**4. Clinical efficacy**

Cyclosporin is one of the most effective antipsoriatic agents available because of its rapid onset of effect and potent immunosuppressive activity against disease flares (Amor et al., 2010; Ryan et al., 2010). Thus, in patients with severe psoriasis refractory to other agents, cyclosporin can produce rapid remission and serve as a useful 'bridge' to other treatments (Menter et al., 2009).

The efficacy of cyclosporin is dose-dependent, and times to psoriasis remission are shorter at higher doses (Faerber et al., 2001; Timonen et al., 1990). Results from key dose-finding studies and meta-analyses for cyclosporin in psoriatic patients are shown in Table 1. In patients treated with cyclosporin 1.25–5 mg/kg/day for 10–36 weeks, the PASI70 or PASI75 response rate (i.e. the proportion of patients with a decrease in Psoriasis Area and Severity Index [PASI] score of ≥70% or ≥75% from baseline, or with a decrease to a PASI score of ≤8)


a Proportion of patients with a decrease in Psoriasis Area and Severity Index (PASI) score of ≥75% from

baseline, or with a PASI score ≤8. b Percentage decrease in score from baseline. c PASI70 response.

db = double-blind; df = dose-finding; ma = meta-analysis; mos = months; r = randomised; wks = weeks.

Table 1. Key dose-finding studies and meta-analyses for cyclosporin in psoriatic patients.

to proteins (~90%), primarily lipoproteins,(Novartis Pharmaceuticals Corporation 2009) and transfer of the drug may occur between various lipoprotein subfractions, and between albumin and lipoproteins (Ryan et al., 2010). Cyclosporin is excreted in breast milk, such that mothers treated with the compound should not breastfeed (Novartis Pharmaceuticals

Cyclosporin is metabolised by the cytochrome P450 (CYP) system, primarily by isozymes CYP3A4 and CYP3A5 in the liver and small intestine; the p-glycoprotein pump also has a major influence on cyclosporin bioavailability and clearance (Novartis Pharmaceuticals Corporation 2009; Ryan et al., 2010). Cyclosporin is eliminated primarily via the bile. The terminal half-life of cyclosporin in plasma has varied from 6–24 hours in various populations,(Novartis Pharmaceuticals UK Ltd 2011; Ryan et al., 2010) but in patients with psoriasis, the value is probably closer to the lower end of this range (Berth-Jones 2005).

Cyclosporin is one of the most effective antipsoriatic agents available because of its rapid onset of effect and potent immunosuppressive activity against disease flares (Amor et al., 2010; Ryan et al., 2010). Thus, in patients with severe psoriasis refractory to other agents, cyclosporin can produce rapid remission and serve as a useful 'bridge' to other treatments

The efficacy of cyclosporin is dose-dependent, and times to psoriasis remission are shorter at higher doses (Faerber et al., 2001; Timonen et al., 1990). Results from key dose-finding studies and meta-analyses for cyclosporin in psoriatic patients are shown in Table 1. In patients treated with cyclosporin 1.25–5 mg/kg/day for 10–36 weeks, the PASI70 or PASI75 response rate (i.e. the proportion of patients with a decrease in Psoriasis Area and Severity Index [PASI] score of ≥70% or ≥75% from baseline, or with a decrease to a PASI score of ≤8)

> Cyclosporin dosage (mg/kg/day)

et al., 1992 r, df 217 1.25–5 12–36 wks 18–56 -

<sup>2001</sup>ma 597 1.25–5 10–12 wks 16–50c -

al., 1990 ma 457 1.25–5 3 mos 24–88 -

a Proportion of patients with a decrease in Psoriasis Area and Severity Index (PASI) score of ≥75% from

db = double-blind; df = dose-finding; ma = meta-analysis; mos = months; r = randomised; wks = weeks. Table 1. Key dose-finding studies and meta-analyses for cyclosporin in psoriatic patients.

<sup>1991</sup>r, db 85 3–7.5 16 wks - 59–77

Study duration Clinical response

Global disease severity scoreb

PASI75a

Corporation 2009).

