What is the recommended dose of upadacitinib (Janus kinase inhibitor) for adult patients with moderate to severe rheumatoid arthritis (RA)?

Recommended Dose of Upadacitinib in Rheumatoid Arthritis

The recommended dose of upadacitinib for adults with moderate to severe rheumatoid arthritis is 15 mg orally once daily, which can be used as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) such as methotrexate. 1, 2

Standard Dosing Regimen

• Upadacitinib 15 mg once daily is the FDA and EMA-approved dose for RA treatment 1, 2
• This dose has demonstrated superior efficacy compared to placebo in all RA patient populations including:
  • Methotrexate-inadequate responders (MTX-IR) 1
  • Biologic DMARD-inadequate responders (bDMARD-IR) 1
  • MTX-naïve patients 1
• The 15 mg dose can be administered as monotherapy or combined with background csDMARDs 1, 2

Comparative Efficacy Evidence

• In head-to-head trials, upadacitinib 15 mg plus methotrexate demonstrated superior efficacy compared to adalimumab plus methotrexate, particularly for patient-reported outcomes, though not consistently for joint counts 1
• The superiority was primarily observed in ACR50/70 responses and clinical remission rates (SDAI, CDAI, DAS28) 1
• Clinical response is typically observed within 1-2 weeks of treatment initiation 2, 3

Dose Modifications and Contraindications

Renal Impairment

• No dose adjustment is required for renal impairment, including severe renal disease 1
• This contrasts with other JAK inhibitors like tofacitinib and baricitinib which require dose reduction 1

Hepatic Impairment

• Upadacitinib is contraindicated in severe hepatic impairment (Child-Pugh C) 1
• No dose adjustment needed for mild to moderate hepatic impairment 1

Drug Interactions

• Dose reduction may be necessary when co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole), as these inhibit upadacitinib metabolism 1
• Dose increase may be required with rifampin or other strong CYP3A4 inducers used in tuberculosis treatment 1

Higher Dose Considerations (30 mg)

• While a 30 mg once daily dose was studied in clinical trials, the 15 mg dose is the approved and recommended dose for RA 1, 2
• The 30 mg dose showed higher efficacy but also increased adverse events including gastrointestinal perforations and CPK elevations 1, 4
• The 30 mg dose is approved for atopic dermatitis but not for RA 1

Critical Safety Monitoring Requirements

Pre-Treatment Screening

• Complete tuberculosis screening with IGRA or tuberculin skin test is mandatory before initiation 1, 5
• Baseline laboratory testing should include: complete blood count with differential, liver enzymes, renal function, and lipid profile 1, 5, 2
• Hepatitis B and C testing is required 5
• Herpes zoster vaccination (Shingrix 2-dose series) is recommended before starting therapy in patients ≥18 years 6, 5

During Treatment Monitoring

• Check complete blood count and liver enzymes at 4 weeks after initiation, then every 3 months 1, 5
• Lipid levels should be checked at 12 weeks after initiation 1, 2
• Monitor for signs of infection, particularly herpes zoster which occurs at higher rates than with adalimumab 4

Special Population Warnings

Elderly Patients (≥65 years)

• Patients ≥65 years with cardiovascular risk factors have significantly higher serious infection rates 1
• According to EMA guidance, tofacitinib (and by extension other JAK inhibitors) should be used in these patients only if no alternative exists 1
• Consider preferring biologics over JAK inhibitors in this population 5

Cardiovascular Risk Factors

• FDA black box warnings apply to all JAK inhibitors based on increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignancies, and death in patients ≥50 years with cardiovascular risk factors 5
• For patients ≥50 years with cardiovascular risk factors, biologics should be preferred over JAK inhibitors 5

Common Pitfalls to Avoid

• Do not use the 30 mg dose for RA - this is not the approved dose and carries increased safety risks 1
• Do not initiate during active serious infections 1, 5
• Do not combine with other potent immunosuppressants or biologics beyond established csDMARD combination therapy 6
• Do not overlook the need for herpes zoster vaccination prior to treatment initiation, as herpes zoster rates are elevated compared to TNF inhibitors 4

1, 5, 2, 4, 3