How much more effective is Rinvoq (upadacitinib) than Xeljanz (tofacitinib) for moderate‑to‑severe rheumatoid arthritis in adults without contraindications?

Rinvoq (Upadacitinib) vs Xeljanz (Tofacitinib) for Rheumatoid Arthritis

Upadacitinib demonstrates superior efficacy to tofacitinib in rheumatoid arthritis, with approximately 10-13% higher absolute response rates for ACR50 and significantly better clinical remission rates at 6 months, though both drugs share similar safety concerns including venous thromboembolism and herpes zoster risk. 1, 2

Direct Comparative Evidence

Efficacy Superiority of Upadacitinib

At 3 months, upadacitinib monotherapy achieved 9.9% higher ACR70 response rates compared to tofacitinib combination therapy (p=0.019), while upadacitinib combination therapy showed 12.9% higher ACR50 rates versus tofacitinib combination therapy (p=0.011). 1

At 6 months, upadacitinib combination therapy demonstrated substantially superior clinical remission rates compared to tofacitinib combination therapy: 1

• SDAI remission: 9.1% higher (p=0.011)
• CDAI remission: 7.5% higher (p=0.038)
• DAS28-ESR remission: 11.3% higher (p=0.002)

Network Meta-Analysis Rankings

In Bayesian network meta-analyses comparing JAK inhibitors, upadacitinib 15 mg + methotrexate consistently ranked as the most efficacious treatment with a SUCRA score of 0.820, compared to tofacitinib 5 mg + methotrexate with a SUCRA of 0.424 and tofacitinib 10 mg + methotrexate with 0.623. 2 This represents upadacitinib having approximately double the probability of being the best treatment compared to standard-dose tofacitinib. 2

Upadacitinib 15 mg + methotrexate also ranked highest for ACR20 response (SUCRA=0.838), followed by upadacitinib 30 mg + methotrexate (0.784), with both substantially outperforming adalimumab (0.495). 3

Safety Profile Comparison

Shared Safety Concerns

Both drugs carry identical class-wide JAK inhibitor safety warnings, including increased risks of venous thromboembolism, major adverse cardiovascular events, malignancy, and serious infections. 4 The European League Against Rheumatism determined that despite upadacitinib's greater JAK1 selectivity, it has a similar safety profile to less-selective JAK inhibitors like tofacitinib. 4

Specific Safety Differences

Herpes zoster infection rates are elevated with both agents, occurring more frequently than with TNF inhibitors. 4, 5 In the SELECT-COMPARE trial, upadacitinib showed higher rates of herpes zoster and CPK elevations compared to adalimumab, though serious adverse events were comparable. 5

Tofacitinib 10 mg twice daily carries a five-fold increased risk of pulmonary embolism compared to TNF inhibitors in patients over 50 years with cardiovascular risk factors. 6 The FDA boxed warning for this finding applies to the entire JAK inhibitor class, including upadacitinib. 6

In network meta-analyses of bDMARD-refractory RA patients, tofacitinib 5 mg showed significantly lower serious adverse event rates than upadacitinib 15 mg. 7 However, no significant differences in serious adverse events were observed in other analyses comparing these agents. 2

Clinical Positioning

Regulatory Restrictions

The FDA requires prior failure of or contraindications to TNF antagonists before using any JAK inhibitor (including both upadacitinib and tofacitinib) in rheumatoid arthritis. 6 This restriction stems from the ORAL Surveillance study in older RA patients with cardiovascular risk factors. 6

The European Medicines Agency recommends cautious first-line use of JAK inhibitors in patients ≥65 years, current/previous smokers, those with cardiovascular disease history, or cancer history. 6

Treatment Algorithm

When selecting between these agents after TNF antagonist failure: 4, 1, 2

• Choose upadacitinib 15 mg once daily for maximum efficacy, particularly when targeting clinical remission or in patients requiring rapid disease control
• Consider tofacitinib 5 mg twice daily if patient has extreme VTE risk factors beyond standard JAK inhibitor precautions, though both carry this risk
• Both require identical monitoring: CBC, liver enzymes, and lipids at baseline and periodically (every 1-3 months)

Critical Pitfalls to Avoid

Do not assume upadacitinib's JAK1 selectivity translates to superior safety—all JAK inhibitors share similar class-wide risks including VTE, cardiovascular events, and infections. 4 The efficacy advantage of upadacitinib comes with comparable, not reduced, safety concerns. 7, 2

Do not use either agent as first-line therapy in the United States without documented TNF antagonist failure or contraindication—this violates FDA labeling. 6

Do not overlook herpes zoster vaccination before initiating either agent in patients ≥50 years or those at high risk—wait 4 weeks after live vaccination before starting treatment. 6

Do not use the 10 mg twice-daily tofacitinib dose in patients with increased VTE risk (heart failure, malignancy, recent surgery, inherited coagulation disorders, prior thromboembolism, or hormonal therapy). 6