What cardiac adverse effects, including systemic hypertension and pulmonary arterial hypertension, are associated with leflunomide and how should they be monitored and managed?

Leflunomide Cardiac Effects

Leflunomide is associated with systemic hypertension in a small percentage of patients and has been linked to rare cases of pulmonary arterial hypertension (PAH), requiring blood pressure monitoring during treatment and immediate discontinuation if PAH develops.

Systemic Hypertension

Incidence and Monitoring

• Systemic hypertension develops in a small percentage of patients treated with leflunomide, particularly during the first months of therapy 1
• Blood pressure should be monitored regularly, especially in patients with pre-existing treated hypertension 1
• Patients with controlled hypertension require closer surveillance when leflunomide is initiated, as the drug may destabilize previously controlled blood pressure 1

Management Approach

• Regular blood pressure checks are essential during the initial treatment period 1
• Antihypertensive therapy should be adjusted as needed to maintain blood pressure control 1
• The hypertensive effect does not typically require drug discontinuation if blood pressure can be adequately controlled with antihypertensive medications 1

Pulmonary Arterial Hypertension

Clinical Presentation and Timing

• PAH associated with leflunomide is rare but well-documented, with a median time from drug initiation to PAH diagnosis of 32 months (range 1-120 months) 2
• Patients present with progressive exertional dyspnea (NYHA class II-IV) and clinical signs of right heart failure 3, 4
• Right heart catheterization confirms precapillary PH with elevated mean pulmonary arterial pressure (>25 mmHg), pulmonary capillary wedge pressure <15 mmHg, elevated pulmonary vascular resistance (median 9.63 Wood Units), and reduced cardiac index (median 2.37 L·min⁻¹·m⁻²) 2

Risk Factors and Causality

• In 75% of reported cases, patients had at least one additional risk factor for PAH beyond leflunomide exposure 2
• However, 17.9% of cases had no other identifiable risk factor besides leflunomide, suggesting the drug can independently cause PAH 2
• Pharmacovigilance analysis using the WHO global database revealed significant overrepresentation of leflunomide among reported PAH adverse drug reactions 2
• In vitro studies demonstrate dose-dependent toxicity of leflunomide on human pulmonary endothelial cells, providing mechanistic support for the association 2

Diagnostic Evaluation

• When PAH is suspected in a leflunomide-treated patient, perform echocardiography to assess right ventricular systolic pressure and right heart function 5, 4
• Right heart catheterization is mandatory to confirm precapillary PH and measure hemodynamic parameters 2, 3
• Exclude other causes of precapillary PH: perform ventilation/perfusion lung scan and high-resolution CT to rule out chronic thromboembolic disease, evaluate for connective tissue disease, HIV, portal hypertension, and congenital heart disease 3
• Acute vasoreactivity testing with nitric oxide typically shows no reversibility in leflunomide-associated PAH 2

Management Strategy

• Immediately discontinue leflunomide when PAH is diagnosed, regardless of other risk factors 2, 5, 3, 4
• Initiate PAH-specific therapy according to disease severity: upfront dual combination therapy (phosphodiesterase-5 inhibitor plus endothelin receptor antagonist) is recommended for symptomatic patients 5
• For severe cases (WHO functional class III-IV), consider adding a prostacyclin-pathway agent to dual oral therapy 6
• Monitor response with serial echocardiography, 6-minute walk testing, and clinical assessment 5, 4

Prognosis After Discontinuation

• Clinical and hemodynamic improvement can occur after leflunomide withdrawal, though significant hemodynamic improvement is not consistently observed with drug cessation alone 2
• One case report documented complete normalization of pulmonary arterial pressure within one year after stopping leflunomide without PAH-specific therapy 4
• Another case showed significant improvement with normalization of echocardiographic right ventricular systolic pressure within three months when leflunomide was stopped and dual PAH therapy initiated 5
• The variable response suggests that early detection and prompt discontinuation are critical, but most patients require PAH-specific pharmacotherapy 2, 5, 3

Other Cardiovascular Considerations

Heart Failure

• Leflunomide has not been associated with increased risk of congestive heart failure in the general RA population 1
• No other serious cardiovascular adverse effects beyond hypertension and rare PAH have been reported in the literature 1

Cardiovascular Risk in Rheumatoid Arthritis

• Patients with RA have inherently enhanced cardiovascular risk related to systemic inflammation and unfavorable lipid profiles 1
• The cardiovascular effects of leflunomide must be considered in the context of this baseline elevated risk 1

Clinical Pitfalls

• Do not attribute dyspnea in leflunomide-treated patients solely to underlying rheumatologic disease or deconditioning; maintain high suspicion for PAH 5, 3
• Do not delay right heart catheterization when echocardiography suggests elevated pulmonary pressures; hemodynamic confirmation is essential 2, 3
• Do not continue leflunomide after PAH diagnosis hoping for spontaneous improvement; the drug must be stopped immediately 2, 5, 3, 4
• Do not withhold PAH-specific therapy while waiting to see if leflunomide discontinuation alone will reverse the condition; most patients require pharmacologic treatment 2, 5