What is the recommended treatment approach for a patient with moderate to severe atopic dermatitis, possibly with a history of other atopic diseases such as asthma or allergic rhinitis, using Upadacitinib (Janus kinase inhibitor)?

Upadacitinib in Atopic Dermatitis

Upadacitinib is strongly recommended for adults with moderate-to-severe atopic dermatitis who have failed other systemic therapies (including biologics) or when those therapies are inadvisable, with the 30 mg daily dose providing superior efficacy to all other available treatments including dupilumab. 1, 2

Positioning in Treatment Algorithm

• Upadacitinib is FDA-approved specifically for patients who have failed other systemic therapies (pills or injections, including biologics) or when use of those therapies is inadvisable—it is not first-line systemic therapy. 1, 3
• The American Academy of Dermatology provides a strong recommendation with moderate certainty evidence for upadacitinib in moderate-to-severe AD. 1
• Network meta-analysis confirms upadacitinib 30 mg demonstrates the highest efficacy at reducing EASI scores among all currently available treatments for atopic dermatitis. 1, 2
• In head-to-head trials, upadacitinib 30 mg was superior to dupilumab for disease control. 1, 2

Dosing Strategy

• Start with 30 mg once daily orally for severe disease to achieve rapid control, then decrease to 15 mg once daily for maintenance once control is achieved. 1, 2
• The 15 mg dose is also effective but demonstrates lower efficacy than 30 mg. 1, 2
• Patients should be maintained on the lowest effective dose, as adverse events occur in a dose-dependent manner. 1
• For severe renal impairment (creatinine clearance <30 mL/min), the maximum dose is 15 mg daily. 1, 2

Pre-Treatment Requirements

Before initiating upadacitinib, complete the following mandatory screening: 1, 2

• Tuberculosis screening (risk assessment, chest X-ray, interferon-γ release assay or Mantoux test) and treat latent TB before starting therapy. 1, 2
• Herpes zoster vaccination (Shingrix preferred—two doses separated by 2-6 months) is critical to reduce infection risk; if unavailable, give live zoster vaccine at least 3-4 weeks before starting. 1
• Complete all needed live vaccines at least 3-4 weeks before initiating treatment. 1, 2
• Baseline laboratory testing: complete blood count with differential, liver enzymes, renal function (creatinine/eGFR), and lipid profile. 1, 2
• Viral hepatitis B and C testing (HBsAg, HBsAb, HBcAb, HCV antibody). 1, 2
• Pregnancy testing in patients of childbearing potential. 1

Laboratory Monitoring During Treatment

Follow this monitoring schedule: 1

• At 4-12 weeks after initiation: CBC with differential, complete metabolic panel (liver enzymes, creatinine), lipid panel (HDL, LDL, triglycerides). 1
• Every 3-6 months ongoing: CBC with differential, complete metabolic panel. 1
• Annually: Lipid panel. 1

Treatment interruption thresholds: 1

• Hemoglobin <8 g/dL. 1
• Absolute lymphocyte count <0.5 × 10⁹ cells/L. 1
• Absolute neutrophil count <1 × 10⁹ cells/L. 1
• Platelet count <50 × 10⁹ cells/L (particularly with abrocitinib, but monitor for all JAK inhibitors). 1
• Persistently elevated liver enzymes suggesting drug-induced liver injury—interrupt treatment and refer to gastroenterology. 1

Critical Safety Considerations and Contraindications

FDA black box warnings apply to all JAK inhibitors based on data from older patients with rheumatoid arthritis: 1, 2, 3

• Increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignancies, and death in patients ≥50 years with cardiovascular risk factors. 1, 2
• Patients ≥65 years with cardiovascular risk factors should avoid upadacitinib unless no alternatives exist. 2
• Exercise particular caution in patients ≥50 years—assess age, cardiovascular risk factors, smoking history, and history of thrombosis before prescribing. 1, 2

Absolute contraindications: 1, 2, 3

• Active serious infections. 2, 3
• Severe hepatic impairment (Child-Pugh C). 1, 2
• Pregnancy and lactation (limited human data; animal studies show fetal harm). 1

Do not combine with: 1, 2, 3

• Other JAK inhibitors. 1, 2, 3
• Biologic immunomodulators (including dupilumab, tralokinumab). 1, 2, 3
• Other immunosuppressants (azathioprine, cyclosporine, methotrexate). 1, 2, 3

