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Leflunomide is a new isoxazole drug with disease modifying properties for the treatment of rheumatoid arthritis (RA). Hypertension has been mentioned as a common side effect of the treatment. It was found in up to 10.6% of patients receiving 25 mg leflunomide in a phase II study.1 New onset hypertension occurred in 3.7% of patients in a phase III European study,2 and in 2.1% of patients, with a mean increase in systolic and diastolic blood pressure of 2.2 and 1.9 mm Hg, respectively, in an American phase III study.3 There was no evidence that hypertension was related to an impairment of renal function or proteinuria. The changes in blood pressure during leflunomide treatment have not been studied in detail.
PATIENTS AND METHODS
Thirty consecutive patients fulfilling the American Rheumatism Association criteria for RA were recruited into a prospective study and treated with standard doses of leflunomide. Other enrolment criteria included stable treatment with non-steroidal anti-inflammatory drugs up to the maximum recommended dose and/or corticosteroid treatment up to 10 mg/day for at least three months before starting treatment with leflunomide. The patients were followed up at two week intervals. A trained nurse according to the Slovenian and WHO/ISH hypertension guidelines measured blood pressure.4 Automatic oscillometric monitors (Spacelabs 90209) were used for ambulatory blood pressure monitoring (ABPM).5 Seventeen patients finished the study according to the protocol with 6.5 (1) months between the two ABPM procedures.
RESULTS
A statistically significant increase in conventional blood pressure measurements of both systolic and diastolic blood pressure was seen (table 1). The rise in systolic blood pressure was seen relatively early—in 2–4 weeks (from 127.03 (20.2) mm Hg to 134.1 (24.3) mm Hg, p=0.034). On the contrary, the rise in diastolic blood pressure was not significant after 2–4 and 6–8 weeks, respectively. In 7/17 patients, the initially normal blood pressure values exceeded the systolic and/or diastolic blood pressure values of 140/90 mm Hg in the follow up measurements. Moreover, in four patients the systolic blood pressure was, at least once in the follow up period, more than 40 mm Hg and diastolic blood pressure more than 20 mm Hg above the initial values. According to the ambulatory blood pressure monitoring (ABPM) measurements the overall trend after the start of leflunomide treatment was an increase in both systolic and diastolic blood pressure and heart rate, which was highly statistically significant (table 1). Figure 1 shows individual changes in blood pressure and heart frequency.
Conventional systolic and diastolic blood pressure measurements, 24 hour averages of blood pressure, and heart frequency before (initial ABPM) and after treatment with leflunomide (final ABPM) in 17 patients with rheumatoid arthritis. Twenty four hour, day time (6 00 am to 10 00 pm), and night time (10 00 pm to 6 00 am) mean values and standard deviations are shown. Statistical significance of differences was tested with Student's t test. p Values of ≤0.05 were considered significant
Changes in (A) systolic blood pressure, (B) diastolic blood pressure, and (C) heart rate in 17 patients with RA treated with leflunomide. Twenty four hour averages of individual patients during ABPM performed during and after 6.5 (1) months of treatment with leflunomide are shown. The overall trends in individual variables are shown by the grey line.
DISCUSSION
Using standardised conditions of blood pressure measuring (not the case in phase II and phase III clinical trials) and ABPM, we confirmed the blood pressure rises during treatment with leflunomide. Adding to the knowledge from previous studies, we showed that a statistically significant rise in systolic blood pressure was apparent already after2–4 weeks of the treatment, thus pointing to the need for early blood pressure monitoring. By contrast, the rise in diastolic blood pressure appeared later. Hypertensive values in individual patients suggest that regular measuring of blood pressure is required during treatment with leflunomide.
Employing ABPM, we confirmed the significant rise in blood pressure during the leflunomide treatment, thus making the role of the “white coat” phenomenon unlikely. It should be mentioned that it has been confirmed that non-invasive ABPM has no effect on blood pressure because of discomfort during cuff inflation. We are also not aware of any special device developed to measure blood pressure in patients with painful limbs. However, as a clinically relevant (>5 joints) improvement in tender and swollen joint count was seen in 14 (83%) of the 17 patients analysed, the degree of pain imposed by blood pressure measurements and its effect on blood pressure were expected to decrease rather than rise during the study.
The results do not allow us to speculate on the mechanism of the blood pressure increase associated with the leflunomide treatment. As the heart rate also rises during leflunomide treatment, it has been assumed that hypertension may be caused by an increased sympathetic drive. This hypothesis remains to be tested. The changes in the raised blood pressure after six months of leflunomide treatment will be clarified after the final report of all extended studies.