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Keywords:

  • cyclosporin;
  • microemulsion;
  • Psoriasis Area and Severity Index;
  • psoriasis vulgaris

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

Cyclosporin is used for moderate to severe psoriasis and improves not only the skin lesions but also quality of life of the patients. To improve its safe use, we evaluated a low-dose, intermittent regimen of cyclosporin in the treatment of psoriasis vulgaris. Seventy-three patients received approximately 2.5 mg/kg per day of cyclosporin microemulsion twice daily before breakfast and dinner for 2–12 weeks until 75% reduction was achieved in Psoriasis Area and Severity Index (PASI) score. When the skin lesions relapsed after cessation of cyclosporin and showed less than 50% reduction from baseline in PASI score, cyclosporin was restarted. This cessation and restart cycle was repeated if necessary. Treatment outcomes were assessed at 12, 48 and 96 weeks after initiation of the therapy. The initial dose of cyclosporin was 2.32 ± 0.27 (standard deviation [SD]) mg/kg per day. At baseline, the mean PASI score was 11.3 ± 5.3 (SD). An average of 49.8 ± 23.8 (SD) days of the therapy achieved PASI 75% reduction. In 20 of 73 patients, the second course of cyclosporin was required. The mean interval between the first and second course was 94 days. An average of 60.8 ± 26.9 days was required to achieve PASI 75% reduction in the second course, which was not significantly longer than that in the first course. Only six patients required cyclosporin for 96 weeks. The adverse effects included one case of hypertension. Our study suggests that low-dose, intermittent cyclosporin microemulsion is efficacious for the treatment of moderate to severe psoriasis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

Long-term therapies are often required for improvement of the skin lesions and quality of life (QOL) of patients with psoriasis. In this chronic disease, the treatment goal is disease control, and permanent complete clearance may not be achievable.[1] In addition to topical corticosteroids and vitamin D3 analogs, phototherapy/photochemotherapy, oral cyclosporin (CyA) and etretinate, and systemic biologics are widely used for psoriasis.[1, 2] Biologics such as adalimumab, infliximab and ustekinumab are well known to be effective even for severe psoriasis. However, they may have disadvantages in the inconvenience of administration, secondary unresponsiveness or occurrence of paradoxical adverse effects, and induction of severe infection such as tuberculosis.

Low-dose, intermittent CyA therapies have been used for the treatment of mild to moderate psoriasis vulgaris.[3-9] While 3–5 mg/kg per day is the original dose for severe psoriasis, the dose of 1.5–3 mg/kg per day is employed for this purpose in a number of reports. Patients are treated with CyA at the lower doses over a period of several months to 2 years.[3-9] However, the periods from the drug initiation to the remission, from the remission to the relapse, and from the drug restart to the re-remission remains elusive in low-dose, intermittent CyA therapies. The aim of the present study was to clarify the efficacy and safety of this usage of CyA for mild to moderate psoriasis vulgaris, focusing on these administration periods and intervals.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

Eligibility and exclusion criteria

Patients aged between 16 and 70 years of age with chronic, moderate to severe plaque psoriasis who required systemic therapy to improve their QOL were screened. Patients were eligible for this study if their Psoriasis Area and Severity Index (PASI) score was less than 20 at study entry and if they had shown a poor response to more than 4 weeks of topical agents such as corticosteroids and vitamin D3 analogs. The following patients were excluded from the study: those treated with psoralen plus ultraviolet A therapy or narrowband ultraviolet B therapy in the previous 1-year period; those who underwent systemic therapy in the previous 4-week period; those with known contraindications to CyA; those with a history of malignancy or chronic infection, uncontrolled hypertension, significant impairment of hematopoietic, cardiovascular, liver or renal function; and pregnant and nursing women.

Study design

This prospective, open-label, multicenter study was conducted from 2002 to 2004 at 10 dermatology outpatient clinics affiliated with seven universities (Chiba University, Osaka Medical University, Okayama University, University of Occupational and Environmental Health, Wakayama Medical University, Yamanashi University and Hamamatsu University School of Medicine). Participation was voluntary, and written informed consent was obtained from all patients. The study was approved by the local ethics committee of each participating institution.

