**7.2.1 Management of renal dysfunction**

If plasma creatinine levels are ≥30% above baseline on two consecutive occasions, 2 weeks apart, the cyclosporin dosage should be reduced by 25–50% for at least 4 weeks; this applies even if creatinine values are within the normal reference range (Griffiths et al., 2004; Menter et al., 2009; Pathirana et al., 2009). After 4 weeks of reduced-dosage treatment, if plasma creatinine levels remain elevated, cyclosporin should be discontinued (Neoral® SPC, 2011).

As a preventive measure against renal dysfunction, it is recommended that psoriatic patients receiving long-term cyclosporin therapy should have glomerular filtration rate measured at least once each year (Griffiths et al., 2004; Pathirana et al., 2009). Guidelines from the European Association of Dermatology and Venereology and from the British Association of Dermatology stipulate that the maximum period of continuous cyclosporin therapy in psoriatic patients should not exceed 2 years (Griffiths et al., 2004; Menter et al., 2009; Pathirana et al., 2009). As a comparison, it should be reminded that in graft recipients, life-long regimens with higher cyclosporin doses are routinely used in clinical practice and have proved well tolerated after many years of use.

Generally, if the cyclosporin dosage is ≤5 mg/kg/day, and if patients are closely monitored so that plasma creatinine levels remain ≤30% above baseline, any renal side effects will be wholly reversible after cyclosporin treatment is stopped (Ryan et al., 2010).

### **7.3 Central nervous system effects**

Headache may occur in up to 53% of cyclosporin-treated patients with psoriasis, paraesthesias in up to 40%, and tremor in up to 25% (Table 2). The latter two effects generally occur during the first few weeks of cyclosporin administration and dissipate after a decrease in cyclosporin dosage; hypomagnesaemia has been postulated as a cause of these effects (Ryan et al., 2010).

Seizures have been reported rarely during cyclosporin therapy, but cyclosporin does have the potential to reduce seizure threshold in epileptic patients; the seizure risk is increased in patients taking concurrent, high-dose corticosteroid therapy. Furthermore, patients taking antiepileptic drugs may have reduced circulating cyclosporin levels because of increased metabolism by the cytochrome P450 system (Ryan et al., 2010).

#### **7.4 Gastrointestinal effects**

The rates of cyclosporin-induced gastrointestinal side effects (e.g. abdominal pain, diarrhoea, dyspepsia, nausea, and vomiting) vary markedly: however, a meta-analysis involving 631 psoriatic patients reveals rates of 2.3%, 2.0%, 2.0%, 3.8%, and 1.1%, respectively (Krupp & Monka, 1990).

#### **7.5 Gingival hyperplasia**

300 Psoriasis

cyclosporin therapy is prescribed in psoriasis, since such therapy is associated with

Besides raised plasma creatinine levels, other predictors of cyclosporin-related nephropathy include advanced age, obesity, new-onset or pre-existing hypertension or renal disorders, and other nephrotoxic treatments. Altogether, as relatively low cyclosporin dosages are now used in psoriasis, tubulopathic changes are rare and

If plasma creatinine levels are ≥30% above baseline on two consecutive occasions, 2 weeks apart, the cyclosporin dosage should be reduced by 25–50% for at least 4 weeks; this applies even if creatinine values are within the normal reference range (Griffiths et al., 2004; Menter et al., 2009; Pathirana et al., 2009). After 4 weeks of reduced-dosage treatment, if plasma creatinine levels remain elevated, cyclosporin should be discontinued (Neoral® SPC, 2011). As a preventive measure against renal dysfunction, it is recommended that psoriatic patients receiving long-term cyclosporin therapy should have glomerular filtration rate measured at least once each year (Griffiths et al., 2004; Pathirana et al., 2009). Guidelines from the European Association of Dermatology and Venereology and from the British Association of Dermatology stipulate that the maximum period of continuous cyclosporin therapy in psoriatic patients should not exceed 2 years (Griffiths et al., 2004; Menter et al., 2009; Pathirana et al., 2009). As a comparison, it should be reminded that in graft recipients, life-long regimens with higher cyclosporin doses are routinely used in clinical practice and

Generally, if the cyclosporin dosage is ≤5 mg/kg/day, and if patients are closely monitored so that plasma creatinine levels remain ≤30% above baseline, any renal side effects will be

Headache may occur in up to 53% of cyclosporin-treated patients with psoriasis, paraesthesias in up to 40%, and tremor in up to 25% (Table 2). The latter two effects generally occur during the first few weeks of cyclosporin administration and dissipate after a decrease in cyclosporin dosage; hypomagnesaemia has been postulated as a cause of these

