Long-term efficacy and adverse event of nifedipine sustained-release tablets for cyclosporin A-induced hypertension in patients with psoriasis

ARTICLE

The clinical value of oral cyclosporin A (CYA; Sandimmun^®) in the treatment of chronic severe plaque psoriasis has been established. Many clinical studies of the efficacy and safety of CYA treatment for psoriasis have been performed [1-5]. In Japan, multicenter controlled studies for critical evaluations of effects of CYA on psoriasis have been performed [6], and CYA has been approved for use for severe psoriasis by the Department of Health and Welfare of Japan.

Although the efficacy of CYA in psoriasis is clear, the risk of side effects with its use requires further investigation, especially for extended CYA treatment. It has been reported that hypertension and increases in serum creatinine levels are the two most frequently encountered complications of treatment with CYA [4]. The increase in serum creatinine > 30% above baseline is dose-related and clearly related to the nephrotoxicity of CYA. However, the degree of hypertension does not appear to be related to the dose of CYA [4]. The etiology of the induction of hypertension by CYA is not fully understood.

The development of hypertension appears to be bimodal in onset, during the first 9 months, and after 36 months of treatment [7]. Also, no association has been observed between the onset of hypertension and the 30% increase in serum creatinine levels [7]. It has been suggested that antihypertensive therapy for CYA-induced hypertension can be successfully administered with concomitant administration of calcium channel blockers such as nifedipine or isradipine as first-line drugs because of their nephroprotective effect [8]. However, there have been few detailed studies of the antihypertensive effects or adverse events of calcium channel blockers in hypertensive psoriatic patients under long-term treatment with CYA.

In this paper, we report the practical effectiveness of nifedipine and the adverse events encountered in 13 psoriatic patients during the course of CYA treatment over more than 2 years.

Patients and methods

Patients

The study involved patients with psoriasis whose erythematous plaque or small scaly papular erythematous lesions had spread to include more than 50% of the entire body. They had not been treated with immuno-suppressive agents before entering the study. They began treatment with CYA at a dose of 3.5-4.5 mg/kg/day, with informed consent. Topical corticosteroid or vitamin D3 ointment was used when the dose of CYA was reduced because of improvement of psoriatic eruptions. A subclinical hypertensive state was defined as either systolic pressure of 155-160 mmHg or diastolic pressure 90-95 mmHg. When hypertension was induced by CYA therapy, a calcium channel blocker, nifedipine, was given to treat hypertension as described below.

Study design and treatment

Subjects who received CYA were monitored for blood pressure once every two weeks. When systolic blood pressure was found to be higher than 160 mgHg or diastolic blood pressure was higher than 95 mgHg on two consecutive visits, they began treatment with nifedipine sustained-release tablet (abbreviated as N-SR, Adalat-L^®) at a dose of 20 to 40 mg per day without reducing the dose of CYA. When the severity grades for the skin symptoms improved more than 80%, the dose of CYA was reduced to 2.5 to 3.0 mg/kg/day and topical ointments were additionally applied to maintain the improvement. When careful examination of the blood pressure revealed stable blood pressure (less than 150/90 mgHg) for more than 3 months after initiation of administration of N-SR, doses of N-SR were reduced to 10 to 20 mg per day in selected patients. They were monitored for as long as 25 months as a part of this study.

As a control, randomly selected psoriatic patients whose blood pressure was within normal range during the course of CYA treatment for more than 2 years were also analyzed for adverse events and laboratory data as described below.

Evaluations

Subjects' medical histories were evaluated and a complete physical examination was performed prior to entry. In particular, histories of hyperlipidemia, liver dysfunction, diabetes mellitus or borderline hypertension were carefully evaluated.

At each visit during treatment, patients were questioned about adverse events. Vital signs and laboratory tests for blood urea nitrogen and serum creatinine level were obtained once every two weeks. The following laboratory tests were performed monthly: hemoglobin, hematocrit, blood cell count, leukocyte analysis, platelet count, total protein, albumin, total bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), total cholesterol, triglyceride, serum glucose, uric acid, electrolytes, inorganic phosphorus, magnesium, and urinanalysis. CYA trough levels were also measured, principally on a monthly basis.

Statistical analysis

Statistical comparison of blood pressures before and during treatment was performed using the paired t-test.

Results

Patient background factors

A total of 21 patients with psoriasis were enrolled in the study. The background factors for the patients are shown in Table I and the mean values for each group are shown in Table II.

