Short-term therapy: for induction of remission

In an open, prospective, multicenter trial conducted by Berth-Jones and colleagues, the efficacy and tolerability of intermittent CsA (Neoral) therapy were studied in 41 patients with psoriasis vulgaris. Each patient received 3 treatment periods of up to 12 weeks’ duration of CsA at a divided dosage of 5 mg/kg/d. Treatment was continued until the patient achieved a 90% remission of afflicted areas or for duration of 12 weeks, whichever occurred first. Increases in blood pressure (>95 mm Hg diastolic at 2 consecutive visits), serum creatinine (>30% from baseline), or development of other adverse effects resulted in 25% dose reductions. Satisfactory clinical response to CsA was evaluated using a modified “rule of nines” criteria at the end of each treatment period. There was significant improvement in erythema, infiltration, and desquamation the end of each treatment period as compared with baseline ( P <.01). There was a high proportion of patients achieving clinical remission following each treatment period, including 93% of patients at period 1 (mean 7.2, SD 3.0 days), 85% of patients at period 2 (mean 8.0, SD 3.2 days), and 91% of patients at period 3 (mean 7.4, SD 3.2 days). Patients experienced relapse at a median of 72 days and 53 days for periods 1 and 2, respectively. There was no significant difference between baseline and final follow-up for improvement or tolerability. The study concluded that intermittent courses of CsA could rapidly clear plaque psoriasis.

Faerber and colleagues conducted a meta-analysis of 3 major, prospective, randomized trials investigating CsA for induction of remission in 579 patients with severe plaque-type psoriasis ( Table 6.1 ). Significant Psoriasis Area and Severity Index (PASI) reductions of 44.4%, 69.8%, and 71.5% were demonstrated in patients after 10 to 12 weeks of CsA therapy at dosages of 1.25, 2.5, and 5 mg/kg/d (mean daily dosage 0.53 mg/kg/d). Primary outcome measures included PASI and serum creatinine levels. CsA was found to be highly effective with patients reaching PASI-50 from baseline in 4.3 weeks for 5 mg/kg/d, 6.1 weeks for 2.5 mg/kg/d, and 14.1 weeks for 1.25 mg/kg/d. Moreover, CsA 1.25 mg/kg/d was found to be more efficacious than placebo, and this difference was statistically significant.

Two randomized, controlled clinical trials compared the short-term effectiveness of CsA to that of methotrexate (MTX). In the study by Flytstrom and colleagues, 84 patients were randomized to receive either MTX or CsA for a 12-week duration. The primary endpoint was PASI-75. Patients who received CsA demonstrated greater efficacy than patients receiving MTX therapy, with 72% of CsA patients reaching significant PASI changes from baseline than 58% of MTX patients. In a similar manner, Heydendael and colleagues also compared the efficacy of CsA to MTX. A total of 44 patients were treated with CsA using an initial dose of 3 mg/kg/wk for 16 weeks. In contrast to Flytstrom and colleagues, Heydendael and colleagues found no significant differences in efficacy between CsA and MTX groups.

Intermittent short-term therapy: for maintenance and prevention of relapse

In a 1-year, prospective, open, multicenter, randomized trial, the Psoriasis Intermittent Short Courses of Efficacy of Sandimmune Neoral (PISCES) studied intermittent short-term treatment of CsA in 400 patients with plaque psoriasis who were unresponsive to topical therapy. Patients were initiated at 2.5 mg/kg/d of CsA, which was increased by 0.5 to 1.0 mg/kg/d (maximum of 5 mg/kg/d) until 90% clearance of the affected areas or duration of 12 weeks, whichever occurred first. Patients who achieved satisfactory improvement (defined as PASI-75) were randomly assigned to discontinue treatment or undergo a dose reduction of 1 mg/kg/d until cessation. Patients were administered another course of CsA upon relapse and received as many treatment courses necessary for 1 year. Overall, median time to relapse was 3.6 months and 3.7 months in patients randomized to abruptly stop therapy versus those who were tapered off ( P = .04). Mean area of skin involvement included 4%, 2.6%, 4.4%, and 4.5% at the end of treatment periods 1, 2, 3, and 4, respectively, from a baseline of 25%. In an extension study, the PISCES group administered CsA to 76 patients with chronic plaque psoriasis intermittently over 2 years. Time in remission was the same whether abruptly stopping CsA or tapering over 4 weeks. Median time to relapse was 3.8 months after the first treatment, which progressively shortened after greater number of courses.