Seizures have been reported rarely during cyclosporin therapy, but cyclosporin does have the potential to reduce seizure threshold in epileptic patients; the seizure risk is increased in patients taking concurrent, high-dose corticosteroid therapy. Furthermore, patients taking antiepileptic drugs may have reduced circulating cyclosporin levels because of increased

The rates of cyclosporin-induced gastrointestinal side effects (e.g. abdominal pain, diarrhoea, dyspepsia, nausea, and vomiting) vary markedly: however, a meta-analysis

wholly reversible after cyclosporin treatment is stopped (Ryan et al., 2010).

metabolism by the cytochrome P450 system (Ryan et al., 2010).

normalisation of renal function between treatment courses (Ryan et al., 2010).

reversible (Ryan et al., 2010).

**7.2.1 Management of renal dysfunction** 

have proved well tolerated after many years of use.

**7.3 Central nervous system effects** 

effects (Ryan et al., 2010).

**7.4 Gastrointestinal effects** 

Gingival hyperplasia may occur in up to 30% of patients taking cyclosporin and is often linked with poor oral hygiene (Ryan et al., 2010). Thanks to increased oral health awareness, improved oral hygiene, and better public health service this condition occurs rarely in developed countries. If it occurs, this side effect usually manifests within the first 3–6 months of treatment.

### **7.6 Hyperlipidaemia**

Hypertriglyceridaemia (>750 mg/dL) occurs in approximately 15% of cyclosporin-treated patients, and hypercholesterolaemia in <3% (Neoral® Prescribing Information, 2011). Importantly, hyperlipidaemia normalizes when cyclosporin therapy is stopped (Shupack et al., 1997).

Severe psoriasis is associated with increased cardiovascular morbidity and mortality (see section 7.1.1); thus, hyperlipidaemia should be actively managed in cyclosporin-treated patients with psoriasis. If cyclosporin therapy is continued, the initial intervention is a lipidlowering diet. If this is unsuccessful, the cyclosporin dosage should be reduced, or treatment with a lipid-lowering agent started. Fluvastatin was shown to be well tolerated in association with cyclosporin (Holdaas et al., 1995; Launay-Vacher 2005). In general, however, statins should be used with caution because of the risk, albeit very low, of rhabdomyolysis, as reported in a few cases of transplanted patients treated with cyclosporin and lovastatin or simvastatin (Ryan et al., 2010; Corpier et al., 1988).

#### **7.7 Hypertrichosis**

In large-scale clinical trials and meta-analyses in cyclosporin-treated patients with psoriasis, the incidence of hypertrichosis has varied widely from 1–27% (Table 2); the cause of this side effect is unclear, but it is unlikely to be an altered endocrine status (Ryan et al., 2010).

#### **7.8 Infections**

Cyclosporin-induced infections occur rarely, and are rarely severe; controlled studies in psoriasis report no difference in the incidence of infections between cyclosporin and placebo recipients. Moreover, an overview of 20 years' safety data for cyclosporin in dermatology patients revealed no increases in the risks of opportunistic infections or tuberculosis reactivation (Ryan et al., 2010).

#### **7.9 Malignancies**

#### **7.9.1 Lymphomas**

B- and T-cell lymphomas have rarely been reported in cyclosporin-treated patients with psoriasis (Ryan et al., 2010). For instance, 2/842 patients (0.2%) developed these lymphomas

Systemic Cyclosporin in the Treatment of Psoriasis 303

transaminase levels are >2 x the upper limit of normal, the cyclosporin dosage should be

Several drug interactions have been documented for cyclosporin, which is extensively metabolised by the CYP 3A system in the liver and small intestine. Some of the key interactions include the following: (Novartis Pharmaceuticals Corporation 2009; Ryan et

Erythromycin should be used with caution in cyclosporin-treated patients with infected

Grapefruit juice inhibits cyclosporin metabolism and should be avoided in cyclosporin

 Nephrotoxic drugs, including aminoglycosides, ciprofloxacin, clotrimazole, fibrates, and nonsteroidal anti-inflammatory drugs (NSAIDs), should not be administered, if at all possible, to cyclosporin-treated patients. NSAIDs, especially in dehydrated patients, are likely to potentiate the deleterious effect of cyclosporin on renal function, and

 Cyclosporin may restrict the metabolism of many drugs (e.g. diclofenac, digoxin, methotrexate, prednisolone, repaglinide, simvastatin), thus increasing plasma levels

 Cyclosporin should not be used concomitantly with potassium-sparing diuretics because of the risk of hyperkalaemia, and care should also be exercised if cyclosporin is administered concurrently with potassium-sparing drugs such as angiotensin-