**4. Clinical efficacy** 

(Menter et al., 2009).

Reference Study

Christophers

Faerber et al.,

Timonen et

Ellis et al.,

design

baseline, or with a PASI score ≤8. b Percentage decrease in score from baseline. c PASI70 response.

No. of patients was 16–88% (Christophers et al., 1992; Faerber et al., 2001; Timonen et al., 1990). Moreover, in a 16-week study in 85 patients with severe psoriasis, cyclosporin 3–7.5 mg/kg/day reduced global disease severity score by 59–77% (Ellis et al., 1991); however, although major, additional efficacy benefits can be obtained at cyclosporin doses >5 mg/kg/day, these benefits are offset by increased toxicity (Amor et al., 2010).

Psychological distress is common in psoriatic patients (Colombo et al., 2010c; Finzi et al., 2007). A large, observational, follow-up study of more than 1500 psoriatic patients (the PSYCHAE study) revealed that methotrexate and topical corticosteroids were associated with a significantly increased risk of minor psychological distress, whereas cyclosporin significantly reduced such distress, perhaps because of patients' overall perceptions of efficacy and tolerability (Colombo et al., 2010c). This finding has potentially major clinical significance, since it outlines the possibility for markedly improved quality of life during cyclosporin therapy, but the possibility for detrimental effects on quality of life for certain other psoriasis treatments. Additional, comparative investigations are now warranted to clearly define the relative effects of cyclosporin and other antipsoriatic agents on quality of life (see section 8).

#### **4.1 Intermittent short-term therapy**

Intermittent short-term therapy for 12–16 weeks is the most widely recommended dosing schedule for psoriasis: that is, short courses of cyclosporin are administered until marked improvement is evident, whereupon treatment is stopped; if relapse manifests, cyclosporin is re-started at the dosage that was earlier effective (Menter et al., 2009).

Fig. 2. Maintained efficacy of intermittent short-term cyclosporin therapy during a large, 1 year, multicentre, randomised trial in patients with plaque psoriasis (Ho et al., 1999). Values shown are the probability of a PASI75 response after 12 weeks' treatment with cyclosporin 2.5–5 mg/kg/day.

In a large, multicentre, randomised trial (the Psoriasis Intermittent Short Courses of Efficacy of Sandimmun Neoral® [PISCES] study), 400 patients with plaque psoriasis were initially treated with cyclosporin 2.5–5 mg/kg/day until clearance of psoriasis, or for a maximum of 12 weeks; patients were then randomised to abruptly or gradually discontinue (dosage reduction of 1 mg/kg/day each week) cyclosporin therapy. If relapse occurred, patients received another course of cyclosporin therapy. After 1 year of follow-up, 117 patients had

Systemic Cyclosporin in the Treatment of Psoriasis 293

Short-term cyclosporin therapy has a rapid onset of effect, and can therefore be administered as a rescue or bridging treatment for severe disease flares: that is, until a different maintenance therapy is started. As a bridging therapy, cyclosporin can be 'dovetailed' with the new maintenance regimen (e.g. biological therapy, methotrexate) to avoid clinical deterioration while the new schedule is taking effect. Cyclosporin can then be stopped without a risk of flares, and with a limited risk of adverse effects for only the short time that the cyclosporin bridging schedule and the new maintenance regimen are

Rescue cyclosporin therapy is especially effective in patients with erythrodermic, generalised, or suberythrodermic pustular psoriasis; a reducing-dosage strategy is employed after starting treatment at 5 mg/kg/day (Menter et al., 2009; Pathirana et al., 2009). In a study of 33 patients with erythrodermic psoriasis, the initial intervention was cyclosporin 4.2 mg/kg/day; after remission, the dosage was reduced by 0.5 mg/kg/day every 2 months. At 2–4 months, two-thirds of patients had attained complete remission, and marginally more than one-quarter had attained significant clinical improvement (Rosenbach

European guidelines recommend that the maximum period of continuous cyclosporin therapy in patients with psoriasis should be no more than 2 years (Griffiths et al. 2004; Menter et al. 2009; Pathirana et al. 2009). This is primarily because the incidence of renal dysfunction and nonmelanoma skin cancer may increase markedly with high doses of cyclosporin administered for longer periods (Paul et al. 2003; Ryan et al. 2010). In addition, any cyclosporin-related hypertension or renal dysfunction is generally reversible if the dose is maintained at ≤5 mg/kg/day and treatment duration at ≤2 years (Ryan et al. 2010).

