**7.1 Hypertension**

The incidence of new-onset hypertension during cyclosporin administration to psoriatic patients has varied somewhat in short-term studies (5-14% of patients) and longer-term

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

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

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

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

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

The incidence of new-onset hypertension during cyclosporin administration to psoriatic patients has varied somewhat in short-term studies (5-14% of patients) and longer-term

cyclosporin treatment cycles (Faerber et al., 2001).

(5.0% vs 3.8% of patients) (Colombo et al., 2010a)

(Colombo et al., 2010b).

**7.1 Hypertension** 

are addressed relatively briefly.

& Monika, 1990; Mrowietz et al., 1995; Shupack et al., 1997).

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

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., 1990; Ryan et al., 2010).

### **7.1.1 Management of hypertension**

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