What is the role of Upadacitinib (Janus kinase inhibitor) in treating moderate to severe atopic dermatitis?

Upadacitinib for Moderate to Severe Atopic Dermatitis

Upadacitinib is strongly recommended for adults with moderate to severe atopic dermatitis who have failed other systemic therapies (including biologics, oral immunosuppressants, or corticosteroids) or when those therapies are inadvisable. 1

FDA-Approved Indication and Positioning

• Upadacitinib is FDA-approved specifically for patients aged 12 years and older with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies are inadvisable 2
• This is not a first-line systemic therapy—it is reserved for patients who have failed conventional systemic treatments 1
• The American Academy of Dermatology gives upadacitinib a strong recommendation with moderate certainty evidence for this indication 1

Dosing and Administration

The recommended dosing is 15 mg or 30 mg once daily orally 1, 2:

• The 30 mg daily dose demonstrates the highest efficacy at reducing EASI scores and shows superior results compared to dupilumab in head-to-head trials 1
• The 15 mg dose provides a balance of efficacy with potentially fewer adverse events 3
• Start at the higher end of the dosing range (30 mg) for severe disease, then decrease once control is achieved 1

Efficacy Profile

Upadacitinib demonstrates very high efficacy with rapid onset of action 1:

• In clinical trials, the 30 mg dose achieved 74% mean improvement in EASI score at 16 weeks versus 23% for placebo 4
• Real-world data shows 85-90% of patients achieve EASI-75 by week 16-52 5, 6
• Importantly, upadacitinib remains effective even in patients who previously failed dupilumab and/or baricitinib treatment 7, 5
• Network meta-analysis confirms upadacitinib 30 mg demonstrates the highest efficacy among all currently available treatments for atopic dermatitis 1

Pre-Treatment Requirements

Before initiating upadacitinib, complete the following 1, 2:

• Test for latent tuberculosis (QuantiFERON or PPD) and treat if positive before starting therapy
• Screen for viral hepatitis (hepatitis B and C)
• Check baseline complete blood count with differential, liver enzymes, and lipid panel
• Pregnancy test in women of childbearing potential
• Administer recombinant zoster vaccine (non-live) before starting therapy, particularly in patients ≥50 years or those at increased risk for herpes zoster 1
• Ensure all other needed live vaccines are administered before treatment initiation 1

Laboratory Monitoring

Do not initiate or interrupt upadacitinib if 2:

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

Ongoing monitoring schedule 1, 2:

• Complete blood count with differential and liver enzymes: at baseline and per routine management after baseline
• Lipid panel: at 12 weeks after initiation
• Continue monitoring for tuberculosis during treatment, even if initial testing was negative 2

Safety Considerations and Black Box Warnings

The FDA has applied class-wide warnings for JAK inhibitors based on data from other JAK inhibitors in different populations 1, 2:

Serious risks include 2:

• Increased risk of serious infections (bacterial, fungal, viral, opportunistic) including tuberculosis
• Higher rate of all-cause mortality and sudden cardiovascular death (based on tofacitinib data in rheumatoid arthritis patients ≥50 years with cardiovascular risk factors)
• Malignancies, including lymphomas and lung cancers
• Major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke)
• Thrombosis (pulmonary embolism, deep vein thrombosis, arterial thrombosis)

However, these warnings are based on a different JAK inhibitor (tofacitinib) in a different population (rheumatoid arthritis patients ≥50 years with cardiovascular risk factors), which differs substantially from most atopic dermatitis patients 1

Common Adverse Events

In real-world and clinical trial data with approximately 1 year of follow-up 3:

• Acne/acneiform eruptions: 13-25% of patients 7, 6, 3
• Herpes simplex infections: 10-13% 7, 6
• Nausea: 8-13% 7, 6
• Upper respiratory tract infections: 8-10% 7, 6
• Conjunctivitis (less common than with dupilumab)

Most adverse events are well tolerated and do not lead to treatment discontinuation 6, 3

Discontinuation Rates

• Approximately 29% of patients discontinue upadacitinib due to ineffectiveness, adverse events, or both 7
• In real-world cohorts, 71% of patients continue treatment at median follow-up of 46.5 weeks 6
• Discontinuation due to adverse events alone occurs in approximately 5-6% of patients 3

Use in Patients Who Failed Dupilumab

Upadacitinib is highly effective in patients who previously failed dupilumab therapy 7, 5:

• Effectiveness is comparable between dupilumab-exposed and dupilumab-naïve patients 7, 5
• Real-world data shows 81% of patients treated with upadacitinib had previously failed other targeted therapies including dupilumab 6
• Previous biologic exposure does not affect response to upadacitinib treatment 5

Contraindications and Drug Interactions

Do not use upadacitinib in combination with 1, 2:

• Other JAK inhibitors
• Biologic immunomodulators (including dupilumab, tralokinumab)
• Other immunosuppressants (azathioprine, cyclosporine, methotrexate, mycophenolate)

Critical Clinical Pearls

• Upadacitinib provides rapid symptom relief—patients typically experience significant improvement in pruritus within the first 4 weeks 4, 6
• The higher 30 mg dose is more effective but associated with slightly higher rates of adverse events, particularly acne 1, 3
• Herpes zoster vaccination before treatment is critical to reduce infection risk 1
• Unlike dupilumab, conjunctivitis is not a prominent adverse event with upadacitinib 1
• Exercise particular caution in patients ≥50 years with cardiovascular risk factors due to class-wide safety signals, though these are based on data from different populations 1, 2