The study design is summarized in Figure 1. Patients received approximately 2.5 mg/kg per day of CyA microemulsion in soft gelatin capsules twice daily before breakfast and dinner during 2–12 weeks until remission was achieved. Remission was defined as more than 75% reduction in PASI score (PASI 75). Treatment with CyA was ceased at the time point when PASI 75 was achieved. When the skin lesions relapsed after cessation of CyA and they showed less than 50% reduction from baseline, CyA was restarted at 2.5 mg/kg per day. This cessation and restart cycle was repeated if necessary. Treatment outcomes were assessed at 12, 48 and 96 weeks after initiation of the therapy. The use of topical corticosteroids and vitamin D3 analogs was permitted without restriction in the drug potency, and the doses were adjusted as required. CyA was ceased if side-effects such as renal failure, hypertension, gastrointestinal symptoms or a rise in serum creatinine over 30% of the baseline value were observed.

image

Figure 1. Design of this study. All patients received 2.5 mg/kg per day of cyclosporin (Cy) microemulsion in a soft gelatin capsule twice daily before breakfast and dinner during 2–12 weeks until remission was achieved. Remission was defined as a 75% or more reduction in the Psoriasis Area and Severity Index score (PASI 75). Cyclosporin was ceased at the time point when PASI 75 was achieved. Cyclosporin microemulsion at 2.5 mg/kg per day was restarted upon relapse, which was defined as a less than 50% improvement in PASI score from baseline. The number of treatment courses depended on the responses to cyclosporin microemulsion.

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Safety assessment

The presence of adverse drug events was closely monitored. Parameters including blood pressure, hematology profile and serum biochemistry including serum creatinine were regularly checked. CyA trough levels or plasma concentrations 2 h after administration were measured by radioimmunoassay. The characteristics of enrolled patients and the amount of topical ointments used were also documented.

Assessment of efficacy

Psoriasis Area and Severity Index score was documented at baseline, 2 weeks later, and then monthly until 2 years had passed after commencement of treatment. The applied dose of corticosteroids and vitamin D3 analog ointments were monitored monthly. Self-administered PASI was used to assess QOL. Patient satisfaction was evaluated at 12 weeks, 1 year and on the last day of treatment using the following scoring system: 3, very satisfied; 2, satisfied; and 1, not satisfied.

Statistical analysis

All values were expressed as mean ± standard deviation (SD). Data were analyzed using Kruskal–Wallis anova and Mann–Whitney U-test with Bonferroni correction. P < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

Patient characteristics and CyA dose

A total of 73 patients were enrolled in this study (Table 1), and 68 patients could be evaluated. Male predominance and the mean age of 60.7 years were noted. Comorbidities included hypertension, diabetes mellitus, hyperlipidemia and hyperuricemia. CyA emulsion was administrated to the patients as described in the study design of the Methods section (Fig. 1). The mean initial dose of CyA emulsion was 2.32 ± 0.27 mg/kg per day. Its mean dose was comparable to those at week 12, 48 and 96 (2.32 ± 0.27, 2.33 ± 0.57 and 2.31 ± 0.28 mg/kg per day, respectively). Not all the patients were treated with CyA within 12 weeks until remission. The number of enrolled patients was 73, three of whom were treated with CyA for more than 12 weeks, while two patients withdrew from follow up on their own initiative.

Table 1. Patient characteristics
Patient demographics
Patient (n)68
Age (years)58.7 ± 13.3
Male/female58:10
Disease duration (years)9.9 ± 7.3
Patient's satisfaction at baseline2.9 ± 0.6
Comorbidities (patient number)Hypertension, 7
Diabetes mellitus, 4
Hyperlipidemia, 3
Hyperuricemia, 3

Assessment of efficacy

Percentage reduction in PASI score was used as an indicator of treatment efficacy. At baseline, the mean of PASI score was 11.3 ± 5.3 (SD). In 20 of 68 patients, the second course of CyA was required. Our study showed that 53 patients could keep PASI 50% reduction although the baseline PASI score was not so high in these patients. Only 12 patients required the third course of CyA. Six and three patients received the fourth and fifth courses, respectively. The PASI score of the patients was reduced by 74.8 ± 22.6%, 72.8 ± 21.9% and 84.0 ± 13.4% at weeks 12, 48 and 96, respectively, in patients who were followed up for 96 weeks (Fig. 2a). PASI 75 was achieved in 62% of the patients at week 96. An average of 49.8 ± 23.8 (SD) days of the therapy achieved PASI 75% reduction. Complete clearance of psoriatic lesions in a representative patient at week 96 is shown in Figure 2(b).

image

Figure 2. Clinical improvement by cyclosporin treatment. (a) Improvement in Psoriasis Area and Severity Index (PASI) score from baseline 12, 48 and 96 weeks after cyclosporin treatment. (b) Complete clearance of psoriasis in a representative patient 96 weeks after treatment. Each score was calculated and analyzed by Kruskal–Wallis anova and Mann–Whitney U-test with Bonferroni correction.

