What is the recommended use and dosing of Upadacitinib (Rinvoq) for patients with moderate to severe rheumatoid arthritis or active spondyloarthritis who have had an inadequate response or intolerance to conventional or biologic Disease-Modifying Antirheumatic Drugs (DMARDs)?

Upadacitinib for Spondyloarthritis and Rheumatoid Arthritis

For rheumatoid arthritis, use upadacitinib 15 mg orally once daily as monotherapy or combined with methotrexate after inadequate response to conventional synthetic DMARDs; for active ankylosing spondylitis or non-radiographic axial spondyloarthritis, use the same 15 mg once-daily dose after inadequate response to NSAIDs. 1, 2

Rheumatoid Arthritis: Treatment Positioning and Dosing

When to Initiate Upadacitinib

After csDMARD failure: Upadacitinib is positioned after inadequate response to at least one conventional synthetic DMARD (typically methotrexate, leflunomide, or sulfasalazine), where it can be used as monotherapy or combined with background csDMARDs 3. The EULAR 2020 guidelines classify upadacitinib as a targeted synthetic DMARD (tsDMARD) that may be considered when patients have failed csDMARD therapy 3.

After biologic DMARD failure: Upadacitinib demonstrated significant efficacy in biologic-inadequate responders, with 65% achieving ACR20 response versus 28% with placebo at week 12 2. In this population, JAK inhibitors like upadacitinib may be considered after failure of at least one biologic DMARD 3.

Standard Dosing Regimen

The FDA-approved and recommended dose is 15 mg orally once daily 1, 2. This dose demonstrated:

• ACR20 response rates of 64-76% across multiple patient populations (MTX-naïve, csDMARD-inadequate responders, and biologic-inadequate responders) 2
• Superior efficacy to adalimumab in head-to-head comparison, particularly for ACR50/70 responses and patient-reported outcomes 1, 4
• DAS28-CRP <2.6 (remission) achieved in 29-48% of patients versus 6-17% with placebo 2

Critical: Do not use the 30 mg dose for rheumatoid arthritis - this is not the approved dose and carries increased safety risks without proportional benefit 1, 2.

Combination Therapy Considerations

Upadacitinib can be administered as:

• Monotherapy after switching from methotrexate (68% ACR20 response versus 41% continuing methotrexate) 5
• Combined with methotrexate or other csDMARDs (71% ACR20 response in MTX-inadequate responders) 2, 4

The choice between monotherapy and combination therapy should be based on prior treatment response and tolerability 1, 2.

Axial Spondyloarthritis: Treatment Positioning and Dosing

Ankylosing Spondylitis and Non-Radiographic Axial SpA

Use upadacitinib 15 mg once daily after inadequate response to NSAIDs 3, 6. In the SELECT-AXIS 2 trial for non-radiographic axial spondyloarthritis:

• 45% achieved ASAS40 response versus 23% with placebo at week 14 6
• Significant improvements observed as early as week 2 3
• Similar efficacy pattern demonstrated in ankylosing spondylitis 3

Important Positioning Considerations for SpA

In patients with inflammatory bowel disease (IBD) and spondyloarthritis: JAK inhibitors including upadacitinib may be considered, but TNF inhibitor monoclonal antibodies (infliximab, adalimumab, golimumab) remain strongly recommended as first-line treatment 3. Upadacitinib can be considered:

• After primary non-response to one anti-TNF agent 3
• In ulcerative colitis with contraindication to TNF inhibitors 3
• However, avoid in active Crohn's disease where TNF inhibitors are preferred 3

Avoid IL-17 inhibitors in patients with active IBD - they lack efficacy and may worsen intestinal inflammation 3.

Dose Modifications and Special Populations

No Adjustment Required

• Renal impairment (including severe): No dose adjustment needed 1, 2

Dose Reduction Required

• Severe hepatic impairment: Contraindicated 1, 2
• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Reduce dose or avoid 1, 2

Dose Increase May Be Needed

• Strong CYP3A4 inducers (rifampin): May require dose adjustment 1

Mandatory Pre-Treatment Screening

Before initiating upadacitinib, complete the following:

1. Tuberculosis screening with IGRA or tuberculin skin test - treat latent TB for at least 1 month before starting 1, 7

2. Herpes zoster vaccination (Shingrix 2-dose series) in patients ≥18 years 1, 7

3. Baseline laboratory testing:

   • Complete blood count with differential 1, 7
   • Liver enzymes and renal function 1, 7
   • Lipid profile 1, 7
   • Hepatitis B and C testing 1

4. Do not initiate during active serious infections 1, 7

Ongoing Monitoring Requirements

Laboratory Monitoring Schedule

• CBC with differential: At 4-8 weeks, then every 3 months 7
• Liver enzymes: At 4 weeks, then every 3 months 7
• Lipid profile: At 4-12 weeks, then annually 7

Hold Treatment If:

• Absolute neutrophil count <1000/mm³ 7
• Hemoglobin <8 g/dL 7
• Active serious infection develops 1, 7

Critical Safety Warnings and Black Box Considerations

High-Risk Populations

Patients ≥65 years with cardiovascular risk factors have significantly elevated risks 1, 8:

• Increased serious infection rates
• Higher risk of major adverse cardiovascular events (MACE)
• Elevated venous thromboembolism (VTE) risk
• Increased malignancy risk

The FDA black box warning applies to all JAK inhibitors for patients ≥50 years with cardiovascular risk factors, based on increased risk of MACE, VTE, malignancies, and death 1, 8. Use in elderly patients only if no alternative exists 1, 8.

Infection Risks

• Herpes zoster: Higher incidence with upadacitinib versus placebo or adalimumab (1-3% in clinical trials) 4, 5
• Serious infections: Comparable to adalimumab but higher than placebo 4
• Opportunistic infections: Screen and monitor vigilantly 1

Other Safety Signals

• Venous thromboembolism: Reported in clinical trials; use caution in patients with VTE risk factors 4
• Malignancies: Monitor for new malignancies; avoid in patients with active malignancy 1, 2
• Lipid elevations: Common; manage with statins as needed 1, 7
• CPK elevations: More frequent than with adalimumab; typically asymptomatic 4

Common Pitfalls to Avoid

1. Do not use 30 mg dose for RA - not approved and increases safety risks 1, 2
2. Do not combine with other biologics or potent immunosuppressants beyond established csDMARD combinations 1, 7
3. Do not skip TB screening - mandatory before initiation 1, 7
4. Do not use in severe hepatic impairment - contraindicated 1, 2
5. Do not initiate in patients ≥65 years with CV risk factors without careful risk-benefit assessment and only if no alternatives exist 1, 8
6. In SpA with active IBD, prioritize TNF inhibitor monoclonal antibodies over JAK inhibitors 3

Expected Response Timeline

• Initial response: Typically within 1-2 weeks 2, 9
• Primary efficacy assessment: Week 12-14 2, 6
• Maximal benefit: By 24-26 weeks 2

If inadequate response by 12-14 weeks, consider switching to alternative therapy 3.