What is the role of anti-JAK (Janus kinase) medications, such as tofacitinib (Xeljanz) or baricitinib (Olumiant), in the treatment of skin lesions?

Role of JAK Inhibitors in Skin Lesions

JAK inhibitors are highly effective systemic therapies for moderate-to-severe atopic dermatitis and show efficacy in psoriasis, alopecia areata, and vitiligo, with upadacitinib and abrocitinib demonstrating superior efficacy to dupilumab in head-to-head trials for atopic dermatitis. 1

Primary Indications and Efficacy

Atopic Dermatitis (Strongest Evidence)

• Upadacitinib (15 mg and 30 mg daily) and abrocitinib (200 mg daily) demonstrate the highest efficacy at reducing EASI scores up to 16 weeks among all currently available treatments and were superior to dupilumab in direct comparison trials. 1
• Baricitinib (preferentially inhibits JAK1/2) is approved in Europe for moderate-to-severe atopic dermatitis and shows efficacy, though network meta-analysis suggests it is less efficacious than upadacitinib and abrocitinib. 1
• JAK inhibitors offer rapid reduction in disease burden and itch, with the convenience of oral administration and flexible dosing. 1
• Clinical indications vary by region: some countries endorse JAK inhibitors as first-line treatment in the absence of risk factors, while others limit use to second-line after inadequate response to conventional immunosuppressants or biologics. 1

Psoriasis

• Tofacitinib (5 mg and 10 mg twice daily) showed superiority over placebo for all efficacy endpoints at week 16, with maintained response for 52 weeks. 1
• However, PASI response with tofacitinib appears numerically lower than IL-12/23 or IL-17 inhibitors (PASI75: 43% with tofacitinib 10 mg BID in MTX-inadequate responders vs. ~70-89% with biologics). 1
• Tofacitinib 10 mg twice daily demonstrated greater efficacy (PASI75 at 12 weeks: 43% in MTX-inadequate responders and 21% in TNF inhibitor-inadequate responders) than 5 mg twice daily. 1
• Topical tofacitinib showed significant clinical improvement over placebo in mild-to-moderate psoriasis after 4 weeks. 1
• Despite efficacy data, no JAK inhibitor is FDA-approved for psoriasis except in individual countries like Russia (tofacitinib). 1

Other Dermatologic Conditions

• Baricitinib shows promise in alopecia areata, vitiligo, and other inflammatory dermatoses. 2
• JAK inhibitors demonstrate efficacy across multiple inflammatory skin conditions due to inhibition of multiple pro-inflammatory cytokine pathways simultaneously. 3

Dosing and Administration

FDA-Approved Dosing for Atopic Dermatitis

• Upadacitinib: 15 mg or 30 mg once daily 4
• Abrocitinib: 100 mg or 200 mg once daily 4
• Baricitinib: Not FDA-approved for atopic dermatitis in the US (approved in Europe). 1

Dose Adjustments

• Renal impairment: Baricitinib and abrocitinib are not recommended with severe renal impairment (eGFR <30 mL/min); dose adjustment needed for mild-to-moderate impairment. 1
• Upadacitinib: Maximum 15 mg daily for severe renal impairment (creatinine clearance <30 mL/min); no adjustment for mild-to-moderate impairment. 1
• Hepatic impairment: JAK inhibitors should not be used in severe hepatic disease (Child-Pugh C); no adjustment needed for mild-to-moderate (Child-Pugh A/B) impairment. 1

Pre-Treatment Requirements

Mandatory Screening

• Complete blood count with differential, liver enzymes, renal function tests, lipid panel 4
• Tuberculosis screening per national guidelines 4
• Hepatitis B and C testing 4
• HIV testing in high-risk populations 4
• Pregnancy testing 4