Long-term cyclosporin therapy (for up to 2 years or more) maintains its efficacy in most psoriatic patients; however, the principal goal of maintenance therapy is not routine attainment of clinical remission, but rather attainment of marked clinical improvement with the minimum cyclosporin dosage — generally 3–3.5 mg/kg/day (Griffiths et al., 2000). Rather surprisingly, given the long-term nature of psoriasis, and in contrast to European guidelines, US guidelines stipulate that the duration of cyclosporin therapy should be restricted to ≤1 year in psoriatic patients (Amor et al. 2010; Menter et al. 2010). This restriction appears rather strange when it is considered that, only with longer-term treatment (3–5 years or more) may a substantial proportion of patients experience

In a large-scale study involving 285 patients with psoriasis, cyclosporin 1.25–5 mg/kg/day administered continuously for 6–30 months reduced mean PASI scores by approximately 75–94% from baseline, but after cyclosporin cessation, approximately 50% of patients experienced a relapse requiring antipsoriatic therapy (Mroweitz et al., 1995). Similarly, in another large-scale study (n=181), 86% of patients treated with cyclosporin at a dosage of ~5 mg/kg/day for 16 weeks had a PASI70 response, and subsequent maintenance therapy with cyclosporin 3 mg/kg/day was associated with a significantly longer median time to relapse than placebo (p<0.001); at the end of the 24-week maintenance phase, 42% of patients

**4.2 Rescue therapy** 

dovetailed (Amor et al., 2010).

et al., 2010).

**4.3 Long-term therapy** 

glomerulosclerosis (Menter et al. 2010).

received 3 cyclosporin courses, and 26 had received 4. After the first treatment course, abrupt versus gradual cessation of cyclosporin therapy was associated with a slightly, but significantly, shorter time to disease relapse (median 109 vs 113 days; p=0.038). Overall, the Kaplan-Meier probability of achieving a ≥75% decrease in disease area after 12 weeks' treatment was 83% after the first cyclosporin course, 76% after the second, 73% after the third, and 66% after the fourth [Fig. 2] (Ho et al., 1999).

In an extension of the PISCES trial, 76 patients were followed-up for a total of 2 years. The time in remission during the follow-up period was not significantly different between patients stopping cyclosporin therapy abruptly versus gradually (time in remission: 56.2% vs 61.8%); overall, the mean proportion of follow-up for which patients received cyclosporin was 42.8%. After the first treatment course, the median time to relapse was 115.5 days, but this became progressively shorter with an increasing number of cyclosporin courses (Ho et al., 2001).

#### **4.1.1 Prevention of relapse**

The well-designed PREWENT study assessed the efficacy of microemulsion cyclosporin 5 mg/kg/day, administered each weekend for 24 weeks in a total of 243 adults with chronic plaque psoriasis. The primary study endpoint in this multicenter, randomised, double-blind, placebo-controlled trial was relapse rate at 24 weeks: thus, 66.9% of cyclosporin-treated patients versus 53.2% of placebo recipients (p=0.072) had no worsening of psoriasis (i.e. no increase in PASI score to ≥75% of the value recorded before 8–16 weeks' induction therapy with cyclosporin). Although this difference only approached statistical significance, the time to first relapse was significantly longer in the cyclosporin than placebo group (p=0.0233), and in a *post hoc* analysis of patients with mild-to-moderate psoriasis, significantly more cyclosporin-treated patients than placebo recipients had no worsening of psoriasis (69.9% vs 46.3%; p=0.011) [Fig. 3] (Colombo et al., 2010a).

