The use of cyclosporine in dermatology: Part II

The use of cyclosporine in dermatology: Part II Caitriona Ryan, MBBCh, BAO,a Karrie T. Amor, MD,b and Alan Menter, MDa Dallas and Houston, Texas Cyclosporine is highly effective in the treatment of a multitude of dermatoses. Concern over its side effect profile has limited its use in dermatology. Adverse effects are, for the most part, dose dependent and related to duration of therapy. Using the recommended monitoring protocols results in a significant decrease in the incidence of cyclosporine-related toxicities. This article provides a comprehensive review of the pharmacokinetics of cyclosporine, potential drug interactions, adverse effects, and recommendations for monitoring in patients treated with cyclosporine. The use of cyclosporine in pregnancy and in the pediatric population is also addressed. ( J Am Acad Dermatol 2010;63:949-72.) Learning objectives: After completing this learning activity, participants should be familiar with the monitoring guidelines of cyclosporine, its contraindications, its possible drug interactions, its adverse effect profile, and its use in pregnancy and the childhood and adolescent populations. Key words: atopic dermatitis; calcineurin inhibitors; cyclosporine; drug interactions; pharmacokinetics; psoriasis.

PHARMACOKINETICS Key points d

The specific brand of cyclosporine should be specified at each visit because of differences in bioavailability between the original and

From the Departments of Dermatology at Baylor University Medical Center,a Dallas, and the University of Texas,b Houston, Texas. Bruce H. Thiers, MD, Editor, has disclosed the following financial relationships: Elsevier- Other/Honoraria, Galderma- Other/ Honoraria, Graceways Pharmaceuticals- Consultant/Honoraria. Dirk M. Elston, MD, Deputy Editor, has disclosed the following financial relationships: Intendis- Investigator/No Compensation. Robert T. Brodell, MD, JAAD CME Planner, has disclosed the following financial relationships: 3M/Graceway Pharmaceuticals- Speaker/Honoraria, Allergan- Speaker/Honoraria, Dermik/ BenzaClin- Speaker/Honoraria, Dow Pharmaceutical SciencesConsultant/Honoraria, Galderma Laboratories, LP- Speaker/ Honoraria, GlaxoSmithKline- Speaker/Honoraria, Graceway Pharmaceuticals, LLC- Speaker/Honoraria, Medicis- Advisory Board/ Honoraria, Novaritis Pharmaceuticals- Speaker/Honoraria, Promius- Advisory Board/Honoraria, Sanofi-Aventis- Speaker/Honoraria. Joseph C. English III, MD, JAAD CME Planner, has disclosed the following financial relationships: Centocor- Investigator/No compensation. James R. Treat, MD, JAAD CME Planner, has disclosed the following financial relationships: Pierre Fabre-Investigator/ Grants. Hensin Tsao, MD, JAAD CME Planner, has disclosed the following financial relationships: Genentech- Consultant/ Honoraria, Quest Diagnostics- Consultant/Honoraria, SciBASEConsultant/Honoraria. Matthew Zirwas, MD, JAAD CME Planner, has disclosed the following financial relationships: Astellas Pharmaceuticals- Speaker/Honoraria, Coria LaboratoriesSpeaker/Honoraria, Consultant/Honoraria, Onset TherapeuticsConsultant/Honoraria. Caitrona Ryan, MBBCh, BAO, Author, has disclosed the following financial relationships: Abbott-Other/ Grant, Galderma- Advisory Board/Honoraria. Alan Menter, MD, Author, has disclosed the following financial relationships:

d

microemulsion formulations of cyclosporine (level IB evidencea) A higher serum concentration of cyclosporine results when the drug is administered before rather than after meals

Abbott- Advisory Board/Grant, Consultant/Honoraria, Investigator/ Honoraria, Speaker/Honoraria, Amgen-Speaker/Honoraria, Advisory Board/Grant, Astellas- Consultant/Grant, Advisory Board/Honoraria, Celgene-Investigator/Grant, Centocor- Advisory Board/Honoraria, Consultant/Grant, Eli Lilly-Investigator/Grant, Galderma- Advisory Board/Honoraria, Speaker/Honoraria, Genentech- Advisory Board/Grant, Novartis- Investigator/Grant, Novo Nordisk- Investigator/Grant, Pfizer, Investigator/Grant, Promius-Investigator/ Grant, Stiefel- Investigator/Grant, Syntrix-Investigator/Grant, Warner Chilcott-Advisory Board/Honoraria, Wyeth-Advisory Board/Honoraria, Speaker/Honoraria, Investigator/Grant. All other authors, editors, planners, peer reviewers, and staff have no relevant financial relationships. Reprints not available from the authors. a Levels of evidence: Level IA evidence includes evidence from metaanalysis of randomized controlled trials; level IB evidence includes evidence from at least one randomized controlled trial; level IIA evidence includes evidence from at least one controlled study without randomization; level IIB evidence includes evidence from at least one other type of experimental study; level III evidence includes evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case control studies; and level IV evidence includes evidence from expert committee reports or opinions or clinical experience of respected authorities, or both. Correspondence to: Alan Menter, MD, Department of Dermatology, Baylor Research Institute, 3900 Junius St, Ste 145, Dallas, TX 75246. E-mail: [email protected]. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.02.062

