What is the role of Upadacitinib (Janus kinase inhibitor) in the treatment of moderate to severe psoriasis?

Upadacitinib for Moderate to Severe Psoriasis

Primary Recommendation

Upadacitinib is not FDA-approved for psoriasis and should not be used as first-line therapy; however, it may be considered off-label in select cases of moderate-to-severe psoriasis refractory to approved biologics, particularly when psoriatic arthritis is also present. 1

Current Regulatory Status and Evidence Base

• Upadacitinib (a selective JAK1 inhibitor) is not FDA-approved for plaque psoriasis and remains an off-label use 1
• The drug is FDA-approved for psoriatic arthritis (PsA), where it demonstrated significant efficacy with 52.3% of patients achieving PASI75 at one year in phase 3 trials 2, 3
• No phase 3 clinical trials have evaluated upadacitinib specifically for plaque psoriasis without arthritis 2
• Tofacitinib (another JAK inhibitor) showed PASI75 rates of only 43% at 12 weeks in MTX-inadequate responders and 21% in TNF-inadequate responders—numerically lower than IL-12/23 or IL-17 inhibitors 1

Approved First-Line Options for Psoriasis

The following biologics should be prioritized before considering upadacitinib: 1

• TNF-α inhibitors (infliximab, adalimumab, etanercept): Well-established efficacy with infliximab achieving 79% PASI75 at week 10 1
• IL-12/IL-23 inhibitors (ustekinumab): PASI75 rates of ~70% 1
• IL-23 inhibitors (guselkumab, risankizumab, mirikizumab): PASI75 rates of ~80% 1
• IL-17 inhibitors: PASI75 rates of 89% 1

Clinical Scenarios Where Upadacitinib May Be Considered

Scenario 1: Psoriatic Arthritis with Skin Involvement

• Upadacitinib 15 mg once daily is the preferred dose for PsA with concomitant skin disease 3, 4
• At week 12,56.9% achieved ACR20 response with 15 mg dose 3
• At week 24,25.1% achieved minimal disease activity with 15 mg dose 3
• Skin improvements maintained through 56 weeks of treatment 4

Scenario 2: Overlapping Psoriasis and Atopic Dermatitis

• Case series demonstrated complete remission in patients with concomitant psoriasis and atopic dermatitis using upadacitinib 15-30 mg 2
• This represents a unique clinical scenario where no single biologic is approved for both conditions 2

Scenario 3: Biologic-Refractory Psoriasis

• Consider only after documented failure of multiple approved biologics (TNF inhibitors, IL-12/23 inhibitors, IL-17 inhibitors) 1
• The SELECT-PsA 2 trial specifically enrolled patients with inadequate response or intolerance to at least one biologic DMARD 3, 4

Dosing and Administration

• Standard dose: 15 mg orally once daily 3, 4, 5
• Higher dose: 30 mg once daily may provide greater efficacy but with increased adverse effects 1, 3
• The 30 mg dose showed 63.8% ACR20 response versus 56.9% with 15 mg, but serious infection rates were higher (2.8% vs 0.5%) 3
• Can be used with or without methotrexate (combination showed similar efficacy to monotherapy) 5

Mandatory Pre-Treatment Screening

Before initiating upadacitinib, complete the following: 1, 6

• Tuberculosis screening: PPD, QuantiFERON-Gold, or T-Spot 1
• Hepatitis B and C serologies: HBsAg, anti-HBs Ab, anti-HBc Ab, HCV antibody 1
• Complete blood count with differential: Do not initiate if lymphocytes <500 cells/mm³, ANC <1000 cells/mm³, or hemoglobin <9 g/dL 1
• Liver and renal function tests 1
• Lipid panel 1
• Herpes zoster vaccination (Shingrix): Should be completed before starting therapy due to increased HZ risk with JAK inhibitors 1, 6

Critical Safety Considerations

FDA Black Box Warnings for JAK Inhibitors

The FDA has applied class warnings for all JAK inhibitors based on tofacitinib data in rheumatoid arthritis patients ≥50 years with cardiovascular risk factors: 7

• Increased risk of serious heart-related events
• Increased risk of cancer
• Increased risk of blood clots
• Increased risk of death

Specific Adverse Events with Upadacitinib

• Herpes zoster: Occurs more frequently with 30 mg versus 15 mg dose; most cases non-serious 4
• Serious infections: Exposure-adjusted rate of 2.6 events/100 patient-years with 15 mg and 6.1 events/100 patient-years with 30 mg 4
• Creatine kinase elevation: Monitor regularly 5
• Lymphopenia: Hold therapy if lymphocyte count <500 cells/mm³ confirmed on repeat testing 1
• Neutropenia: Hold therapy if ANC <500 cells/mm³ confirmed on repeat testing 1

Ongoing Monitoring Requirements

Monitor the following parameters regularly: 1

• CBC with differential every 3 months
• Liver function tests every 3 months
• Renal function tests every 3 months
• Lipid profile every 3 months
• Screen for infections at each visit
• Annual tuberculosis screening in high-risk patients 1

Contraindications and Drug Interactions

Do not use upadacitinib in the following situations: 1

• Active serious infection
• Severe hepatic impairment
• Combination with potent immunosuppressants (azathioprine, cyclosporine)
• Combination with biologics used for psoriasis
• Pregnancy or breastfeeding

Dose reduction required: 1

• Moderate to severe renal impairment: 5 mg once daily
• Moderate hepatic impairment: 5 mg once daily
• Concomitant potent CYP3A4 inhibitors (ketoconazole): 5 mg once daily
• Concomitant moderate CYP3A4 + potent CYP2C19 inhibitors (fluconazole): 5 mg once daily

Common Pitfalls to Avoid

1. Do not use upadacitinib as first-line therapy for psoriasis when FDA-approved biologics have not been tried 1
2. Do not administer live vaccines (including Zostavax) to patients on upadacitinib; only Shingrix (recombinant vaccine) is appropriate 1, 6
3. Do not combine with methotrexate solely for enhanced efficacy, as combination therapy showed similar efficacy to monotherapy in PsA trials 5
4. Do not ignore the higher infection risk with 30 mg dosing—reserve this dose only when 15 mg is inadequate 3, 4
5. Do not initiate therapy without completing Shingrix vaccination series when possible, as JAK inhibitors significantly increase herpes zoster risk 1, 6

Algorithm for Clinical Decision-Making

Step 1: Confirm diagnosis of moderate-to-severe psoriasis with inadequate response to topical therapies 1

Step 2: Trial FDA-approved biologics in the following order based on efficacy data:

• IL-17 inhibitors (highest PASI75 rates ~89%) 1
• IL-23 inhibitors (PASI75 rates ~80%) 1
• TNF-α inhibitors (PASI75 rates 70-79%) 1
• IL-12/23 inhibitors (PASI75 rates ~70%) 1

Step 3: If patient has concomitant psoriatic arthritis with inadequate response to ≥1 biologic, consider upadacitinib 15 mg once daily 3, 4

Step 4: If patient has overlapping psoriasis and atopic dermatitis refractory to standard therapies, consider upadacitinib 15-30 mg once daily 2

Step 5: Complete mandatory pre-treatment screening and Shingrix vaccination 1, 6

Step 6: Initiate upadacitinib 15 mg once daily; escalate to 30 mg only if inadequate response and patient can tolerate higher infection risk 3, 4

Step 7: Assess response at 12 weeks; continue if achieving meaningful improvement in joint and skin symptoms 3