Fig. 3. Weekend cyclosporin therapy (5 mg/kg/day) prevents relapse in patients with mildto-moderate psoriasis: results from the PREWENT trial (Colombo et al., 2010a).

#### **4.2 Rescue therapy**

292 Psoriasis

received 3 cyclosporin courses, and 26 had received 4. After the first treatment course, abrupt versus gradual cessation of cyclosporin therapy was associated with a slightly, but significantly, shorter time to disease relapse (median 109 vs 113 days; p=0.038). Overall, the Kaplan-Meier probability of achieving a ≥75% decrease in disease area after 12 weeks' treatment was 83% after the first cyclosporin course, 76% after the second, 73% after the

In an extension of the PISCES trial, 76 patients were followed-up for a total of 2 years. The time in remission during the follow-up period was not significantly different between patients stopping cyclosporin therapy abruptly versus gradually (time in remission: 56.2% vs 61.8%); overall, the mean proportion of follow-up for which patients received cyclosporin was 42.8%. After the first treatment course, the median time to relapse was 115.5 days, but this became progressively shorter with an increasing number of cyclosporin courses (Ho et

The well-designed PREWENT study assessed the efficacy of microemulsion cyclosporin 5 mg/kg/day, administered each weekend for 24 weeks in a total of 243 adults with chronic plaque psoriasis. The primary study endpoint in this multicenter, randomised, double-blind, placebo-controlled trial was relapse rate at 24 weeks: thus, 66.9% of cyclosporin-treated patients versus 53.2% of placebo recipients (p=0.072) had no worsening of psoriasis (i.e. no increase in PASI score to ≥75% of the value recorded before 8–16 weeks' induction therapy with cyclosporin). Although this difference only approached statistical significance, the time to first relapse was significantly longer in the cyclosporin than placebo group (p=0.0233), and in a *post hoc* analysis of patients with mild-to-moderate psoriasis, significantly more cyclosporin-treated patients than placebo recipients had no worsening of psoriasis (69.9% vs

Fig. 3. Weekend cyclosporin therapy (5 mg/kg/day) prevents relapse in patients with mild-

p=0.011

to-moderate psoriasis: results from the PREWENT trial (Colombo et al., 2010a).

third, and 66% after the fourth [Fig. 2] (Ho et al., 1999).

al., 2001).

**4.1.1 Prevention of relapse** 

46.3%; p=0.011) [Fig. 3] (Colombo et al., 2010a).

Short-term cyclosporin therapy has a rapid onset of effect, and can therefore be administered as a rescue or bridging treatment for severe disease flares: that is, until a different maintenance therapy is started. As a bridging therapy, cyclosporin can be 'dovetailed' with the new maintenance regimen (e.g. biological therapy, methotrexate) to avoid clinical deterioration while the new schedule is taking effect. Cyclosporin can then be stopped without a risk of flares, and with a limited risk of adverse effects for only the short time that the cyclosporin bridging schedule and the new maintenance regimen are dovetailed (Amor et al., 2010).

Rescue cyclosporin therapy is especially effective in patients with erythrodermic, generalised, or suberythrodermic pustular psoriasis; a reducing-dosage strategy is employed after starting treatment at 5 mg/kg/day (Menter et al., 2009; Pathirana et al., 2009). In a study of 33 patients with erythrodermic psoriasis, the initial intervention was cyclosporin 4.2 mg/kg/day; after remission, the dosage was reduced by 0.5 mg/kg/day every 2 months. At 2–4 months, two-thirds of patients had attained complete remission, and marginally more than one-quarter had attained significant clinical improvement (Rosenbach et al., 2010).