Cyclosporin was first approved for the treatment of severe psoriasis in the 1990s, and indeed, it is one of the most effective antipsoriatic agents available because of its fast onset of action and potent immunosuppressive activity. Besides psoriasis, other dermatological disorders — most notably, pyoderma gangrenosum and refractory chronic idiopathic urticaria — have seen substantial off-label cyclosporin use in recent years. Nonetheless, concerns remain among some dermatologists about the safety of cyclosporin, even though a growing evidence base exists of a favourable benefit : risk profile for the compound,

Perhaps the most frequent safety concerns, and those potentially explaining underutilisation of cyclosporin by some dermatologists, are hypertension and renal impairment. However, it should be remembered that psoriasis itself is associated with increased cardiovascular morbidity, and any new hypertension emerging during cyclosporin therapy can be managed effectively by dosage reduction and/or antihypertensive therapy. Moreover, persistent renal dysfunction during cyclosporin therapy is usually associated with dosages >5 mg/kg/day, or treatment periods of >2 years; usually, if the dosage is kept

especially in the management of psoriasis, psoriatic arthritis, and atopic dermatitis.

eczema, since the former compound can increase cyclosporin toxicity.

importantly, intermittent NSAID use is often not disclosed by patients.

converting enzyme inhibitors or angiotensin II receptor antagonists.

Heavy alcohol ingestion should be avoided, as it can increase cyclosporin levels.

reduced by 25% (Pathirana et al., 2009).

**8. Drug interactions** 

recipients.

and toxicity.

**9. Conclusions** 

al., 2010)

in a large-scale trial (Krupp & Monka, 1990), whereas no increase in the incidence of lymphomas was noted in another large-scale trial (Paul et al., 2003). Significantly, psoriasis itself leads to chronic immunological overactivation, and to greater risks of lymphoma and other malignancies than in the general population (Ryan et al., 2010).

#### **7.9.2 Nonmelanoma skin cancers**

In 1252 patients with severe psoriasis, low-dosage cyclosporin (2.7–3.1 mg/kg/day) was associated with a 6-fold increase in cutaneous squamous cell carcinomas after up to 5 years' follow-up. The greatest risks of these nonmelanoma skin cancers were in patients treated with cyclosporin for >2 years, in patients previously exposed to PUVA, and in patients exposed to other immunosuppressants or methotrexate (Paul et al., 2003). In another large-scale study, 6/842 psoriatic patients (0.7%) developed premalignant or malignant skin lesions during cyclosporin therapy, but nearly all of these patients had received previous treatment with PUVA, ultraviolet B, or methotrexate (Krupp & Monka, 1990).

The current recommendation is that if phototherapy is considered in psoriatic patients, narrowband ultraviolet B should be the first choice; cyclosporin can then be reserved for future therapy, if necessary (Griffiths et al., 2004; Pathirana et al., 2009). Cyclosporin should not be used together with phototherapy, or immediately before or after PUVA (see section 5); in patients with a high total dose of PUVA, or with a history of squamous cell carcinoma or melanoma, cyclosporin should be avoided (Griffiths et al., 2004; Pathirana et al., 2009).

### **7.9.3 Solid organ tumours**

Numerous case reports exist of solid organ tumours developing during cyclosporin treatment in dermatology patients (Ryan et al., 2010). However, no increase in the incidence of solid organ tumours was noted in a study of 1252 psoriatic patients treated with cyclosporin (Paul et al., 2003), and although another large-scale study reported solid organ tumours in 5/842 patients (0.6%), the lead investigator considered any relationship between these tumours and cyclosporin to be unlikely (Krupp & Monka, 1990). Large case-control studies suggest that cyclosporin plus other immunosuppressive therapies may actually have immunoprotective effects against, and reduce the risks of, some tumour types (e.g. breast and rectal cancers) (Ryan et al., 2010).

#### **7.10 Other side effects**

Fatigue and influenza-like symptoms may occur in up to 20% of cyclosporin-treated patients (Table 2), and joint pain and muscle aches are also frequently reported (10–40% of patients) (Pathirana et al., 2009).

Hyperbilirubinaemia manifests in up to one-third of cyclosporin recipients (Pathirana et al., 2009), but this effect is usually dose-related, and does not require further investigation if other liver function abnormalities are absent (Ryan et al., 2010). Transaminase elevations may also occur in up to one-third of cyclosporin-treated patients. If plasma bilirubin or transaminase levels are >2 x the upper limit of normal, the cyclosporin dosage should be reduced by 25% (Pathirana et al., 2009).