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Periods of CyA therapy and remission

The period of each course of CyA therapy varied from 45 to 65 days to obtain PASI 75 (Fig. 3a). An average of 60.8 ± 26.9 days was required to achieve PASI 75% reduction in the second course, which was not significantly longer than that in the first course. In the individual patients who underwent several courses of the therapy, there were no significant differences in the period between the courses (Fig. 3a). CyA was restarted at the remission time interval, when the skin lesions were worsened, as the reduction of PASI score was less than 50% from baseline. The mean interval between the first and second course was 160 days. Although not significantly different, these remission times tended to be shorter as the number of the re-administration courses increased (Fig. 3b).

image

Figure 3. Periods of cyclosporin treatment and remission. Cyclosporin treatment was ceased at the time point when 75% or more reduction in the Psoriasis Area and Severity Index score (PASI 75) was achieved. The period of cyclosporin treatment in each course (1st to 5th courses) was calculated and analyzed by Kruskal–Wallis anova and Mann–Whitney U-test with Bonferroni correction.

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Doses of topical corticosteroids and vitamin D3 analogs

The doses of topical corticosteroids used for psoriatic lesions at 0 (just before CyA therapy), 12 and 48 weeks after commencement of CyA were gradually declined from 75.8 ± 37.2 to 30.7 ± 8.28 g/month, and retained at week 96 (Fig. 4a). The mean dose of corticosteroids 1 year after initiation of CyA was significantly decreased (= 0.006 [Kruskal–Wallis anova];= 0.28, 0 vs 12 weeks; = 0.023, 0 vs 48 weeks; and = 0.0032, 0 vs 96 weeks [Mann–Whitney U-test with Bonferroni correction]). No significant changes in the dose of topical vitamin D3 analogs were noted (Fig. 4b), but the post-1-year dose also tended to be declined (= 0.063).

image

Figure 4. Amounts of corticosteroid and vitamin D3 ointments used in the patients. Topical corticosteroids and vitamin D3 were allowed in this study. The applied dose of corticosteroids and vitamin D3 ointments were monitored monthly. Each dose was calculated and analyzed by Kruskal–Wallis anova and Mann–Whitney U-test with Bonferroni correction. *< 0.05, **< 0.01.

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Patient satisfaction

Evaluation of patient satisfaction using a 3-point rating system revealed satisfaction scores were 1.07 ± 0.26, 2.43 ± 0.63 and 2.62 ± 0.35 at weeks 12, 48 and 96, respectively. A significant increase in the satisfaction score from baseline was seen during the course of the study (= 0.011 [Kruskal–Wallis anova]; = 0.00013, 12 vs 48 weeks; and = 0.00005, 12 vs 96 weeks [Mann–Whitney U-test with Bonferroni correction]; Fig. 5a). Self-administered PASI scores significantly decreased from 12.5 ± 8.5 to 0.84 ± 0.05 (= 1.12 × 10−14 [Kruskal–Wallis anova]; = 0.033, 0 vs 12 weeks; = 0.022, 0 vs 48 weeks; and = 0.013, 0 vs 96 weeks [Mann–Whitney U-test with Bonferroni correction]; Fig. 5b).

image

Figure 5. Patient satisfaction and self-administered Psoriasis Area and Severity Index (PASI) score. Patient satisfaction was evaluated at 12 weeks and 1 year after treatment, and on the last day of treatment using the following scores: 3, very satisfied; 2, satisfied; and 1, not satisfied. Self-administered PASI was used to assess quality of life. Each score was calculated and analyzed by Kruskal–Wallis anova and Mann–Whitney U-test with Bonferroni correction. *< 0.05, **< 0.01.