The ages of the 13 patients (11 male and 2 female) who received N-SR ranged from 46 to 73 years (mean: 58.5 years). Eleven of these patients had exhibited severe skin symptoms, and two had exhibited moderate symptoms before treatment with CYA. Nine of the 13 patients had exhibited hyperlipidemia before treatment. Patients were considered hyperlipidemic if either the serum cholesterol level was higher than 220 mg/l or the triglyceride level was higher than 150 mg/l. Three patients had exhibited liver dysfunction before treatment.

The mean blood pressures of the patients enrolled in the treatment protocol with both CYA and N-SR were 143 mmHg systolic, and 87 mmHg diastolic. None of the patients had received anti-hypertensive drugs before initiation of CYA treatment. Seven patients had exhibited a prehypertensive state before the CYA treatment.

As shown in Tables I and II, the ages of the 8 patients (5 male and 3 female) who were not treated with N-SR because they were normotensive during CYA treatment, ranged from 30 to 61 years (mean: 43.5 years). All 8 patients had exhibited severe skin symptoms before treatment with CYA. Five patients had exhibited hyperlipidemia, and one patient liver dysfunction. The mean blood pressures of the patients before CYA treatment were 119 mmHg systolic and 74 mmHg diastolic. None of the patients of this group had exhibited a prehypertensive state (Table I).

Effects of N-SR on CYA-induced hypertension

Figure 1 shows the time course of changes in blood pressure for the 13 psoriatic patients who were treated with both CYA and N-SR for as long as 25 months. As shown in Table I, all 13 patients had exhibited CYA-induced hypertension prior to N-SR treatment. Hypertension developed as early as 2 weeks after the initiation of CYA therapy. The mean systolic and diastolic pressures of these patients just before initiation of N-SR treatment were 164 mmHg and 100 mmHg, respectively (Table II). Ten patients became hypertensive during the first 8 weeks and 3 patients became hypertensive after the first 5 months of therapy (Table I).

As shown in Table I and Figure 1, the increases in systolic and diastolic blood pressures in the patients by CYA therapy returned to nearly normal levels as early as 4 weeks after starting N-SR therapy. The systolic and diastolic pressures of the 13 patients who were treated with N-SR for 4 weeks decreased to 143 mmHg and 78 mmHg, respectively. The latter pressures were significantly lower than those before treatment with N-SR (Fig. 2). Both systolic and diastolic blood pressures were maintained within the normal range for as long as 25 months (Fig. 1).

The means of the systolic and diastolic pressures of the 8 psoriatic patients who did not receive N-SR because they remained normotensive during CYA therapy are shown in Figure 3. The blood pressures at 3 timepoints (before treatment with CYA, after 8 weeks of treatment with CYA, after 1 year of treatment with CYA) did not differ at all.

The dosage of CYA received by the 13 psoriatic patients who received N-SR could be maintained because of the maintenance of blood pressure within the normal range with N-SR during the course of the CYA therapy (Fig. 4). Thus, treatment with both CYA and N-SR made remission of psoriatic eruptions possible without reducing the dosage of CYA. The mean dosages of CYA at several timepoints during CYA therapy were as follows: 8 weeks before treatment with CYA: 3.4 ± 0.7 mg/kg, immediately before treatment with N-SR: 4.1 ± 1.2 mg/kg, after 2 months, 6 months and 12 months of treatment with CYA and N-SR: 2.7 ± 0.8 mg/kg, 3.0 ± 1.3 mg/kg, and 3.3 ± 1.3 mg/kg, respectively. These doses were maintained for as long as 2 years. The mean dosages of CYA for the 8 control psoriatic patients who were not treated with N-SR during CYA therapy for 2 years were around 3.0 mg/kg. Thus, the dosage of CYA did not differ between the two groups of patients.

Adverse events

Nine of the 13 patients who were treated with N-SR exhibited abnormal increases in blood urea nitrogen (BUN) level (BUN > 22 mg/dl) during the course of CYA and N-SR treatment (Table I). The mean serum BUN level before CYA therapy in the hypertensive group was 19.8 and it had increased to 20.8 after 1 year of treatment (Table II). The increase in BUN levels appeared as early as 2 weeks after starting CYA therapy. In one case (case 9 in Table I (A)), an increase in the BUN level appeared 1 year after initiation of CYA therapy. BUN levels during CYA therapy in these patients ranged from 25 to 30 mg/dl, except for one patient (case 3 in Table I (A)) with a BUN level 50 mg/dl due to complications of renal dysfunction prior to treatment with CYA. A few patients exhibited transient increases in serum creatinine (around 20 to 30% above baseline values), but levels were always within the normal range. The patient with renal dysfunction described above (case 3 in Table I (A)) also exhibited an abnormal increase in serum creatinine level.

