What is the role of Upadacitinib (Janus kinase inhibitor) in treating inflammatory skin conditions, such as moderate to severe psoriasis or atopic dermatitis, in adult patients with inadequate response to conventional therapies?

Upadacitinib in Dermatology

Upadacitinib is a highly effective JAK1 inhibitor strongly recommended for moderate-to-severe atopic dermatitis in adults who have failed conventional systemic therapies, with the 30 mg daily dose demonstrating superior efficacy compared to all other available treatments including dupilumab. 1

Primary Indication: Atopic Dermatitis

Positioning in Treatment Algorithm

• Upadacitinib is reserved for patients who have failed conventional systemic treatments, not as first-line therapy 1
• The American Academy of Dermatology provides a strong recommendation with moderate certainty evidence for its use in moderate-to-severe atopic dermatitis 1

Dosing Strategy

• Standard dosing is 15 mg or 30 mg once daily orally 1
• The 30 mg daily dose demonstrates the highest efficacy at reducing EASI scores and is superior to dupilumab in head-to-head trials 1, 2
• Initiate with 30 mg daily for severe disease, then decrease to 15 mg once control is achieved 1
• A clear dose-response relationship exists, with the 30 mg dose showing greatest clinical benefit 3

Efficacy Data

• Network meta-analysis confirms upadacitinib 30 mg demonstrates the highest efficacy among all currently available treatments for atopic dermatitis 1
• Upadacitinib demonstrates high efficacy with rapid onset of action 1
• At week 16, the 30 mg dose achieved 74% mean improvement in EASI scores versus 23% for placebo (P<0.001) 3
• Efficacy is consistent across all patient subgroups regardless of age, sex, race, BMI, AD severity, body surface area involvement, history of atopic comorbidities, or previous systemic therapy exposure 4

Emerging Role in Psoriasis

Current Evidence Status

• Upadacitinib is NOT currently approved for plaque psoriasis, and no clinical trials are evaluating its efficacy in this indication 5
• Limited data exists: In psoriatic arthritis trials, 52.3% of patients achieved PASI75 after one year with 15 mg daily 5
• Case series report complete remission in patients with concomitant psoriasis and atopic dermatitis treated with upadacitinib 15-30 mg 5
• This represents off-label use and should only be considered when both conditions coexist and standard therapies have failed 5

Contrast with Established Psoriasis Biologics

The provided guidelines extensively cover ustekinumab (IL-12/IL-23 antagonist) for psoriasis with Grade A recommendations, achieving PASI75 rates of 67-76% at week 12 6. For isolated moderate-to-severe plaque psoriasis, established biologics remain the evidence-based standard.

Pre-Treatment Requirements

Mandatory Screening

• Test for latent tuberculosis and treat if positive before initiating therapy 1
• Ensure all needed live vaccines are administered before treatment initiation 1
• Herpes zoster vaccination before treatment is critical to reduce infection risk 1
• Baseline laboratory testing: complete blood count with differential, liver enzymes, renal function, and lipid profile 2
• Test for viral hepatitis B and C 2

Safety Profile and Monitoring

Comparative Safety Advantages

• Unlike dupilumab, conjunctivitis is not a prominent adverse event with upadacitinib 1
• Conjunctivitis is less common with upadacitinib compared to dupilumab 1

Common Adverse Events

• Acne is the most frequently reported adverse event (13.3 events per 100 patient-years for 15 mg; 20.2 for 30 mg) 7
• Nasopharyngitis, headache, creatine phosphokinase elevation, and anemia occur with moderate frequency 7
• Treatment-emergent adverse events are more frequent with 30 mg (311.9 per 100 PY) versus 15 mg (274.6 per 100 PY) 7
• Serious adverse event rates are similar between doses (7.1-7.7 events per 100 PY) 7

Critical Safety Warnings

• FDA has applied class-wide black box warnings for JAK inhibitors based on increased risk of major adverse cardiovascular events, venous thromboembolism, malignancies, and death in patients ≥50 years with cardiovascular risk factors 8, 2
• Exercise particular caution in patients ≥50 years with cardiovascular risk factors 1
• Patients ≥65 years with cardiovascular risk factors should avoid upadacitinib unless no alternatives exist 2
• Current or previous long-term smokers represent the highest-risk population 2
• Adjudicated major adverse cardiovascular event and venous thromboembolic event rates were ≤0.1 events per 100 PY in atopic dermatitis trials 7
• Malignancy rates were within the expected range for the general population 7

Contraindications and Drug Interactions

Absolute Contraindications

• Do not use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants 1
• Severe hepatic impairment (Child-Pugh C) 2
• Active serious infections 8

Dose Modifications

• For severe renal impairment (CrCl <30 mL/min), maximum dose is 15 mg daily 2
• Dose reduction necessary with strong CYP3A4 inhibitors 8
• Dose increase may be required with rifampin or other strong CYP3A4 inducers 8
• No dose adjustment required for mild-to-moderate renal impairment 8

Clinical Pearls and Pitfalls

Key Practice Points

• Do not use the 30 mg dose for rheumatoid arthritis—this is not the approved dose and carries increased safety risks 8
• The 30 mg dose is specifically appropriate for severe atopic dermatitis, then reduced to 15 mg for maintenance 1
• Upadacitinib was well tolerated by both adults and adolescents in trials with approximately 1 year of exposure 7
• Serious infection rates are similar across treatment groups and comparable to placebo 7

Risk Stratification Algorithm

For patients ≥50 years, assess:

1. Age ≥65 years + any cardiovascular risk factor = avoid unless no alternatives 2
2. Current or past smoking + cardiac disease = highest-risk population, carefully evaluate alternatives 2
3. History of VTE, cardiovascular disease, or cancer = enhanced monitoring required 2
4. If TNF inhibitors remain viable options, use those first in high-risk patients 2