Vaccination Recommendations

• Recombinant zoster vaccine (Shingrix) for adults ≥50 years or immunocompromised adults ≥19 years, ideally completed 3-4 weeks before JAK inhibitor initiation 1
• Inactivated pneumococcal and influenza vaccines should be considered. 1
• Live vaccines (including live zoster vaccine if recombinant unavailable) must be administered at least 3-4 weeks before initiating JAK inhibitors. 1
• Avoid live vaccines once JAK inhibitor therapy has started. 4

Monitoring Requirements

Laboratory Monitoring

• Abrocitinib: Check CBC with differential and liver enzymes at baseline and 4 weeks after initiation or dose escalation; lipids at 4 weeks 1, 4
• Upadacitinib: Check CBC with differential and liver enzymes at baseline; lipids at 12 weeks 1, 4
• The optimal frequency of ongoing lab monitoring for patients continuously using JAK inhibitors remains unclear. 1

Clinical Monitoring

• Monitor for infections, particularly herpes zoster, which occurs more frequently with JAK inhibitors 4
• Monitor for thrombotic events, especially in patients with cardiovascular risk factors 4

Safety Considerations and Boxed Warnings

Cardiovascular and Thrombotic Risk

• FDA boxed warnings include increased risk of major adverse cardiovascular events, venous thromboembolism (VTE), cancer, and death based on tofacitinib data in rheumatoid arthritis patients ≥50 years with cardiovascular risk factors. 1
• In tofacitinib trials (RA patients on methotrexate), VTE incidence was dose-dependent: 0.33 events/100 patient-years (5 mg BID) vs. 0.70 events/100 patient-years (10 mg BID) vs. 0.20 events/100 patient-years (TNF inhibitor group). 1
• However, atopic dermatitis cohort studies failed to show a link between AD and VTE risk, with overall low incidence of VTEs in AD populations. 1
• In upadacitinib trials, VTE rate was <0.1/100 patient-years, occurring only in patients with VTE history and risk factors. 1

Infection Risk

• Increased risk of serious and opportunistic infections, including herpes zoster 1
• Rates of safety events (except herpes zoster) were similar to other systemic psoriasis therapies in tofacitinib trials. 1
• JAK inhibitors should be avoided during active serious infections. 4

Malignancy Risk

• All JAK inhibitors carry boxed warnings for increased malignancy risk. 1
• Tofacitinib in RA patients showed hazard ratio of 1.48 (95% CI 1.04-2.09) for cancer vs. TNF inhibitors, with lung cancer most common and higher incidence in patients ≥65 years. 1
• In atopic dermatitis trials, baricitinib showed lower malignancy incidence rate (0.22/100 patient-years) compared to placebo (0.66/100 patient-years). 1
• Most malignancies occurred in patients aged ≥53 years. 1

Contraindications

• Severe active or chronic infections (including TB and opportunistic infections) 4
• Current malignancies 4
• Severe hepatic disease (Child-Pugh C) or severe renal disease 4
• Pregnancy and lactation 4

Clinical Decision-Making Algorithm

When to Use JAK Inhibitors for Skin Lesions

1. First-line consideration (where approved): Moderate-to-severe atopic dermatitis in patients without cardiovascular risk factors, age <50 years, no malignancy history, and no active infections 1
2. Second-line consideration: After inadequate response to conventional immunosuppressants or biologics in regions with restrictive guidelines 1
3. Alternative consideration: Psoriasis patients inadequate responders to conventional therapy, recognizing lower efficacy than IL-17/IL-23 inhibitors 1

Risk Stratification

• Avoid as first-line in patients: Age ≥65 years, current/long-term smokers, cardiovascular disease history, malignancy history, or VTE risk factors 1, 4
• Use with extreme caution: Patients with multiple cardiovascular risk factors, considering the RA trial safety signals despite different patient populations 1

Choosing Between JAK Inhibitors

• For maximum efficacy in atopic dermatitis: Upadacitinib 30 mg daily or abrocitinib 200 mg daily (highest EASI score reduction) 1
• No direct evidence demonstrates superiority of one JAK inhibitor over another regarding safety 4
• Consider renal function when choosing between agents due to different dose adjustment requirements 1