The PREWENT (Psoriasis Relapse Evaluation with Week-End Neoral Treatment) study was a randomized, double-blind, multicenter, controlled study that evaluated the efficacy and tolerability of weekend CsA for the reduction of relapse rate in patients who had previously achieved remission with continuous CsA therapy. The primary endpoint was no relapse or a 75% improvement in PASI from baseline at week 24. Eighty-one patients received placebo and 162 received CsA for 2 consecutive days a week for 24 weeks. Weekend CsA reduced time to first relapse in psoriasis patients, with time to first relapse prolonged in patients receiving CsA versus placebo ( P <.05). In addition, PASI was lower from weeks 4 to 16 in CsA recipients. In patients with moderate-severe psoriasis, the clinical success rate was increased with CsA compared with placebo (69.9% vs 46.3%; P = .011).

Continuous long-term therapy

Smaller studies have studied the effectiveness and safety associated with CsA in continuous, long-term therapy. Chaidemenos and colleagues conducted an open, randomized single-center study studying intermittent versus ongoing CsA therapy in 51 patients with chronic plaque psoriasis. Intermittent administration was less efficacious than continuous treatment (PASI-75 62% vs 92%, P <.05). However, patients administered continuous treatment received 139% of the mean cumulative CsA dose of intermittent therapy.

Long-term therapy should remain an option for patients who are recalcitrant to intermittent therapy. Lowe and colleagues evaluated the efficacy of CsA at 12 weeks and 3 to 5 years. Forty-two patients received CsA 5 to 6 mg/kg/d for 12 weeks, and 14 of 42 patients (33.33%) received maintenance treatment for 3.5 years. At the end of 12 weeks, 36 patients (86%) were clear or almost clear of psoriatic lesions. Dosages were increased from 5 to 6 mg/kg/d in 15 patients who remained unresponsive to therapy. Sixty-seven percent of this subgroup achieved clearance within 4 weeks.

A German multicenter study assessed the results of long-term CsA therapy in 285 patients with severe psoriasis. Patients were treated with 1.25 to 5 mg/kg/d of CsA for 6 to 30 months. PASI scores were reduced by 75% to 94% from baseline; however, half of the patients experienced relapse following cessation of therapy. In a 16-week unblinded study, 181 patients received 3.0 to 6.0 mg/kg/d CsA. Eighty-six percent of patients achieved a PASI-70 response. Patients entered a 24-week maintenance phase wherein they were randomly assigned to receive CsA 1.5 mg/kg/d or CsA 3 mg/kg/d or placebo. Longer time to relapse was associated with long-term maintenance therapy with CsA 3 mg/kg/d than placebo ( P <.01). Furthermore, approximately half the patients treated with CsA 3 mg/kg/d experienced relapse as compared with placebo (42% vs 84%) at the end of the 24-week maintenance period.

Additional studies have studied novel outcomes that affect the overall efficacy of CsA. Sandimmune and Neoral formulations were compared in patients with severe plaque psoriasis in a prospective, randomized, double-blind study. PASI-75 was achieved by 80% of patients in both groups by week 12. However, the Neoral group achieved a faster response and remission rates between the 2 formulations. An open trial study investigated the efficacy of Neoral administered before and after meals in 37 patients with psoriasis vulgaris. CsA microemulsion of 1.5 to 3.0 mg/kg/d was administered before or after meals for 6 weeks. Giving CsA before meals improved psoriasis more than giving CsA after meals ( P <.05). Another trial evaluated the value of a fixed dose microemulsion of 100 mg/d CsA in psoriasis. Forty patients were administered either 100 mg/d CsA (group A) or 50 mg CsA twice daily (group B). PASI-50 was achieved by 82% in group A and 84% in group B. PASI-50 was significantly higher in group A than in group B at 6 weeks; however, no difference in PASI-75 and PASI-90 was seen between groups.

Topical therapy

Combination treatments, including topical forms of CsA, have been studied for moderate-to-severe plaque psoriasis. Various smaller studies have evaluated topical CsA in combination with other agents, including the vitamin D analogue calcipotriol, corticosteroids, anthralin, and dithranol. One randomized, double-blind, multicenter, placebo-controlled study evaluated the combination of topical CsA with calcipotriol ointment. Patients were randomized to receive either 2 mg/kg/d of CsA with 50 μg/g of calcipotriol ointment or 2 mg/kg/d of CsA combined with placebo ointment. More patients in the calcipotriol/CsA group (50%) achieved complete or 90% improvement in PASI scores than in the placebo/CsA group (12%).

Systemic therapy

Concurrent administration of CsA with other systemic psoriasis agents, including MTX, mycophenolate mofetil (MMF), and fumaric acid esters, has been studied. The combination of 3 mg/kg/d of CsA and 7.5 to 15 mg/wk of MTX was more effective than monotherapy with either CsA or MTX alone in 19 patients with severe, recalcitrant psoriasis. The addition of MFF (maximum dosage 3.0 g/d) to low-dose CsA (2.5 mg/kg/d) in 9 patients with severe, recalcitrant psoriasis resulted in moderate-to-good clinical improvement of psoriasis over 3 to 11 months.