In an adult patient without contraindications, what are the recommended starting and escalation doses of tofacitinib for rheumatoid arthritis or psoriatic arthritis, the required infection screening and baseline laboratory tests, the monitoring schedule, and the major safety concerns?

Tofacitinib for Rheumatoid Arthritis and Psoriatic Arthritis

Recommended Dosing

For rheumatoid arthritis and psoriatic arthritis, initiate tofacitinib at 5 mg orally twice daily, which is the approved dose in the EU and provides the optimal risk-benefit profile. 1, 2

• The standard dose of 5 mg twice daily should not be escalated to 10 mg twice daily in RA or PsA, as the higher dose substantially increases risks of serious infections, pulmonary embolism (five-fold increase), major adverse cardiovascular events, and malignancy without proportionate efficacy gains. 3, 4
• An extended-release formulation of 11 mg once daily is available as an alternative to 5 mg twice daily for RA and PsA. 1, 2
• Tofacitinib can be used as monotherapy or in combination with methotrexate or other conventional synthetic DMARDs. 3, 5

Dose Adjustments for Organ Impairment

• Moderate to severe renal impairment (CrCl <60 mL/min): Reduce to 5 mg once daily. 1, 3
• Moderate hepatic impairment (Child-Pugh B): Reduce to 5 mg once daily. 1, 3
• Severe hepatic impairment (Child-Pugh C): Tofacitinib is contraindicated. 1

Drug Interaction Dose Adjustments

• When combining with potent CYP3A4 inhibitors (e.g., ketoconazole) or medications causing both moderate CYP3A4 and potent CYP2C19 inhibition, reduce dose to 5 mg once daily. 3, 6

Mandatory Pre-Treatment Screening

Before initiating tofacitinib, complete the following baseline assessments: 3, 6

Infection Screening

• Tuberculosis: Perform interferon-gamma release assay (IGRA) or tuberculin skin test; if latent TB is detected, treat for at least 1 month before starting tofacitinib. 6
• Hepatitis B and C screening 6
• HIV screening 3

Baseline Laboratory Tests

• Complete blood count with differential: Do not initiate if lymphocyte count <500 cells/mm³, absolute neutrophil count <1,000 cells/mm³, or hemoglobin <9 g/dL. 3, 6
• Comprehensive metabolic panel including liver enzymes and renal function 6
• Lipid profile 6
• Pregnancy test in all patients of childbearing potential 3

Vaccination Requirements

• Recombinant zoster vaccine (Shingrix): Administer as a 2-dose series separated by 2-6 months before starting therapy in patients ≥18 years old, given the significantly elevated risk of herpes zoster with tofacitinib. 6
• For patients over 70 years or over 50 years at high risk, strongly consider zoster vaccination before initiation. 3

Monitoring Schedule During Treatment

Laboratory Monitoring

• CBC with differential: Check at 4-8 weeks after initiation, then every 3 months. 6
• Liver enzymes: Check at 4 weeks, then every 3 months as part of comprehensive metabolic panel. 6
• Lipid profile: Measure at 4-12 weeks after initiation, then annually. 6

Thresholds for Discontinuation or Holding Treatment

• Discontinue immediately if: Lymphocyte count <500 cells/mm³, absolute neutrophil count <500 cells/mm³, or hemoglobin decreases ≥2 g/dL or falls <8.0 g/dL. 4
• Hold until values normalize if: Anemia develops during treatment. 3, 6

Major Safety Concerns and Contraindications

High-Risk Populations Requiring Extreme Caution

Patients aged ≥65 years or those aged ≥50 years with cardiovascular risk factors should only receive tofacitinib if no suitable alternatives exist, based on the ORAL Surveillance study showing increased risks of major adverse cardiovascular events, venous thromboembolism, cancer, and serious infections compared to TNF inhibitors. 1, 3

• The European Medicines Agency specifically recommends avoiding tofacitinib in patients aged 65 years or above, current or long-term past smokers, those with history of cardiovascular disease, and those at increased risk of cancer unless no alternatives are available. 3
• In the United States, the FDA recommends using tofacitinib only after prior failure of or contraindications to TNF antagonists. 1, 3

Absolute Contraindications

• Active serious infections (acute or chronic, including latent TB and opportunistic infections) 1, 3
• Severe hepatic impairment (Child-Pugh C) 1
• Pregnancy and lactation: Use only if potential benefit justifies fetal risk; contraception is advised for both female and male patients. 1, 3

Specific Safety Risks

Cardiovascular and Thrombotic Events:

• Increased risk of major adverse cardiovascular events (MACE) in patients over 50 with cardiovascular risk factors 3
• Five-fold increase in pulmonary embolism risk with 10 mg twice daily compared to TNF inhibitors 3
• Consider prophylactic-dose anticoagulation in high-risk patients 3

Malignancy:

• Increased cancer risk compared to TNF inhibitors in high-risk populations; use shared decision-making if history of malignancy, considering timing and type 1, 3

Infections:

• Serious infection rates comparable to adalimumab at 5 mg twice daily, but higher in elderly patients 1
• Significantly elevated risk of herpes zoster, though typically clinically mild and manageable 1, 5
• Higher rates of serious infections in patients over 65 years, particularly with 10 mg twice daily 1

Prohibited Combinations

• Do not combine with: Other potent immunosuppressants (beyond methotrexate/corticosteroids), biologics used for inflammatory diseases, tocilizumab, or other IL-6 inhibitors 3
• Live vaccines are contraindicated once tofacitinib is started 3, 6

Common Pitfalls to Avoid

• Do not escalate to 10 mg twice daily for RA or PsA, as this dose is only approved for ulcerative colitis induction and carries substantially higher risks. 1, 3
• Do not skip baseline TB screening, as reactivation of latent TB can occur. 6
• Do not use in patients over 65 years without exhausting other options, given the significantly elevated serious infection and cardiovascular event rates. 1, 3
• Do not combine with multiple immunosuppressants, as this increases infection and malignancy risk. 3, 4
• Do not forget to adjust dose for renal or hepatic impairment and drug interactions, as standard dosing in these contexts increases toxicity risk. 1, 3