What are the indications, recommended dosing, baseline and ongoing monitoring, contraindications, and alternative systemic therapies for oral tofacitinib (a Janus kinase inhibitor) in treating inflammatory skin diseases such as plaque psoriasis, alopecia areata, vitiligo, and chronic atopic dermatitis?

Oral Tofacitinib in Dermatology

Primary Indications

Tofacitinib is not FDA-approved for any dermatologic indication in the United States, but demonstrates efficacy in plaque psoriasis, alopecia areata, vitiligo, and atopic dermatitis as off-label use. 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
• The 10 mg twice daily dose demonstrated greater efficacy: PASI75 at 12 weeks was 43% in methotrexate-inadequate responders and 21% in TNF-inhibitor failures 1, 2
• However, PASI response appears numerically lower than IL-12/23 or IL-17 inhibitors, making biologics the preferred first-line option 1

Atopic Dermatitis

• While newer JAK inhibitors (upadacitinib, abrocitinib, baricitinib) have FDA approval and stronger recommendations for atopic dermatitis, tofacitinib shows efficacy in refractory eczematous conditions 1, 2, 3
• For atopic dermatitis specifically, prefer FDA-approved JAK inhibitors (upadacitinib 15-30 mg daily, abrocitinib 100-200 mg daily, or baricitinib) over tofacitinib 1, 2

Other Dermatologic Conditions

• Alopecia areata, vitiligo, and refractory eczematous dermatoses show response to tofacitinib in case series and small studies 4, 3, 5
• Topical tofacitinib formulations have shown efficacy in mild-to-moderate psoriasis and vitiligo 1, 5

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Dosing Recommendations

Standard Dosing for Psoriasis

• 5 mg orally twice daily or 10 mg orally twice daily 1
• The 10 mg twice daily dose provides superior efficacy but carries higher safety concerns 1, 2

Dose Modifications

• Reduce to 5 mg once daily in patients with moderate to severe renal impairment (eGFR <60 mL/min) or hepatic impairment 1
• Avoid use entirely in severe hepatic impairment 1
• Reduce to 5 mg once daily when combining with potent CYP3A4 inhibitors (e.g., ketoconazole) or medications causing both moderate CYP3A4 inhibition and potent CYP2C19 inhibition (e.g., fluconazole) 1, 6

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Pre-Treatment Requirements

Mandatory Screening

• Complete blood count with differential, comprehensive metabolic panel (liver enzymes, renal function), and lipid panel 1, 2, 6
• Tuberculosis screening with interferon-gamma release assay (IGRA) or tuberculin skin test; treat latent TB for at least 1 month before starting tofacitinib 1, 2, 6
• Hepatitis B and C testing 2, 7
• HIV testing in high-risk populations 2, 7
• Pregnancy test in women of childbearing potential 1

Vaccination Requirements

• Administer recombinant zoster vaccine (Shingrix) as a 2-dose series separated by 2-6 months, completing 3-4 weeks before tofacitinib initiation in adults ≥50 years or immunocompromised adults ≥19 years 2, 6
• Avoid live vaccines once tofacitinib is started 1

Baseline Laboratory Thresholds

• Do not initiate if lymphocyte count <500 cells/mm³, absolute neutrophil count (ANC) <1000 cells/mm³, or hemoglobin <9 g/dL 1, 6

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Ongoing Monitoring

Laboratory Monitoring Schedule

• CBC with differential at 4-8 weeks after initiation, then every 3 months 1, 2, 6
• Liver enzymes (as part of comprehensive metabolic panel) at 4 weeks, then every 3 months 1, 2, 6
• Lipid panel at 4-12 weeks after initiation, then annually 1, 2, 6
• Renal function every 3 months 2, 6

Laboratory-Based Treatment Modifications

• Hold tofacitinib if lymphocyte count drops to <500 cells/mm³ (confirmed by repeat testing) 1
• Hold if ANC <500 cells/mm³ (confirmed by repeat testing); for persistent ANC <1000 cells/mm³, hold until ANC ≥1000 cells/mm³ 1
• Hold if hemoglobin decreases by ≥2 g/dL or falls to <8.0 g/dL (confirmed by repeat testing) until values normalize 1

Clinical Monitoring

• Monitor for infections at every visit, particularly herpes zoster, which occurs more frequently with JAK inhibitors 2, 7
• Monitor for signs of thrombotic events, especially in patients with cardiovascular risk factors 2
• Semiannual physical examination focusing on lymphadenopathy and non-melanoma skin cancers 1

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Absolute Contraindications

• Active serious infection 1, 2, 6
• Severe hepatic impairment 1
• Lymphocyte count <500 cells/mm³, ANC <1000 cells/mm³, or hemoglobin <9 g/dL 1, 6

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Critical Safety Warnings

FDA Black Box Warnings

The FDA has issued black box warnings for all JAK inhibitors based on the ORAL Surveillance trial in rheumatoid arthritis patients ≥50 years with cardiovascular risk factors, showing increased risk of: 2, 7

• Major adverse cardiovascular events (MACE)
• Venous thromboembolism (VTE) and pulmonary embolism
• Malignancies (particularly lymphoma and lung cancer)
• Death