## **4.3 Long-term therapy**

European guidelines recommend that the maximum period of continuous cyclosporin therapy in patients with psoriasis should be no more than 2 years (Griffiths et al. 2004; Menter et al. 2009; Pathirana et al. 2009). This is primarily because the incidence of renal dysfunction and nonmelanoma skin cancer may increase markedly with high doses of cyclosporin administered for longer periods (Paul et al. 2003; Ryan et al. 2010). In addition, any cyclosporin-related hypertension or renal dysfunction is generally reversible if the dose is maintained at ≤5 mg/kg/day and treatment duration at ≤2 years (Ryan et al. 2010).

Long-term cyclosporin therapy (for up to 2 years or more) maintains its efficacy in most psoriatic patients; however, the principal goal of maintenance therapy is not routine attainment of clinical remission, but rather attainment of marked clinical improvement with the minimum cyclosporin dosage — generally 3–3.5 mg/kg/day (Griffiths et al., 2000). Rather surprisingly, given the long-term nature of psoriasis, and in contrast to European guidelines, US guidelines stipulate that the duration of cyclosporin therapy should be restricted to ≤1 year in psoriatic patients (Amor et al. 2010; Menter et al. 2010). This restriction appears rather strange when it is considered that, only with longer-term treatment (3–5 years or more) may a substantial proportion of patients experience glomerulosclerosis (Menter et al. 2010).

In a large-scale study involving 285 patients with psoriasis, cyclosporin 1.25–5 mg/kg/day administered continuously for 6–30 months reduced mean PASI scores by approximately 75–94% from baseline, but after cyclosporin cessation, approximately 50% of patients experienced a relapse requiring antipsoriatic therapy (Mroweitz et al., 1995). Similarly, in another large-scale study (n=181), 86% of patients treated with cyclosporin at a dosage of ~5 mg/kg/day for 16 weeks had a PASI70 response, and subsequent maintenance therapy with cyclosporin 3 mg/kg/day was associated with a significantly longer median time to relapse than placebo (p<0.001); at the end of the 24-week maintenance phase, 42% of patients

Systemic Cyclosporin in the Treatment of Psoriasis 295

avoid any possible confusion among healthcare professionals, and to avoid any potential for major fluctuations in cyclosporin bioavailability, cyclosporin should be prescribed by brand

To induce remission of psoriasis, the recommended starting dosage of oral cyclosporin is 2.5 mg/kg actual bodyweight each day, administered in two divided doses; however, when a rapid initial response is required, a starting dosage of 5 mg/kg/day can be used (Neoral® SPC, 2011). If no improvement is evident after 1 month of 2.5 mg/kg/day, the dosage can be gradually increased in 0.5–1 mg/kg increments, at intervals of 2–4 weeks, up to a maximum of 5 mg/kg/day (Menter et al., 2009; Neoral® SPC, 2011). Cyclosporin should be stopped if the response is inadequate after 6 weeks' administration of 5 mg/kg/day. However, after an initially good response, the cyclosporin dosage can be reduced for maintenance therapy in steps of 0.5–1 mg/kg, at intervals of 2 weeks, until the lowest effective dosage level is attained (Amor et al., 2010; Neoral® SPC, 2011). Intermittent cyclosporin therapy may be appropriate for some psoriatic patients: that is, when an initial satisfactory response has been attained, cyclosporin therapy can be stopped and any subsequent relapses treated with

reintroduction of cyclosporin at the previously effective dosage (Neoral® SPC, 2011).

Before starting cyclosporin therapy, baseline renal function and blood pressure should be measured. Plasma creatinine should be measured every month. If an increase in plasma creatinine occurs to ≥30% above baseline, cyclosporin dosage should be reduced by 25–50%, even if levels are within the reference range (see section 7.2.2). If such dosage reduction does not successfully reduce plasma creatinine within 1 month, cyclosporin should be stopped. Similarly, if elevated blood pressure occurs and cannot be controlled by cyclosporin dosage reduction, or by intervention with antihypertensive therapy, cyclosporin cessation is

