Can serum uric acid be used to counteract the increased risk of major adverse cardiovascular events (MACE) in patients treated with tofacitinib (Janus kinase (JAK) inhibitor)?

Serum Uric Acid Cannot Counteract MACE Risk with Tofacitinib

There is no evidence that serum uric acid monitoring or management can reduce the increased risk of major adverse cardiovascular events (MACE) associated with tofacitinib therapy. The cardiovascular risk mitigation strategy for tofacitinib must focus on patient selection, avoiding use in high-risk populations, and managing traditional cardiovascular risk factors—not uric acid levels.

Evidence-Based Risk Factors for MACE with Tofacitinib

The established risk factors for MACE in tofacitinib-treated patients are:

• Age ≥50 years with cardiovascular risk factors is the primary high-risk population identified in the ORAL Surveillance study, which demonstrated increased MACE compared to TNF inhibitors 1
• Baseline age, hypertension, and total cholesterol to HDL cholesterol ratio remained significantly associated with MACE risk in multivariable analyses 2
• History of atherosclerotic cardiovascular disease (ASCVD) confers the highest risk, with incidence rates of 0.95 per 100 patient-years in UC patients 3
• High baseline 10-year ASCVD risk (calculated using standard risk calculators) correlates with increased MACE rates 4, 3

Regulatory Restrictions Based on Cardiovascular Risk

The European Medicines Agency mandates that JAK inhibitors including tofacitinib should only be used when no suitable alternatives are available in:

• Patients aged ≥65 years 1, 5
• Those at increased risk of major cardiovascular problems (heart attack or stroke) 1
• Current or long-term past smokers 1
• Those at increased risk of cancer 1

The FDA requires prior failure of or contraindications to TNF antagonists before tofacitinib use, based on the ORAL Surveillance findings 1, 5.

Lipid Parameters—Not Uric Acid—Show Prognostic Value

The only laboratory parameter demonstrated to associate with future MACE risk after tofacitinib initiation is HDL cholesterol:

• Increased HDL cholesterol after 24 weeks of tofacitinib treatment was associated with decreased future MACE risk 2
• Decreased total cholesterol to HDL cholesterol ratio after 24 weeks correlated with lower MACE risk 2
• Changes in total cholesterol, LDL cholesterol, and disease activity measures showed no association with MACE risk 2

Lipid monitoring should occur at 1-2 months after initiating tofacitinib, then every 6 months or annually 6, but this is for managing dyslipidemia as a cardiovascular risk factor, not for predicting or preventing tofacitinib-specific MACE.

Recommended Monitoring Strategy

The consensus monitoring approach focuses on traditional cardiovascular parameters:

• Complete blood count with differential every 3 months 1, 7
• Comprehensive metabolic panel (including creatinine) every 3 months 1, 7
• Lipid panel at 12 weeks, then annually 1, 6, 7
• Clinical assessment for cardiovascular symptoms at each visit 7

Notably, serum uric acid is not included in any guideline-recommended monitoring protocol for tofacitinib 1.

Clinical Decision Algorithm for Tofacitinib Use

Step 1: Assess absolute contraindications

• Age ≥65 years without alternative treatments 1
• Active serious infection 7
• Pregnancy or lactation 1

Step 2: Calculate baseline cardiovascular risk

• Use 10-year ASCVD risk calculator in patients without prior ASCVD 4, 3
• Document history of atherosclerotic cardiovascular disease 2, 3
• Identify metabolic syndrome components (diabetes, hypertension, obesity) 4

Step 3: Apply risk-stratified approach

• High risk (prior ASCVD or high 10-year ASCVD risk): Use only if no alternatives available; consider TNF inhibitor preferentially 1
• Intermediate risk: Acceptable with enhanced cardiovascular monitoring 3
• Low risk: Standard monitoring protocol 3

Step 4: Optimize modifiable cardiovascular risk factors before and during treatment

• Manage hypertension aggressively 2
• Optimize lipid profile (target improved HDL cholesterol) 2
• Smoking cessation 1
• Weight management if metabolic syndrome present 4

Critical Pitfalls to Avoid

• Do not assume uric acid management will mitigate MACE risk—there is zero evidence supporting this approach
• Do not use tofacitinib as first-line therapy in patients aged ≥50 years with cardiovascular risk factors when TNF inhibitors remain an option 1
• Do not rely solely on disease activity improvement to assess cardiovascular safety—disease activity measures did not correlate with MACE risk 2
• Do not overlook age-related risk escalation—for patients without prior ASCVD who developed MACE, 10-year ASCVD risk scores increased numerically (>1%) prior to the event primarily due to increasing age 3

Divergent Evidence Considerations

While the ORAL Surveillance study in rheumatoid arthritis demonstrated increased MACE with tofacitinib versus TNF inhibitors 1, post hoc analyses in ulcerative colitis populations did not identify a clear increase in MACE risk compared to TNF therapy 1. However, this likely reflects the younger age and lower baseline cardiovascular risk profile of UC trial populations rather than a disease-specific protective effect 3. The most conservative approach prioritizes the ORAL Surveillance findings across all indications 1.