High-Risk Populations

• Patients ≥50 years with cardiovascular risk factors should preferentially receive biologics over tofacitinib 2, 7
• Patients ≥65 years have significantly higher serious infection rates and should only receive tofacitinib if no alternative exists 6
• Current or past smokers have elevated malignancy risk 2

Infection Risk

• Herpes zoster occurs more frequently with tofacitinib than other systemic psoriasis therapies, hence the importance of pre-treatment Shingrix vaccination 1, 2
• Avoid initiation or continuation during any active serious infection 1, 2, 6

Pregnancy and Lactation

• Tofacitinib can be used during pregnancy only if the potential benefit justifies the potential risk to the fetus 1
• Pregnancy testing is indicated before initiation and ongoing if clinically appropriate 1

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Drug Interactions and Combination Therapy

Prohibited Combinations

• Do not combine tofacitinib with potent immunosuppressants such as azathioprine, cyclosporine, or biologics used for psoriasis 1, 6
• There is insufficient evidence to support combined use with other systemic agents or phototherapy 1

Permitted Combinations

• Tofacitinib can be used with methotrexate 1

Drug Interactions Requiring Dose Adjustment

• Reduce to 5 mg once daily with potent CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin) 1, 6
• Reduce to 5 mg once daily with medications causing both moderate CYP3A4 inhibition and potent CYP2C19 inhibition (fluconazole) 1, 6

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Alternative Systemic Therapies

For Psoriasis

Biologics are preferred over tofacitinib due to superior efficacy and more established long-term safety profiles: 1, 2

• IL-17 inhibitors (secukinumab, ixekizumab, brodalumab) achieve PASI75 rates of approximately 89% 1
• IL-12/23 inhibitor (ustekinumab) achieves PASI75 rates of approximately 70% 1
• IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab) achieve PASI75 rates of approximately 80% 1
• TNF inhibitors (adalimumab, etanercept, infliximab, certolizumab) remain viable options 1

For Atopic Dermatitis

The American Academy of Dermatology makes strong recommendations for the following agents over tofacitinib: 1, 2

• Dupilumab (IL-4/IL-13 inhibitor)
• Tralokinumab (IL-13 inhibitor)
• Upadacitinib (JAK1 inhibitor) 15-30 mg daily
• Abrocitinib (JAK1 inhibitor) 100-200 mg daily
• Baricitinib (JAK1/JAK2 inhibitor) 2-4 mg daily

Conditional recommendations for: 1

• Phototherapy (narrowband UVB)
• Azathioprine
• Cyclosporine
• Methotrexate
• Mycophenolate

Conditional recommendation against: 1

• Systemic corticosteroids (due to rebound and long-term adverse effects)

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Clinical Decision Algorithm

When to Consider Tofacitinib

Use tofacitinib for dermatologic conditions only when: 1, 2

1. Patient has failed or is intolerant to conventional systemic therapies
2. Patient is <50 years old without cardiovascular risk factors
3. No history of malignancy
4. No active infections
5. Biologics are unavailable, contraindicated, or refused by the patient
6. Patient understands the off-label nature and black box warnings

When to Avoid Tofacitinib

Do not use tofacitinib if: 1, 2, 6, 7

1. Patient is ≥50 years with cardiovascular risk factors (prefer biologics)
2. Active serious infection
3. History of VTE or significant cardiovascular disease
4. History of malignancy (especially lymphoma or lung cancer)
5. Severe hepatic impairment
6. Baseline cytopenias (lymphocytes <500, ANC <1000, hemoglobin <9)
7. FDA-approved alternatives are available and appropriate (especially for atopic dermatitis)

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Common Pitfalls and How to Avoid Them

Pitfall 1: Inadequate Pre-Treatment Screening

• Always complete TB screening and treat latent TB for at least 1 month before starting tofacitinib 2, 6
• Ensure Shingrix vaccination is completed 3-4 weeks before initiation in eligible patients 2, 6

Pitfall 2: Ignoring Black Box Warnings

• Do not prescribe tofacitinib to patients ≥50 years with cardiovascular risk factors without exhausting biologic options first 2, 7
• Document informed consent discussion about MACE, VTE, malignancy, and death risks 2

Pitfall 3: Inadequate Monitoring

• Do not skip the 4-8 week CBC and liver enzyme checks; early cytopenias or transaminitis require prompt intervention 1, 2, 6
• Check lipids at 4-12 weeks, as dyslipidemia is common and requires management 1, 2, 6

Pitfall 4: Inappropriate Combination Therapy

• Never combine tofacitinib with azathioprine, cyclosporine, or biologics 1, 6
• Remember to dose-reduce to 5 mg once daily with potent CYP3A4 inhibitors 1, 6

Pitfall 5: Using Tofacitinib as First-Line for Atopic Dermatitis

• For atopic dermatitis, FDA-approved JAK inhibitors (upadacitinib, abrocitinib, baricitinib) or dupilumab have stronger evidence and regulatory approval 1, 2
• Reserve tofacitinib for refractory cases where approved agents have failed 3

Pitfall 6: Continuing Therapy During Active Infection

• Hold tofacitinib immediately if serious infection develops 1, 2, 6
• Maintain high suspicion for opportunistic infections, particularly herpes zoster 1, 2