To improve clinical efficacy, cyclosporin has been administered with various topical therapies (e.g. corticosteroids, dithranol, vitamin D3 analogues [e.g. calcipotriol]) (Amor et al., 2010). However, data supporting such strategies stem mainly from small-scale, uncontrolled studies (Gottlieb et al., 1995; Griffiths et al., 1989). For example, in 12 psoriatic patients treated with cyclosporin 5 mg/kg/day for up to 18 weeks, and who applied topical dithranol to plaques on half of their bodies, improved clinical efficacy (e.g. significantly reduced severity index) was noted for combination therapy in 58% of patients (Gottlieb et al., 1995). In 13 patients with severe persistent psoriasis, cyclosporin 1–4 mg/kg/day was administered for 12–25 months, and an 81% decrease was noted in mean PASI score; 85% of the patients had received topical corticosteroid therapy after the first 3 months of cyclosporin (Griffiths et al., 1989). A larger randomised, double-blind, placebo-controlled trial in 69 cyclosporin-treated (2 mg/kg/day) patients with severe chronic plaque psoriasis revealed clinical improvement in a significantly greater proportion of patients who used concomitant calcipotriol 50 µg/g ointment versus vehicle: 50% vs 12% of patients (p=0.0019) had complete clearing of psoriasis or a ≥90%

(Neoral® SPC, 2011).

advocated (Neoral® SPC, 2011).

improvement in PASI score (Grossman et al., 1994).

**6. Combination therapy** 

**6.1 Topical treatments** 

treated with cyclosporin 3 mg/kg/day compared with 84% of placebo recipients had relapsed (Shupack et al., 1997).

A recent, retrospective evaluation of 193 patients with moderate-to-severe psoriasis revealed that cyclosporin 1.5–3.1 mg/kg/day (mean dosage) administered for 12–36 (mean 14) months reduced mean PASI score from 23.3 to 5.6; the PASI75 response rate was 73.9%. In this trial, 83/193 patients (43%) received cyclosporin monotherapy, whereas the remainder received polytherapy. Among monotherapy recipients, the physician's judgement of therapeutic success (total clearance of lesions) was 71% of patients, whereas that of clinical remission (clearance of lesions with some remaining pigmentation) was 19% of patients. Costs to the Italian healthcare system, based on a mean 1.5 cyclosporin courses administered over 14 months, were estimated at €2,984 per patient overall; the direct costs of cyclosporin acquisition were €2,058 per patient, which are approximately 4½–7 times less than annual treatment courses of etanercept and infliximab (Colombo et al., 2010b). To support and extend these cost findings, the design and execution of comparative economic evaluations of cyclosporin versus biological therapies in patients with moderate-to-severe psoriasis would now be particularly pertinent (see section 8).

In smaller studies, continuous versus intermittent cyclosporin therapy was significantly more effective over a 1-year period in 51 patients with chronic plaque psoriasis (PASI75 response rate: 92% vs 62%, p=0.008), although the mean cumulative annual dose of cyclosporin was 1.4-fold greater for continuous therapy (Chaidemenos et al., 2007). Furthermore, 60 patients with clearance or near clearance of psoriasis during cyclosporin induction therapy (3–7.5 mg/kg/day for 4 months) subsequently received cyclosporin maintenance therapy 1.5 or 3 mg/kg/day, or placebo, for up to 4 months (Ellis et al., 1995). Mean time to relapse was significantly longer in the higher-dose versus lower-dose cyclosporin group (12 vs 9 weeks; p=0.04), and in the higher-dose group versus placebo recipients (12 vs 7 weeks; p=0.002). At study completion, markedly fewer patients in the higher-dose versus lower-dose versus placebo group had relapsed: 43% vs 79% vs 95% (Ellis et al., 1995).

#### **4.4 Rotational therapy**

Rotational therapy with various systemic agents (e.g. acitretin, fumaric acid esters, methotrexate, mycophenolate mofetil) has occasionally been advocated as a means of reducing the duration, and any potential toxicity, of cyclosporin therapy (Amor et al., 2010). While most patients require additional antipsoriatic therapy after cyclosporin cessation (Amor et al., 2010), some patients may have an extended period of remission after cyclosporin therapy (Ho et al., 1999, 2001).