As shown in Table I, only one patient (case 3 in Table I (B)) of the 8 control patients exhibited a slight increase in the BUN level (maximum 25 mg/dl), and the other 7 patients exhibited no renal dysfunction. The mean serum BUN level before CYA therapy was 14.5 mg/dl and it was not increased after 1 year of therapy (Table II).

Gingival hyperplasia was observed in two patients, both of whom received N-SR in combination with CYA therapy (cases 12 and 13 in Table I (A)). Gingival hyperplasia developed in these patients after approximately 2 years of combined treatment.

The numbers of patients with side effects and abnormal laboratory findings in the two groups are shown in Table I. The group of patients treated with N-SR in combination with CYA exhibited a higher frequency of renal dysfunction (increase in BUN levels) than the group of patients treated with CYA alone. Gingival hyperplasia was not found in the control group.

Discussion

Long-term treatment of chronic severe plaque psoriasis with oral CYA in the out-patient dermatology clinic is now commonly performed. In Japan, a study of the effectiveness and adverse events of CYA therapy over 5 years was performed at four institutions [9]. In that study, we found that hypertension was the most common side effect (7 of 52 patients, 13.5%). These findings stimulated study of how CYA-induced hypertension can be controlled with anti-hypertensive medications.

The frequency of CYA-induced elevations of blood pressure in psoriatic patients has been reported to be 5-45% [1-4, 7]. This discrepancy in findings may be due to the use of different protocols for CYA therapy. The dose of CYA has been claimed to be clearly related to increases in serum creatinine levels due to nephrotoxicity, but the degree of CYA-induced hypertension does not appear to be clearly related to the CYA dose [4]. There is a report that initial diastolic pressure higher than 75 mmHg was significantly related to the development of hypertension in psoriatic patients treated with CYA [7]. In fact, the mean initial diastolic pressure in the 13 enrolled patients in our study who were treated with both CYA and N-SR was 87 mmHg, while that of the 8 control normotensive patients who were treated with CYA alone was 74 mmHg.

The increase in blood pressure due to CYA therapy appears to be bimodal in onset: it appears during the first 3-9 months of therapy, and after 36 months of therapy [4, 7]. In our study, hypertension developed as early as 2 weeks after initiation of CYA therapy, and most of the patients who developed hypertension did so during the first 8 weeks of therapy, although a few patients developed hypertension after 5 months of therapy. The mechanisms responsible for the increase in blood pressure may differ in the two groups of patients.

Hypertension which develops early during CYA therapy may be related to latent hypertension in patients, while that which develops later may result from renal dysfunction. Thus, the blood pressure of psoriatic patients should be monitored along with renal function as long as they are being treated with CYA.

Concerning the clinical effects of N-SR on CYA-induced hypertension, our findings indicate that N-SR was able to control the CYA-induced hypertension without reducing the CYA dose. Clinical improvement of psoriatic eruptions was also obtained and maintained in the 13 patients who were treated with both CYA and N-SR.

Abnormal increases in serum BUN level were found during the course of CYA therapy in 9 of the 13 patients who received N-SR, while only 1 of the normotensive 8 patients exhibited a slightly abnormal serum BUN level. This fact may lead to the conclusion that N-SR apparently induces abnormal BUN levels. However, it has been reported that nifedipine significantly suppresses the reduction in total renal blood flow and glomerular filtration rate by CYA [8]. So, it is considered that the renal function of patients who require N-SR may be easily affected by CYA therapy. Thus, the use of N-SR for CYA-induced hypertension should be recommended not only for control of blood pressure but also for prevention of the deterioration of renal function associated with CYA.

The striking adverse event of combined treatment with both CYA and N-SR was gingival hyperplasia, which was observed in 2 patients. The hyperplasia developed in both patients after approximately 2 years of combined treatment. Both CYA and N-SR are known to cause gingival hyperplasia, but the precise mechanisms of the development of this condition are unclear. Genetic factors which give rise to fibroblast heterogeneity or gingival inflammation appear to be significantly related to gingival overgrowth [10]. The combination of N-SR and CYA causes gingival hyperplasia more than the use of each agent alone does. It has been reported that the degree of gingival overgrowth differed significantly in the papillary and dental areas between patients treated with CYA alone and those treated with CYA plus nifedipine [11]. A study of the prevention of the induction of such gingival overgrowth by concomitant administration of CYA and N-SR remains to be performed.

CONCLUSION

Acknowledgements

Statistical analysis was kindly carried out by Mr. K. Tsukahara of Bayer Yakuhin, Ltd. (Osaka, Japan).

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