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Adverse side-effects

There were a total of 16 adverse events in 14 patients at week 12, two adverse events in two patients at week 48, and three adverse events in two patients at week 96. The adverse events included facial nerve paralysis, general fatigue, polyuria, tinea corporis, decreased serum immunoglobulin M, proteinuria, hyperlipidemia, hypertension, elevated levels of creatinine and blood urea nitrogen, and elevated total bilirubin. Ten patients were withdrawn from the study because of facial nerve paralysis, elevated creatinine, hyperlipidemia, proteinuria or general fatigue. These events resolved after cessation of CyA.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References

The present study showed that low-dose, intermittent CyA microemulsion therapy is effective and useful for the treatment of mild to moderate psoriasis. PASI 75 was achieved approximately 48 weeks after CyA therapy. Only 27.4% of patients required the second course of the therapy, and further CyA was unnecessary in these patients for approximately 3 months after achievement of remission. The third course of CyA was required in only 12 patients. As the adverse effect, one case of hypertension was observed.

Biologics have become a mainstay therapy for severe psoriasis,[1] which can induce dramatic skin improvement and improve patients' QOL.[10, 11] However, the use of these agents requires monitoring for infections such as tuberculosis and pneumocystis pneumonia. In addition, the annual cost of biologics is relatively higher than other systemic therapies including CyA microemulsion. Furthermore, continuous treatment with biologics is required to maintain therapeutic effect and to avoid a loss of response.

Cyclosporin belongs to the second-line treatment for psoriasis and has been widely used for moderate and severe psoriasis.[2] This immunosuppressant can be used either continuously or intermittently depending on the patient's condition. Several studies have suggested that CyA serves as maintenance therapy in psoriasis vulgaris. Ohtsuki et al.[3] conducted a multicenter, randomized, controlled study to assess the long-term efficacy and safety of CyA for psoriasis using either a continuous or an intermittent regimen. In their study, the initial dose was 3–5 mg/day in both regimens, and patients in the continuous treatment group received 0.5–3 mg/day once remission was achieved. In the event of relapse, the dose was gradually escalated to 3–5 mg/kg per day until remission was obtained. In the intermittent group, the dose was tapered once remission was achieved and the drug was eventually ceased. The PASI score was decreased by more than 70% with no significant difference between the two regimens.

A study of daily versus intermittent application of high concentration tacalcitol ointment combined with low-dose CyA microemulsion was reported by Abe et al. in 2006.[4] Although patients in both groups showed significant improvement, patients in the intermittent application group were more satisfied, and intermittent topical therapy was associated with superior cost performance. The cost of low-dose CyA microemulsion with intermittent application of tacalcitol ointment was less than half of that of high-dose CyA microemulsion with daily application of tacalcitol. The same authors also reported a study of low-dose CyA preconcentrate (2.5 mg/kg per day) over 12 weeks in 2007.[5] The dose of CyA was reduced to 1.5 mg/kg per day and topical vitamin D3 was commenced once PASI 75 was achieved. All patients showed improvement within 12 weeks, and 10 of 19 patients achieved over 75% reduction in PASI score. No adverse effects were noted during treatment.

In a randomized, controlled study, Shintani et al.[7] treated psoriatic patients with either 100 mg CyA emulsion once daily (group A) or 50 mg twice daily (group B). The improvement rate was 69.4% in group A and 73.4% in group B. PASI 75 and 90 were achieved in both groups with no significant difference at 12 weeks. Vena et al.[8] reported that a greater PASI reduction was achieved after combined therapy with low-dose CyA (2 mg/kg per day) and calcipotriol-betamethasone dipropionate ointment compared with CyA and emollient treatment in patients with moderate to severe plaque psoriasis.

Our study monitored psoriatic patients treated with CyA over a greatly longer period than the other studies. This study confirmed the efficacy of CyA in the treatment of psoriasis without the development of severe adverse effects. Repeated courses of CyA therapy improved psoriatic skin eruptions and well controlled the condition. The amount of topical corticosteroids was significantly reduced by repeated therapy, and the skin eruptions could be maintained by topical vitamin D3 analogs. CyA-induced liver and kidney dysfunction may be avoided by using intermittent therapy. However, our study also showed that 10 patients withdrew because of their adverse effects. Therefore, we should always use CyA carefully on patients with psoriasis.

Even for psoriatic patients under regular dermatological care, the QOL of patients with psoriasis vulgaris is comparable to that of patients with diabetes, coronary heart disease and cancer.[12] Currently, the PASI score and body surface area involvement are the most commonly used parameters in Europe for evaluating the clinical severity of psoriasis vulgaris.[2] PASI 75 is the benchmark used in clinical studies, and the majority of patients with PASI 75 experience improvements in QOL and in the Dermatology Life Quality Index. Despite the limitation of the open-label design, our present study suggests that low-dose, intermittent CyA microemulsion is efficacious with a favorable risk/benefit ratio.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. References