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Ideal body weight rather than actual body weight should be used to calculate the required dose (Level IIB evidence)

Currently, there is significant variability in the pharmacokinetics of newer generic forms of the microemulsion formulation of cyclosporine.9,10 Different brands should not be used interchangeably Absorption without strict supervision. It is recommended that Cyclosporine is a lipophilic molecule that is poorly the brand be specified with each prescription at each absorbed when administered orally, with wide varivisit, to avoid alterations in cyclosporine concentraations in inter- and intrapation resulting in a lower effitient bioavailability, ranging cacy or increased toxicity of CAPSULE SUMMARY from 1% and 89%.1,2 Bile salts the drug. are required to facilitate abThe dose of cyclosporine There is significant variability in the sorption,3 which occurs should be divided into a pharmacokinetics of newer generic within approximately 30 mintwice daily dose, and optiforms of the microemulsion formulation utes, while peak serum conmally should be taken at the of cyclosporine. centration (cmax) occurs 2 to 4 same time each day to miniDrugs that inhibit or stimulate the hours after the dose.2,4,5 mize intraindividual variation cytochrome P450 system increase or Original and microein serum concentration.11 decrease cyclosporine levels, mulsion formulations. Cyclosporine emulsion is respectively. Because of the variability in available in capsule form (in absorption of the original 25- or 100-mg capsules) or as Side effects are dose dependent and formulation of cyclosporine a bioequivalent solution related to the duration of therapy. Doses (Sandimmune; Novartis, (100 mg/5 mL).12 The oral of up to 5 mg/kg/day should be used for East Hanover, NJ), a more solution should be drawn up a maximum of 1 year. hydrophilic microemulsion with the syringe provided (Neoral; Novartis) was develand mixed with orange or oped that allowed greater bioavailability and less apple juice or milk.13 intraindividual fluctuation in serum concentration of the drug.6,7 A randomized, double-blind study comDistribution paring the two formulations showed a more rapid Cyclosporine is widely distributed in the body response, higher remission rates in the first 8 weeks, because of its lipophilic nature. Once absorbed, and a 10% lower dose to maintain efficacy with the cyclosporine binds to erythrocytes, leukocytes, and microemulsion.8 These preparations of cyclosporine lipoproteins. In plasma, cyclosporine is almost are not bioequivalent. Most patients who have norexclusively bound to lipoproteins ([90%), and mal absorption of the original formulation have there is transfer of cyclosporine between different equivalent absorption of the microemulsion, while lipoprotein classes and from albumin to lipoproa small subset of patients who absorb the original teins.14 Because cyclosporine is highly lipophilic, a formulation poorly have an increased absorption of high dietary fat intake can affect serum concentrathe microemulsion compared to the original, leading tions related to increased serum lipid levels. One to an increased serum cyclosporine concentration. study showed that high dietary fat intake can When converting patients from the original cyclosporincrease the total body clearance of cyclosporine ine formulation to the microemulsion formulation, a without changing the elimination rate constant.15 1:1 mg:mg dose conversion is used in order to maintain A higher serum concentration of cyclosporine is steady-state trough concentration in the target theraproduced when the drug is administered before rather peutic range.1,6 Particular caution should be exercised than after meals.2,16 This also translates into higher in those changing from high doses of the original clinical efficacy of the drug, highlighting the imporformulation to the microemulsion, with blood pressure tance of taking cyclosporine consistently before or and serum creatinine being monitored more closely in after meals where possible.17 Cyclosporine has been the subsequent weeks. When used in organ transplanreported to have a first-pass effect of 27% in the liver.5 tation, serial serum trough cyclosporine concentrations The biphasic distribution of cyclosporine is thought to are routinely measured after changes in formulation be caused by the enterohepatic recirculation of cyclobecause of the narrow therapeutic window between sporine from the bile to the small intestine.2 prevention of graft rejection and drug toxicity. This is not necessary in the dermatology setting, because the Metabolism and elimination incidence of adverse events following changes in The oral bioavailability and the systemic clearance formulations is relatively low.6 of cyclosporine is controlled by the cytochrome P450 d

