Why should C-Reactive Protein (CRP) or D-Dimer be checked in select cases before initiating tofacitinib (Janus kinase inhibitor) therapy?

Why CRP or D-Dimer Should Be Checked in Select Cases with Tofacitinib

CRP and D-dimer should be checked in select high-risk patients before initiating tofacitinib to assess baseline thrombotic and cardiovascular risk, particularly in patients aged ≥50 years with cardiovascular risk factors, as elevated D-dimer at baseline or during treatment correlates with increased venous thromboembolism (VTE) risk on tofacitinib therapy. 1, 2

Primary Rationale: VTE Risk Assessment

The critical reason for checking these biomarkers relates to tofacitinib's established association with increased VTE risk:

• Patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor demonstrated higher pulmonary embolism rates with tofacitinib 10 mg twice daily compared to TNF inhibitors in the ORAL Surveillance study. 2

• Month 12 D-dimer levels showed positive association with subsequent VTE risk within both tofacitinib 5 mg and 10 mg twice daily treatment arms, suggesting D-dimer may serve as a monitoring biomarker during therapy. 2

• The overall VTE risk in RA patients is approximately doubled compared to the general population (0.25/100 patient-years), and JAK inhibitors further increase this baseline risk. 1

When to Check These Biomarkers

D-dimer and CRP should be measured in patients with the following high-risk characteristics before tofacitinib initiation: 1, 3

• Age >65 years
• History of previous venous thromboembolism
• Active smoking
• Obesity
• Inherited thrombophilias
• Current exogenous estrogen use (oral contraceptives, hormone replacement)
• Recent surgery or prolonged immobilization
• Multiple cardiovascular risk factors
• Uncontrolled cardiac risk factors

CRP's Dual Role: Inflammation Monitoring and Cardiovascular Risk

CRP serves two distinct purposes in tofacitinib management: 4

1. Pharmacodynamic monitoring: Tofacitinib causes rapid, sustained decreases in serum CRP that persist throughout dosing and do not fully reverse within 2 weeks after discontinuation, indicating longer pharmacodynamic activity than the pharmacokinetic half-life. 4

2. Cardiovascular risk stratification: Elevated baseline CRP independently predicts cardiovascular events, with patients in the highest tertile having 4 times the risk (hazard ratio 4.04) of new cardiovascular events. 5

Critical Clinical Pitfall: Blunted Acute Phase Response

A major caveat when using tofacitinib is that fever and elevation of acute phase reactants (including CRP) may be blunted during therapy, potentially masking serious complications such as gastrointestinal perforation or severe infections. 1

• This means baseline CRP values are essential for comparison, as on-treatment CRP cannot be reliably interpreted for acute illness detection
• Clinicians must maintain high clinical suspicion for serious infections or complications even with normal inflammatory markers during tofacitinib therapy

D-Dimer as a Monitoring Tool

While D-dimer did not explain the mechanistic association between tofacitinib and increased VTE risk, elevated D-dimer during treatment (particularly at month 12) identifies patients at higher subsequent VTE risk. 2

• Baseline D-dimer establishes pre-treatment thrombotic activity
• Serial D-dimer measurements during therapy may identify patients requiring enhanced VTE surveillance or prophylaxis
• D-dimer elevation should prompt reassessment of VTE risk factors and consideration of anticoagulation in appropriate clinical contexts

Practical Algorithm for Biomarker Use

For patients being considered for tofacitinib: 1, 2, 3

1. Assess VTE risk factors (age, obesity, smoking, prior VTE, thrombophilia, immobility, estrogen use)

2. If ≥2 VTE risk factors present: Measure baseline D-dimer and CRP

3. If D-dimer elevated at baseline: Consider alternative therapy or implement VTE prophylaxis strategies

4. If CRP markedly elevated: Ensure adequate disease control and cardiovascular risk optimization before initiating tofacitinib

5. During treatment: Recheck D-dimer at 12 months in high-risk patients; persistently elevated levels warrant enhanced VTE surveillance

Contraindications Based on Risk Assessment

Tofacitinib should be avoided or used with extreme caution in: 3

• Elderly patients (>65 years) with multiple cardiovascular comorbidities
• Patients with uncontrolled cardiac risk factors
• Previous thrombotic episodes
• High baseline thrombotic risk (multiple VTE risk factors)
• Previous malignancy

In these populations, the decision to use tofacitinib requires careful consideration of whether benefits outweigh the elevated VTE and cardiovascular risks, with baseline biomarkers informing this risk-benefit assessment. 1, 2