What is the role of Tofacitinib (Janus kinase inhibitor) in the treatment of moderate to severe plaque psoriasis in adult patients who have failed or are intolerant to other systemic therapies, including those with a history of recurrent infections or malignancies?

Tofacitinib in Dermatology: Role in Moderate to Severe Plaque Psoriasis

Tofacitinib can be considered as an off-label treatment option for moderate to severe plaque psoriasis in adult patients who have failed or are intolerant to other systemic therapies, but it requires careful patient selection and heightened vigilance in those with history of recurrent infections or malignancies due to significant safety concerns. 1

FDA Approval Status and Clinical Context

• Tofacitinib is not currently FDA approved for psoriasis treatment, though it has demonstrated efficacy in multiple phase III clinical trials 1
• It is FDA approved for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis, providing established safety data from these indications 1
• The drug functions as an oral Janus kinase inhibitor targeting JAK1 and JAK3, interrupting inflammatory cytokine signaling pathways critical to psoriasis pathogenesis 1

Dosing Recommendations

The recommended off-label dosing for psoriasis is 5 mg orally twice daily, with 10 mg twice daily reserved for patients requiring greater efficacy despite accepting higher adverse event risks. 1

• Tofacitinib 10 mg twice daily demonstrates superior efficacy compared to 5 mg twice daily, achieving PASI 75 response rates of 63.6% vs 39.5% at week 12 2
• The 10 mg twice daily dose showed non-inferiority to etanercept 50 mg twice weekly in head-to-head comparison 2
• However, the 10 mg dose carries significantly higher risks of infection, cytopenia, and pulmonary embolism (five-fold increased risk compared to TNF inhibitors) 1, 3

Dose Adjustments for Special Populations

• Moderate to severe renal or hepatic impairment: Reduce to 5 mg once daily 1
• Severe hepatic impairment: Tofacitinib is not recommended 1
• Concurrent potent CYP3A4 inhibitors (ketoconazole) or combined moderate CYP3A4/potent CYP2C19 inhibitors (fluconazole): Reduce to 5 mg once daily 1

Critical Safety Considerations for High-Risk Patients

Patients with History of Recurrent Infections

Tofacitinib should be avoided during active serious infections and used with extreme caution in patients with recurrent infection history. 1

• Serious infection incidence rate is 1.16 per 100 patient-years over long-term follow-up 4
• Herpes zoster represents the most significant infection risk, occurring at substantially higher rates than with TNF inhibitors or in the general population 1, 3
• Zoster vaccination (Shingrix) should be administered before initiating tofacitinib therapy 1
• Common serious infections include cellulitis, urinary tract infection, pneumonia, and herpes zoster 3
• Tuberculosis screening is mandatory before initiation 5
• Live vaccines must be avoided during treatment 1

Patients with History of Malignancy

Tofacitinib carries FDA boxed warnings for malignancy risk and should be used with extreme caution or avoided in patients with prior malignancy history. 5

• Malignancy incidence rate is 0.67 per 100 patient-years 4
• Lung cancer and breast cancer are the most common non-hematologic malignancies reported 3
• Lymphoma has been documented, including Epstein-Barr virus-associated post-transplant lymphoproliferative disorder 3
• All JAK inhibitors carry FDA boxed warnings for malignancy based on the ORAL Surveillance trial data 5

Absolute Contraindications to Initiation

Do not initiate tofacitinib if: 1

• Lymphocyte count <500 cells/mm³
• Absolute neutrophil count (ANC) <1000 cells/mm³
• Hemoglobin <9 g/dL
• Active serious infection is present 1

Mandatory Monitoring Requirements

Baseline Screening

• Complete blood count with differential 1
• Comprehensive metabolic panel including liver and renal function 1
• Lipid profile 1
• Tuberculosis screening 5
• Hepatitis B and C screening 5
• Pregnancy test in women of childbearing potential 1

Ongoing Monitoring

Discontinue tofacitinib (at least temporarily) if: 1

• Lymphocyte count <500 cells/mm³ (confirmed by repeat testing)
• ANC <500 cells/mm³ (confirmed by repeat testing)
• For persistent ANC decreases to <1000 cells/mm³, hold until ANC ≥1000 cells/mm³
• Hemoglobin decreases by ≥2 g/dL or falls to <8.0 g/dL (confirmed by repeat testing)

Additional Safety Warnings

Cardiovascular and Thromboembolic Events

• Major adverse cardiovascular events occur at a rate of 0.26 per 100 patient-years 4
• Pulmonary embolism risk increases five-fold with the 10 mg twice daily dose compared to TNF inhibitor therapy 3
• The European Medicines Agency advises against using the 10 mg dose in patients at increased risk of pulmonary embolus 3
• FDA boxed warnings include thrombosis risk 5

Laboratory Abnormalities

• Dose-related elevations in serum lipids occur, including triglycerides, total cholesterol, LDL, and HDL 3
• Liver enzyme elevations to >3 times upper limit of normal have been recorded 3
• Serum creatinine increases occur in a dose-related manner 3
• Lymphopenia (0.04% after 3 months) correlates with increased infection risk 3

Drug Interactions and Combination Therapy

Tofacitinib can be combined with methotrexate but should NOT be combined with: 1

• Potent immunosuppressants (azathioprine, cyclosporine)
• Biologics used for psoriasis
• Live vaccines

There is insufficient evidence to support combination with other systemic agents or phototherapy. 1

Efficacy Data Supporting Use

• PASI 75 response rates at week 16: 39.5% (5 mg BID) and 63.6% (10 mg BID) vs 5.6% (placebo) 2
• PGA "clear" or "almost clear" response rates: 47.1% (5 mg BID) and 68.2% (10 mg BID) vs 15.0% (placebo) 2
• Efficacy is sustained through 54 months of continuous treatment 4
• Significant improvements in quality of life measures including DLQI, anxiety/depression scores, and pruritus 6

Pregnancy and Fertility

• Tofacitinib can be used during pregnancy only if the potential benefit justifies the potential risk to the fetus 1
• JAK inhibitors are generally advised against in pregnancy and lactation due to potential teratogenic effects 5

Clinical Algorithm for Patient Selection

Use tofacitinib in psoriasis when:

1. Patient has moderate to severe plaque psoriasis (PASI ≥10, DLQI >10) 1
2. Patient has failed, has contraindications to, or is intolerant of conventional systemic therapies (methotrexate, cyclosporine, PUVA) 1
3. Patient prefers oral therapy over injectable biologics
4. Patient has no active serious infection 1
5. Baseline laboratory parameters meet initiation criteria 1

Exercise extreme caution or avoid in patients with:

• Age ≥65 years with cardiovascular risk factors 5
• History of malignancy (particularly lung, breast, or lymphoma) 3, 5
• Recurrent serious infections 1, 3
• Risk factors for venous thromboembolism 3, 5
• Severe hepatic impairment 1

Start with 5 mg twice daily in most patients, reserving 10 mg twice daily only for those requiring maximum efficacy who accept substantially higher safety risks, particularly avoiding the higher dose in patients with cardiovascular risk factors or VTE risk. 1, 3