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isoenzymes 3A4 (CYP3A4) and 3A5 (CYP3A5) in the liver and small intestine, and by the efflux p-glycoprotein pump (PGP), a transmembrane transporter, which is expressed in the gastrointestinal tract and liver and encoded for by the multidrug resistance1 gene (MDR1, also known as adenosine triphosphateebinding cassette B1 [ABCB1]).18-25 Many single-nucleotide polymorphisms in the genes encoding CYP3A4, CYP3A5, and PGP have been identified and are thought, in part, to account for the variability in pharmacokinetics of cyclosporine. Much of our knowledge on the effects of genetic polymorphisms on variability in pharmacokinetics of cyclosporine comes from transplantation research, but much of the published data to date has shown conflicting or nonsignificant results.18-25 Cyclosporine elimination follows first-order kinetics with a constant fraction of drug eliminated per unit time.2 Metabolites of cyclosporine are excreted primarily in the bile. Only 6% of the dose is excreted by the urine, mainly as cyclosporine metabolites with 0.1% of the dose excreted unchanged in urine.2 The half-life of cyclosporine in serum is between 6 and 24 hours.2,5 The pharmacokinetics of cyclosporine are altered in children, with clearance rates of up to four times that of adults over 40 years of age, resulting in lower blood concentrations for the same dose.26,27 Because the clearance of cyclosporine after intravenous administration does not appear to be related to age,28 it has been proposed that the decreased bioavailability is related to shorter bowel length rather than to metabolic differences.29 Body weight issues Cyclosporine is dosed on a weight per weight basis. Although highly lipophilic, observations suggest that distribution of the drug is limited primarily to lean body mass in obese patients and can lead to increased toxicity if patients are dosed according to their actual body weight.30,31 One study showed no significant differences in bioavailability, elimination half-life, clearance, or steady-state volume of distribution of cyclosporine when these calculations were normalized by ideal body weight. Following dosage based on actual body weight, obese transplant recipients had a mean serum trough level almost double that of nonobese recipients.32 Trough levels of cyclosporine have also been shown to increase with the obesity index, with a resulting increase in nephrotoxicity.33 While ideal body weight rather than actual body weight should be used to calculate the required dose, some guidelines recommend dosing obese patients according to their actual body weight.11 Body weighteindependent dosage regimens for both psoriasis and atopic dermatitis have, in fact, been shown to be

equally effective and safe as weight-orientated dosage regimens.34,35 In the clinical setting, however, it is generally the lowest effective dose to achieve disease control that guides the maintenance dose. Ethnic variation Studies of transplant recipients have shown significant differences in bioavailability of cyclosporine between different ethnic populations. African Americans have decreased absorption and markedly lower bioavailability of cyclosporine compared to whites.36,37 This is most likely caused by significant ethnic variation in the frequency of polymorphisms in MDR1 and the genes encoding the CYP3A enzymes.38,39 Localized administration of cyclosporine Placebo controlled studies of topical preparations of cyclosporine have shown it to be ineffective in the treatment of psoriasis and alopecia areata.40,41 A double-blind randomized controlled trial of topical cyclosporine rinse 500 mg/5 mL three times a day for 8 weeks for oral lichen planus, however, showed a marked improvement in all patients compared to placebo,42 a finding supported by other studies.43,44 This success is most likely related to a significantly higher local absorption of cyclosporine in mucosa compared to skin, with cyclosporine levels measured in the oral mucosa being comparable to those found in lesional skin of patients treated with high-dose systemic cyclosporine. Two double-blind trials of intralesional injections of cyclosporine for psoriasis also showed a significant improvement in all patients compared to controls—again, most likely because of the higher local concentration achieved by intralesional versus topical administration.45,46 Clearance of pyoderma gangrenosum with intralesional cyclosporine has also been reported.47 Unfortunately, the intralesional formulation of the drug is not commercially available because of unacceptable pain at the injection site.

