What is the recommended dosage and usage of Tofacitinib (Janus kinase inhibitor) for treating rheumatoid arthritis and ulcerative colitis?

Tofacitinib Dosing and Usage

Rheumatoid Arthritis

For rheumatoid arthritis, tofacitinib 5 mg orally twice daily is the recommended dose in most countries for patients with moderate to severe active disease who have inadequate response or intolerance to conventional synthetic DMARDs. 1, 2

Dosing Specifics for RA

• The standard 5 mg twice daily dose demonstrated superiority to placebo across all efficacy measures (ACR20/50/70 responses, HAQ-DI improvement, and DAS-defined remission) at 3 months in multiple phase III trials 3
• In the head-to-head ORAL Standard trial, tofacitinib 5 mg twice daily plus methotrexate was non-inferior to adalimumab 40 mg every 2 weeks plus methotrexate, though tofacitinib monotherapy failed to show non-inferiority to either combination regimen 1
• Clinical and radiographic benefits are sustained through 24 months of continuous treatment 4
• Initial response typically occurs within 2-4 weeks, with maximal benefit by 3-6 months 2

Dose Modifications for RA

• Reduce to 5 mg once daily in patients with creatinine clearance <30 mL/min 1
• Reduce to 5 mg once daily when combining with potent CYP3A4 inhibitors or medications causing both moderate CYP3A4 and potent CYP2C19 inhibition 5
• Consider 2 mg baricitinib (alternative JAK inhibitor) for patients ≥75 years or those with chronic/recurrent infections, though this applies to baricitinib specifically 1
• Tofacitinib is contraindicated in severe hepatic impairment (Child Pugh C) 1

Ulcerative Colitis

For ulcerative colitis, tofacitinib 10 mg orally twice daily is recommended for induction therapy, followed by 5 mg twice daily for maintenance. 1, 6

Dosing Specifics for UC

• Induction: 10 mg twice daily for 8 weeks in the OCTAVE trials demonstrated superiority over placebo for clinical remission 1
• Maintenance: After successful induction, patients in OCTAVE Sustain were randomized to either 5 mg or 10 mg twice daily, with both doses showing high certainty for large benefit in maintaining remission over placebo 1
• The 10 mg twice daily dose is recommended only for ulcerative colitis, not for rheumatoid arthritis in most jurisdictions 6

Critical Safety Warnings and Patient Selection

Tofacitinib should be avoided in patients ≥65 years, those with cardiovascular risk factors, current/former long-term smokers, and those at increased risk for malignancy or venous thromboembolism, unless no suitable alternatives exist. 1, 2

Black Box Warning Context

• The FDA issued black box warnings based on the ORAL Surveillance trial in RA patients ≥50 years with cardiovascular risk factors, showing increased risks of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignancies, and death compared to TNF inhibitors 2
• The European Medicines Agency restricts use to patients where no suitable alternatives are available if they are ≥65 years, have cardiovascular risk factors, are current/former long-term smokers, or have increased cancer risk 1
• Importantly, safety data from tofacitinib use in ulcerative colitis does not corroborate the heightened risks seen in the RA population, though caution is still warranted 1
• For UC specifically, doses should be reduced where possible in patient groups at risk of VTE, cancer, or major cardiovascular problems 1

Infection Risk Management

• Herpes zoster infection rates are elevated with tofacitinib compared to the general RA population, though infections are typically mild and clinically manageable 1, 7
• Serious infections occur more frequently than with placebo but are similar in type and frequency to biological DMARDs 3
• Do not initiate or continue during any active serious infection 5

Pre-Treatment Requirements

Complete tuberculosis screening, hepatitis B/C testing, and administer recombinant zoster vaccine (Shingrix) before initiating tofacitinib. 2, 5

Specific Screening Steps

• Perform tuberculin skin test or interferon-gamma release assay (IGRA) for tuberculosis; treat latent TB for at least 1 month prior to starting tofacitinib 2, 5
• Test for hepatitis B and C before initiation 2
• Administer Shingrix as a 2-dose series separated by 2-6 months in patients ≥18 years old 5
• Obtain baseline complete blood count with differential, comprehensive metabolic panel (including liver enzymes and renal function), and lipid profile 5
• Do not initiate if lymphocyte count, absolute neutrophil count, or hemoglobin are below safe thresholds 5

Monitoring During Treatment

Monitor complete blood count at 4-8 weeks, then every 3 months; check lipids at 4-12 weeks, then annually; and assess liver enzymes at 4 weeks, then every 3 months. 2, 5, 8

Monitoring Rationale

• Tofacitinib blocks IL-6 receptor signaling, which reverses inflammation-induced lipid suppression, leading to increases in both LDL-C and HDL-C 8
• This dyslipidemia mechanism differs fundamentally from glucocorticoid-induced dyslipidemia and represents normalization of lipid metabolism rather than pathologic elevation 8
• Despite lipid elevations, major adverse cardiovascular events remain infrequent (0.24-0.37 per 100 patient-years) in immune-mediated inflammatory diseases 8
• Creatine kinase (CK) elevations occur with tofacitinib (mean increase 91.1 U/L at week 8 in UC induction) but appear reversible and are not associated with clinically significant adverse events or myopathy 9
• Liver enzyme elevations >3 times the upper limit of normal can occur and require monitoring 8

Action Thresholds

• Hold tofacitinib until hemoglobin values normalize if anemia develops during treatment 5
• Reduce dose or discontinue based on severity of laboratory abnormalities per standard clinical judgment 2

Combination Therapy Considerations

Tofacitinib can be used as monotherapy or in combination with methotrexate for RA, but should not be combined with biological DMARDs or other potent immunosuppressants beyond established regimens. 1, 5

Combination Therapy Evidence

• Combination with methotrexate provides superior structural outcomes compared to methotrexate alone in RA 1
• Tofacitinib monotherapy at 5 mg twice daily showed similar clinical and functional outcomes to combination therapy, though structural benefit was better with combination 1
• Do not combine with biologics or other JAK inhibitors 5
• Tofacitinib has never been compared to methotrexate plus glucocorticoids, the EULAR-recommended standard therapy for over a decade 1