Efficacy Outcomes

Upadacitinib demonstrates rapid and sustained efficacy through at least 140 weeks: 4, 5, 6

• At week 16, EASI 75 is achieved by approximately 70-80% of patients on 15 mg and 80-90% on 30 mg. 4, 6
• At week 16, vIGA-AD 0/1 (clear/almost clear) is achieved by approximately 50-60% on 15 mg and 60-70% on 30 mg. 4
• Over 60% of patients achieve ≥4-point improvement in itch (WP-NRS) at week 16, with sustained response through 140 weeks. 4
• EASI 90 and EASI 100 (complete clearance) are achievable optimal outcomes sustained long-term. 4
• Efficacy is consistent across patient subgroups regardless of age, sex, race, BMI, AD severity, body surface area involvement, history of atopic comorbidities/asthma, or previous systemic therapy exposure. 6

Common Adverse Events and Management

The most frequently reported adverse events are: 1, 3, 7

• Acne/acneiform eruption (dose-dependent; up to 20% with 30 mg)—treat with standard acne therapies; generally responds well. 1, 3, 7, 8
• Elevated creatine phosphokinase (CPK)—monitor but usually clinically insignificant. 8
• Dyslipidemia (increased total cholesterol, LDL, HDL, triglycerides)—measure lipids and treat according to national guidelines. 1, 8
• Nausea (7-20% in AD trials, most common in first week, median duration 15 days, more frequent in women)—usually self-limited. 1
• Headache (up to 10%)—generally mild and brief (median duration <1 day). 1
• Upper respiratory tract infections—common but generally mild. 3, 7

Herpes virus infections: 1, 3, 7

• Herpes zoster rates are <3% in AD trials but higher than with dupilumab—hence the critical importance of pre-treatment vaccination. 1
• Eczema herpeticum can occur but rates are low. 1
• Herpes simplex infections occur but are generally manageable. 1, 3

Unlike dupilumab, conjunctivitis is NOT a prominent adverse event with upadacitinib. 1, 2

Special Populations

Adolescents (12 years and older): 3, 4, 7

• Upadacitinib is FDA-approved for adolescents ≥12 years with moderate-to-severe AD. 3
• Safety and efficacy profiles in adolescents are similar to adults. 4, 7
• Nausea may be more frequent in adolescents. 1

Renal impairment: 1

• No dose adjustment needed for mild-to-moderate renal impairment. 1
• Maximum dose 15 mg daily for severe renal impairment (CrCl <30 mL/min). 1, 2
• Not recommended for patients with eGFR <30 mL/min in some guidelines. 1

Hepatic impairment: 1

• No dose adjustment needed for mild-to-moderate hepatic impairment (Child-Pugh A/B). 1
• Contraindicated in severe hepatic impairment (Child-Pugh C). 1, 2

Critical Pitfalls to Avoid

• Do NOT use the 30 mg dose for rheumatoid arthritis—this is not the approved dose for RA and carries increased safety risks; the 30 mg dose is specifically appropriate for severe atopic dermatitis. 2
• Do NOT use upadacitinib as first-line systemic therapy—FDA approval requires failure of other systemic therapies or when they are inadvisable. 1, 2, 3
• Do NOT skip pre-treatment TB screening and herpes zoster vaccination—these are critical safety measures. 1, 2
• Do NOT combine with biologics or other immunosuppressants—this increases infection risk without added benefit. 1, 2, 3
• Prior cyclosporine use is associated with poorer outcomes—consider this when selecting patients. 8
• Head and neck involvement may predict poorer response. 8
• Higher baseline EASI score is a positive predictor of response. 8

Long-Term Use Considerations

• Safety and efficacy data extend to 140 weeks (nearly 3 years) with sustained disease control and no new safety signals. 4
• Malignancy rates in AD trials are within the expected range for the general population. 7
• Adjudicated MACE and VTE rates are ≤0.1 events per 100 patient-years in AD populations. 7
• The safety concerns from tofacitinib (a pan-JAK inhibitor) in elderly RA patients should not be directly extrapolated to upadacitinib (a selective JAK1 inhibitor) in younger AD populations, though caution remains warranted in older patients with cardiovascular risk factors. 1