**7. Side effects**

Side effects, such as hypertension and renal impairment, may be associated with continuous cyclosporin therapy and appear related to treatment duration and dose (Colombo et al., 2010a). Generally, such side effects are reversible after cyclosporin discontinuation, although rarely chronic renal impairment and structural abnormalities in the kidneys may persist and be irreversible (Ryan et al., 2010). To minimise the risk of nephrotoxicity, the most widely recommended cyclosporin regimen in psoriasis is a short-term schedule of 2.5–5.0 mg/kg/day for 12–16 weeks (see section 5); this short course is repeated if subsequent disease flares occur (Amor et al., 2010; Griffiths et al., 2004). Adhering to present guidelines about appropriate dosage and monitoring protocols for cyclosporin use in psoriatic patients will substantially reduce the risk of side effects (Griffiths et al., 2004; Menter et al., 2009; Pathirana et al., 2009).

Although the mechanisms for many cyclosporin-related adverse effects have not been clearly defined, immunophilin inhibition (especially inhibition of immunophilins involved

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

 Cyclosporin plus methotrexate was administered for a mean of up to about 3½ years in 19 patients with severe recalcitrant psoriasis, and the combination schedule produced good control of psoriasis using lower doses of each agent than would have been used for monotherapy; however, 6 patients developed renal impairment, which normalised (n=3), or which improved but did not normalise (n=3), after cyclosporin dosage

 Cyclosporin 2.5 mg/kg/day plus mycophenolate mofetil 3 g/day led to moderate or good clinical improvement over 3–11 months' follow-up in 78% of patients with severe

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

Side effects, such as hypertension and renal impairment, may be associated with continuous cyclosporin therapy and appear related to treatment duration and dose (Colombo et al., 2010a). Generally, such side effects are reversible after cyclosporin discontinuation, although rarely chronic renal impairment and structural abnormalities in the kidneys may persist and be irreversible (Ryan et al., 2010). To minimise the risk of nephrotoxicity, the most widely recommended cyclosporin regimen in psoriasis is a short-term schedule of 2.5–5.0 mg/kg/day for 12–16 weeks (see section 5); this short course is repeated if subsequent disease flares occur (Amor et al., 2010; Griffiths et al., 2004). Adhering to present guidelines about appropriate dosage and monitoring protocols for cyclosporin use in psoriatic patients will substantially reduce the risk of side effects (Griffiths et al., 2004; Menter et al., 2009;

Although the mechanisms for many cyclosporin-related adverse effects have not been clearly defined, immunophilin inhibition (especially inhibition of immunophilins involved

adverse effects (Amor et al., 2010). For instance, in small-scale, uncontrolled trials:

**6.2 Systemic treatments** 

reduction (Clark et al., 1999).

(Neoral® Prescribing Information, 2009).

**7. Side effects** 

Pathirana et al., 2009).

recalcitrant psoriasis (Ameen et al., 2001).

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


a Percentage of patients, unless otherwise stated.

b Chest pain, premature ventricular contraction, tachycardia.

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

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

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

AE = adverse effect; CNS = central nervous system; CV = cardiovascular; GI = gastrointestinal; mos = months; na = not available; wks = weeks.

Table 2. Principal side effects reported in large-scale, well-designed clinical trials and metaanalyses of cyclosporin therapy in patients with psoriasis.

Systemic Cyclosporin in the Treatment of Psoriasis 299

trials (8–26%; Table 2). Such hypertension is generally reversible after the cyclosporin dosage is reduced, or after antihypertensive medications are added (Ho et al., 1999; Ryan et al., 2010). Importantly, besides specific drug therapy, psoriasis per se may contribute to an increased risk of hypertension, since psoriatic patients have increased incidences of obesity

Pooled data from 10 studies involving 563 patients with severe psoriasis revealed an overall incidence of new-onset hypertension of 10.6% during cyclosporin therapy (Feutren et al., 1990). However, the occurrence of hypertension was not dose-related (10.0% of patients at 2.5 mg/kg/day; 11.9% at 5.0 mg/kg/day) (Feutren et al., 1990), and this finding agrees with that of several randomised trials (Ryan et al., 2010). The implication, therefore, is that a subset of psoriatic patients exists with heightened sensitivity to cyclosporin, and enhanced susceptibility to hypertension, even at low cyclosporin doses (Ryan et al., 2010). Thus, cyclosporin-induced hypertension may best be managed with antihypertensive therapy rather than with a reduced cyclosporin dosage (Feutren et al.,

Psoriatic patients have an increased risk of cardiovascular morbidity and mortality (Gelfand et al., 2006). Regular blood pressure monitoring (e.g. weekly self-monitoring) is therefore important in cyclosporin-treated patients with psoriasis. If hypertension occurs, current guidelines advocate a cyclosporin dosage reduction of 25–50%, or commencement of antihypertensive therapy (Griffiths et al., 2004; Pathirana et al., 2009). Dihydropyridine calcium-channel blockers (e.g. amlodipine, isradipine) are generally the interventions of

