**6.1 Topical treatments**

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

Systemic Cyclosporin in the Treatment of Psoriasis 297

in the regulation of mitochondrial ion channels) and mitochondrial dysfunction may have significant pathogenetic roles (Ryan et al., 2010). Adverse effects reported in large-scale randomised controlled trials and meta-analyses of short-term or longer-term cyclosporin therapy in psoriatic patients are documented in Table 2. As can be seen, in short-term

No. of patients 85 579 285 631 88 181

(mg/kg/day) 3–7.5 1.25–5 1.25–5 1.25–5 1.25–5 1.5–6

discontinuation 4.7 4.1 1.6–3.2 5.9 5.7 7.0–11.0 Renal dysfunction 18e ≤8 1–13 na 5 17–43 Hypertension na 5–14 11–26 na 8 9f GI side effects 28–55 3–8 4–5 12 22 12f Headache 20–53 2–4 ≤5 6 3 30f Tremor 4–25 na ≤2 1 2 na Paraesthesias 16–40 na ≤1 11 na 18f Hypertrichosis 24–27 ≤5 1–2 7 2 17f

ia na na 12–25 na na na

ia na na 20–53 na 13 na CV symptomsb 5–8 na na na na na CNS symptomsc 7–25 1–6 na na na na Fatigue 12–20 ≤4 1–2 3 na 11f

symptoms 5–20 na na na 9 na Infectiond 20–27 na 2 na na na Gum hypertrophy 8–15 na 1–2 4 2 na

c Anxiety, depression, dizziness, insomnia, nervousness, syncope, visual changes, transient ischaemic

AE = adverse effect; CNS = central nervous system; CV = cardiovascular; GI = gastrointestinal; mos =

Table 2. Principal side effects reported in large-scale, well-designed clinical trials and meta-

cyclosporin therapy Longer-term cyclosporin therapy

Krupp & Monka, 1990

mos

Mrowietz et al., 1995

6–30 mos 40 wks

Shupack et al., 1997

Christophers et al., 1992

Short-term

Faerber et al., 2001

Duration 16 wks 10–12 wks 12–36 wks 12 wks–16

Ellis et al., 1991

Study features/AEsa

Dosage

AEs requiring

Hypercholesterolaem

Hypertriglyceridaem

a Percentage of patients, unless otherwise stated.

During 16-wk induction phase (5 mg/kg/day).

months; na = not available; wks = weeks.

b Chest pain, premature ventricular contraction, tachycardia.

d Non-influenza-like viral, bacterial, and fungal infections. e <sup>≥</sup>15% decrease in glomerular filtration rate. f

analyses of cyclosporin therapy in patients with psoriasis.

Influenza-like

attack.

#### **6.2 Systemic treatments**

Combination schedules of cyclosporin plus other systemic antipsoriatic agents (e.g. fumaric acid esters, methotrexate, mycophenolate mofetil) have been used in patients with severe psoriasis to facilitate cyclosporin dosage reduction and to reduce the risk of potential adverse effects (Amor et al., 2010). For instance, in small-scale, uncontrolled trials:


Interestingly, in a retrospective assessment of 193 cyclosporin-treated patients with moderate-to-severe plaque psoriasis, 110 patients (57%) had received concurrent therapy with systemic methotrexate or retinoids, or topical and/or phototherapy. In the physician's judgement, a clinical response (therapeutic success or clinical remission) occurred in 80% of combination therapy recipients (Colombo et al., 2010b). Cyclosporin was also investigated in combination with phototherapy. In a study comparing sequential cyclosporin and narrowband (NB) UVB phototherapy versus NB UVB phototherapy alone in patients with severe psoriasis, both treatments were effective and well tolerated, but the sequential therapy showed a greater efficacy on lesions of UV-shielded body areas and on itching (Calzavara-Pinton et al., 2005). The increased efficacy of the sequential therapy allowed for the reduction of NB UVB dosage and exposure. Nonetheless, it should be remembered that psoriatic patients previously treated with psoralen and ultraviolet A (PUVA), and to a lesser extent UVB, have increased risks of skin malignancies during cyclosporin therapy. Psoriatic patients receiving cyclosporin should not receive concomitant PUVA or UVB therapy (Neoral® Prescribing Information, 2009).
