Is upadacitinib (Rinvoq) necessary as a first-line treatment for this patient with Giant Cell Arteritis (GCA)?

Upadacitinib is NOT Necessary as First-Line Treatment for Giant Cell Arteritis

For this patient with Giant Cell Arteritis, upadacitinib should not be given as first-line therapy. The 2021 American College of Rheumatology/Vasculitis Foundation guidelines establish glucocorticoids as the standard initial treatment for GCA, with tocilizumab or methotrexate as preferred glucocorticoid-sparing agents 1. Upadacitinib is reserved for refractory disease after failure of established therapies.

Evidence-Based Treatment Algorithm for GCA

First-Line Therapy

• Initiate high-dose oral glucocorticoids (prednisone 40-60 mg daily or 1 mg/kg/day) immediately for all patients with newly diagnosed GCA 1
• Add tocilizumab (600 mg loading dose, then 300 mg subcutaneously every 2 weeks) or methotrexate (10-25 mg weekly) as glucocorticoid-sparing agents from the start, particularly for patients with cranial ischemic symptoms 1
• Tocilizumab demonstrates substantially greater glucocorticoid-sparing effect than methotrexate and is preferred for preventing ischemic complications including vision loss 2

When Upadacitinib Becomes Appropriate

• Upadacitinib is indicated only after failure of glucocorticoids plus tocilizumab or methotrexate 1
• The 2025 phase III SELECT-GCA trial demonstrated that upadacitinib 15 mg daily achieved 46.4% sustained remission at week 52 versus 29.0% with placebo (P=0.002), but this was studied in patients who had already received standard therapy 3
• Real-world data from 35 GCA patients showed that 86% had previously failed biologics (primarily tocilizumab) before receiving JAK inhibitors, with 57% achieving clinical remission 4

Positioning in Treatment Hierarchy

• JAK inhibitors like upadacitinib are not considered first-line systemic therapy for GCA, similar to their positioning in atopic dermatitis where they are approved only after failure of other systemic therapies 1
• The evidence base for upadacitinib in GCA comes from refractory populations: 70% had new-onset disease but all received the drug alongside glucocorticoid tapers, not as monotherapy 3

Critical Safety Considerations

JAK Inhibitor Class Warnings

• FDA boxed warnings exist for JAK inhibitors based on the ORAL Surveillance trial in rheumatoid arthritis patients aged ≥50 years with cardiovascular risk factors, showing increased major adverse cardiovascular events and malignancy with tofacitinib 10 mg twice daily compared to TNF inhibitors 1
• While no major adverse cardiovascular events occurred in the SELECT-GCA trial during 52 weeks, the study population and duration were limited 3
• Required baseline monitoring includes complete blood count with differential, liver enzymes, lipid panel, viral hepatitis screening, tuberculosis testing, and pregnancy testing 1

Monitoring Requirements During Treatment

• Check complete blood count and liver enzymes at baseline and per routine management after baseline 1
• Lipid panel should be checked at 12 weeks after initiation 1
• The optimal frequency of ongoing laboratory monitoring for continuous JAK inhibitor use remains unclear 1

Clinical Decision Framework

Start with Standard Therapy

1. Immediate glucocorticoid initiation (prednisone 40-60 mg daily) 1
2. Add tocilizumab or methotrexate within the first week of diagnosis 1
3. Taper glucocorticoids according to protocol (typically over 26-52 weeks) 1

Escalate to Upadacitinib Only If

• Patient experiences disease relapse despite tocilizumab or methotrexate 4, 3
• Patient develops intolerable adverse events to tocilizumab (such as severe injection site reactions, recurrent infections, or hepatotoxicity) 5
• Patient has contraindications to both tocilizumab and methotrexate 4

Dosing When Indicated

• Upadacitinib 15 mg orally once daily is the effective dose; the 7.5 mg dose failed to show superiority over placebo in the phase III trial 3
• Continue alongside a glucocorticoid taper rather than as monotherapy 3

Common Pitfalls to Avoid

Do Not Use Upadacitinib First-Line

• Premature use bypasses proven therapies with longer safety track records (glucocorticoids, tocilizumab, methotrexate) 1
• The evidence base for upadacitinib specifically studied refractory populations, not treatment-naïve patients 3

Do Not Ignore Cardiovascular Risk Assessment

• Evaluate cardiovascular risk factors before considering any JAK inhibitor, particularly in patients aged ≥50 years, current or former smokers, or those with known cardiovascular disease 1
• The European Medicines Agency advises caution in older adults and smokers even when not recommending against first-line use 1

Do Not Skip Required Monitoring

• Failure to perform baseline and ongoing laboratory monitoring increases risk of undetected cytopenias, hepatotoxicity, or lipid abnormalities 1
• Unlike tocilizumab or methotrexate, JAK inhibitors require lipid monitoring due to dose-dependent increases in LDL and HDL cholesterol 1

Do Not Use Lower Doses

• The 7.5 mg dose of upadacitinib was ineffective (41.1% remission, not statistically different from placebo's 29.0%) 3
• Only the 15 mg daily dose demonstrated superiority in the phase III trial 3

Real-World Context

• Among 35 real-world GCA patients treated with JAK inhibitors (including upadacitinib, baricitinib, tofacitinib), 63% had previously received conventional immunosuppressants and 86% had received biologics before JAK inhibitor initiation 4
• After median 11 months follow-up, 57% achieved clinical remission, but 31% relapsed and 11% discontinued due to serious adverse events 4
• An 82-year-old woman with GCA refractory to both prednisone and tocilizumab achieved substantial symptom improvement with upadacitinib, demonstrating its role as salvage therapy 5

The evidence unequivocally supports reserving upadacitinib for refractory GCA after standard therapies have failed, not as initial treatment 1, 4, 3.