
• Do not ignore conjunctivitis with dupilumab: Most cases are self-limited and managed with artificial tears, but refer to ophthalmology if severe, persistent, or refractory 1