Though renal dysfuntion is recognized as a cyclosporin-related side effect, the real impact of cyclosporin on kidney function may need to be reassessed. The experience in transplant patients, particularly in kidney transplant recipients where cyclosporin is used at higher doses in life-long regimens shows, that these regimens are well tolerated (Cho & Terasaki, 1988; Opelz, 1994). An Italian study conducted in 573 kidney transplant recipients showed that creatinine plasma levels remain constant and around 1.5 mg/dl over 15 years after the intervention, a clear indication of stable kidney function ( Sandrini, data presented at SIN

When renal dysfunction persists during cyclosporin therapy, it is usually related to higher doses (>5 mg/kg/day) or extended treatment (>2 years), and both of these factors may lead to structural renal damage. Renal dysfunction may also comprise functional impairment (i.e. vascular or tubular dysfunction), which may be evident soon after starting treatment. The consequences of vascular dysfunction are reduced glomerular filtration rate and renal blood flow, and reduced creatinine clearance, whereas the consequences of tubular dysfunction may include hypomagnesaemia, reduced plasma bicarbonate levels, hyperuricaemia, and hyperkalaemia. Acute functional impairment is generally reversible when cyclosporin treatment is discontinued; thus, the risk of renal toxicity is minimised when intermittent

choice, since they confer some degree of nephroprotection (Ryan et al., 2010).

and metabolic syndrome (Gelfand et al., 2006).

1990; Ryan et al., 2010).

**7.2 Renal dysfunction** 

2003 Bologna).

**7.1.1 Management of hypertension** 

studies of up to 16 weeks' duration, about 4–5% of cyclosporin-treated patients had adverse effects requiring treatment discontinuation (Ellis et al., 1991; Faerber et al., 2001). In a metaanalysis of 3 major German studies in approximately 600 patients with severe plaque psoriasis, and across the dosage range 1.25–5.0 mg/kg/day, the principal side effects were hypertension (5–14% of patients), renal dysfunction (≤8%), and gastrointestinal problems (3– 8%); increased plasma creatinine levels required intervention in only 3.4% of the total 756 cyclosporin treatment cycles (Faerber et al., 2001).

In longer-term studies of up to 30 months' duration, but across the same dosage range 1.25– 6 mg/kg/day, up to 11% of patients discontinued cyclosporin because of adverse effects; hypertension occurred in 8–26% of patients, gastrointestinal problems in 1–22%, and renal dysfunction in 1–43%. Lipid disorders also manifested: hypercholesterolaemia in 12–25% of patients, and hypertriglyceridaemia in 13–53% of patients (Christophers et al., 1992; Krupp & Monika, 1990; Mrowietz et al., 1995; Shupack et al., 1997).

Interestingly, in a recent, well-designed evaluation of relapse rates in patients with chronic plaque psoriasis who had achieved clinical remission after continuous cyclosporin therapy, 243 patients were randomised to 24 weeks of weekend cyclosporin microemulsion therapy 5 mg/kg/day or placebo (the Psoriasis Relapse Evaluation with Week-End Neoral Treatment [PREWENT] study) (Colombo et al., 2010a). In this investigation in a 'real-life' clinical setting, rather than in a group of carefully selected psoriatic patients, cyclosporin was well tolerated: no significant difference was evident in the incidence of adverse events between cyclosporin and placebo recipients (38.4% vs 21.5%). Only one patient (a cyclosporin recipient) had a serious adverse event (breast mass), but this was considered unrelated to study treatment. Furthermore, at no time during the study were mean plasma creatinine levels, or systolic and diastolic blood pressure values, different between the two groups; the incidence of plasma creatinine levels >30% above baseline was similar in the two groups (5.0% vs 3.8% of patients) (Colombo et al., 2010a)

In a retrospective assessment of 193 patients with moderate-to-severe psoriasis who had received a mean cyclosporin dosage of 1.5–3.1 mg/kg/day for 14 months, 83 patients (43%) received cyclosporin as monotherapy (Colombo et al., 2010b). Altogether, marginally more than one-third of patients experienced at least one adverse event. The most frequent events were hypertension (17.6% of patients), hypercholesterolaemia (14.0%), raised plasma creatinine level to >30% above baseline (6.7%), and gastrointestinal symptoms (6.2%). The clinician's assessment of cyclosporin tolerability was 'very good' or 'good' in 90% of cases (Colombo et al., 2010b).

Overall, the possibilities of cyclosporin-induced hypertension and renal dysfunction are perhaps the major tolerability concern among prescribers, and might explain a certain degree of cyclosporin 'under-utilisation' by dermatologists (Ryan et al., 2010). These two side effects are discussed in more detail below, whereas other potential tolerability issues are addressed relatively briefly.
