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Cyclosporine
Key points
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Cyclosporine (CsA) is a highly effective treatment option for patients with moderate-to-severe plaque psoriasis with a rapid onset of action.
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Its mode of action includes the formation of a CsA-cyclophilin complex, which binds to and inhibits calcineurin. Inhibition of calcineurin activity depresses T-cell differentiation and inhibits interleukin-2 activity.
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CsA is dosed at 2.5 to 5.0 mg/kg/d in 2 divided oral doses, which may be increased or decreased by 0.5 to 1.0 mg/kg/d.
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Important adverse effects of CsA therapy include the development of hypertension and nephrotoxicity; for this reason, routine monitoring of serum creatinine and blood pressure levels are indicated.
Introduction
Cyclosporine (CsA) is an effective medication used for the treatment of severe plaque psoriasis in adult patients. It is commonly known for its ability to effectively prevent allograft rejection and is widely administered following kidney, liver, and heart transplantation. The capability of CsA to drastically reduce immunologic activity within short time spans has also made it a popular drug of choice for the treatment of various immune-mediated disorders, including moderate-to-severe plaque psoriasis.
In 1997, the US Food and Drug Administration (FDA) officially approved CsA for the treatment of plaque psoriasis. Today, CsA is indicated for adults who are not otherwise immunosuppressed and experience severe, recalcitrant psoriasis, including patients with extensive or disabling forms of psoriasis (plaque, generalized pustular, palmoplantar, and erythrodermic) that have failed at least 1 other systemic therapy or are unable to take other systemic therapies due to contraindications or intolerable side effects. Although it has only 1 dermatologic-approved indication, CsA has been used for various off-label dermatologic disorders, including severe atopic dermatitis, chronic idiopathic uticaria refractory to treatment, and pyoderma gangrenosum.
Novartis Pharmaceuticals Corporation manufactures CsA under the trade names Sandimmune (available as 25-mg or 100-mg soft gelatin capsules, 50 mL per bottle oral solution, and 5-mL sterile ampul intravenous injections) and Neoral (available as 25-mg or 100-mg soft gelatin capsules or 50 mL per bottle oral solution). Neoral and its bioequivalents include Gengraf by Abbott Laboratories Incorporated (available in 25-mg or 100-mg capsules) and the generic version “CsA USP modified.” Neoral and Gengraf are newer, microemulsion formulations with better absorption and greater bioavailability than the original Sandimmune formulation.
The current recommended starting dosage of CsA for patients with psoriasis is 2.5 to 3 mg/kg/d taken in 2 divided doses (1.25 mg/kg twice a day) for a short-term course of 12 to 16 weeks ( Fig. 6.1 ). If there is no significant clinical improvement following at least 4 weeks of treatment, CsA dosages are increased in incremental dosages by 0.5 mg/kg/d until the disease is stable. The maximum dosage per day is 5.0 mg/kg. Alternatively, CsA may be started at the maximum dosage and be reduced in 0.5-mg/kg/d increments in severe disease. CsA is metabolized by hepatic cytochrome P450-3A, and its plasma half-life is approximately 8 hours, with a range of 5 to 18 hours.
Mechanism of action
CsA is a lipophilic cyclic polypeptide composed of 11 amino acids. It suppresses the immune system by inhibiting T-cell differentiation and activation. The drug itself binds a cytosolic protein named cyclophilin. The subsequent CsA-cyclophilin complex binds to and inhibits calcineurin. By inhibiting calcineurin, CsA blocks activation of the transcription factor, Nuclear Factor of Activated T cells (NFAT); this prevents NFAT from activating transcription of genes coding for interleukin-2 and other cytokines. The blockade of calcineurin halts signal transduction mechanisms required for the activation and differentiation of T lymphocytes ( Fig. 6.2 ). Downstream consequences of the inhibition of calcineurin include reduction of lymphocytes and macrophages in the epidermis and dermis, downregulation of cellular adhesion molecule expression in the dermal capillary endothelium, restricted activation of antigen-presenting cells, natural killer cells, and T cells, inhibition of keratinocyte proliferation, and restricted release of histamine from mast cells.
Efficacy
CsA is one of the most effective drugs for the treatment of moderate-to-severe plaque psoriasis, with rapid onset of action and powerful immunosuppressive activity. An extensive number of clinical trials have investigated the efficacy of CsA in the treatment of moderate-to-severe plaque psoriasis using various drug regimens, including monotherapy versus combination therapy; short, intermittent, and long-term therapy; and topical versus systemic therapy.
Monotherapy
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.
Table 6.1
Comparison of 3 major, prospective, randomized trials investigating cyclosporine for induction
Data from Refs.
| Meffert et al, 1997 ( N = 133) | Laburte et al, 1994 ( N = 251) | Christophers et al, 1992 ( N = 217) | |
|---|---|---|---|
| Baseline PASI | 8–25 | ≥18 | ≥15 |
| CsA dosages (mg/kg/d) | 1.25 2.5 |
2.5 5 |
1.25 2.5 a |
| Duration (wk) | 10 | 12 | 12–36 |
| CsA PASI improvement from baseline (%) | 27.2 51 |
69 89 |
18 56 |
| Placebo PASI improvement from baseline (%) | 5.9 | NR | NR |
| Conclusions | CsA 1.25 mg/kg/d is superior to placebo Consider dosage reductions to 1.25 mg/kg/d once patients stable at higher doses |
CsA 5 mg/kg/d is superior to 2.5 mg/kg/d in chronic plaque psoriasis | CsA 2.5 mg/kg/d is the optimal starting dosage as compared with 1.25 mg/kg/d in chronic plaque psoriasis |
a Patients with no significant improvement had dosages doubled up to 5 mg/kg/d until response reached.
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.
Combination Therapy
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