CONTRAINDICATIONS Key points d

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Cyclosporine is contraindicated in uncontrolled hypertension, renal disease, serious infections, and in those with a previous history of malignancy, excluding basal cell carcinoma (level IV evidence) Cyclosporine should be avoided in those with a high cumulative dose of previous psoralen and ultraviolet A light phototherapy (level III evidence)

Cyclosporine is contraindicated in uncontrolled hypertension, significant renal impairment, serious

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infections, and in those with a current or previous history of malignancy (except basal cell carcinoma).11,48-51 Skin infections in atopic eczema are not an absolute contraindication, but appropriate antibiotic therapy should be instituted before commencing cyclosporine.51 Caution and careful clinical judgment should also be used in pregnancy, lactation, epilepsy, severe hepatic dysfunction, primary or secondary immunodeficiency disorders, diabetes, obesity, premalignant conditions, advancing age ([65 years), a tendency to drug or alcohol abuse, and the inability to attend for regular monitoring. In those patients with a high cumulative dose of previous psoralen plus ultraviolet A light (PUVA) phototherapy, severe actinic damage or who have been treated with radiotherapy, cyclosporine may increase cutaneous carcinogenicity and should be avoided whenever possible.11

DRUG INTERACTIONS Key points d

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Cyclosporine is metabolized by the cytochrome P450 system and interacts with drugs that inhibit or stimulate this system Nephrotoxic drugs should be avoided A full drug history should be taken at every patient visit

Cyclosporine is almost entirely metabolized in the liver by the cytochrome P450 IIIA system. Drugs that inhibit or stimulate the cytochrome P450 system increase or decrease cyclosporine levels respectively (Table I). In particular, caution must be exercised with the use of erythromycin to treat infected eczema, because it can increase cyclosporine toxicity.51 Grapefruit juice also inhibits the metabolism of cyclosporine by inhibiting cytochrome P450 enzymes in the intestinal wall, and should be avoided during cyclosporine treatment, especially when using the oral suspension in the pediatric population. Heavy alcohol intake can also increase cyclosporine levels.52 Nephrotoxic drugs, such as nonsteroidal antiinflammatory drugs (NSAIDs), aminoglycosides, ciprofloxacin, clotrimazole, and fibrates can impair renal function during cyclosporine treatment and should be avoided if possible. Treatment with NSAIDs for psoriatic arthritis can potentiate nephrotoxicity caused by cyclosporine.53 Cyclosporine can delay the metabolism of multiple agents, including digoxin, simvastatin, prednisolone, diclofenac, and methotrexate, leading to increased concentration and toxicity of these drugs (Table II). It is important to assess possible drug interactions with all other systemic medications before treatment with cyclosporine is initiated. In particular, patients

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often do not report intermittent use of NSAIDs, and so specific instructions must be given to patients. It is important to inquire at every subsequent visit if a patient has begun taking any new medications. Likewise, patients should be instructed to inform their other physicians that they are taking cyclosporine and share the drug interaction information with them.

ADVERSE EFFECTS Key points d

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A maximum dose of 5 mg/kg should be used for up to 1 year only (level IV evidence) Acute renal deterioration is typically reversible on withdrawal of cyclosporine treatment, while chronic impairment may be irreversible If serum creatinine increases 30% over the patient’s baseline value on two consecutive readings 2 weeks apart, the dose should be reduced (level IV evidence) When hypertension develops, the dose should be reduced by 25% to 50% or antihypertensive therapy introduced (level IV evidence); calcium channel blockers of the dihydropyridine class are the antihypertensives of choice (level IIB evidence) Tetracyclines should not be used to treat cyclosporine-induced acne because there is a risk of pseudotumor cerebi (level III evidence)

Statin therapy should be used with caution in the treatment of cyclosporine-induced hyperlipidemia because of the rare occurrence of rhabdomyolysis (level III evidence). The concern over the side effect profile of cyclosporine has largely limited its use in dermatology. For the most part, these side effects are dose dependent, related to the duration of therapy, and reversible on discontinuation, although structural renal abnormalities may be persistent.31,54-57 Adherence to current guidelines on the appropriate dosage and monitoring of cyclosporine will considerably decrease the risk of side effects.11,48-51 A summary of the frequency of adverse events reported in the largest studies (n [50 patients) of cyclosporine in the treatment of psoriasis and atopic dermatitis is represented in Table II (long-term observational and retrospective studies are included because these add important information for assessing the frequency of side effects). While the mechanisms involved in many cyclosporine-induced side effects remain poorly understood, it has been suggested that mitochondrial dysfunction and the inhibition of immunophilins—especially those involved in mitochondrial ion channel regulation— may play an important role.58,59

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Table I. Drug interactions with cyclosporine Drugs that inhibit the cytochrome P450 system, leading to a higher concentration of cyclosporine

Drugs that stimulate the cytochrome P450 system, leading to a lower cyclosporine level

Drugs that impair renal function during cyclosporine treatment

Calcium channel blockers (diltiazem, nicardipine, verapamil, and mibefradil) Antifungals (fluconazole, itraconazole, ketoconazole, and voriconazole) Macrolide antibiotics (erythromycin, clarithromycin, and josamycin) Doxycycline Gentamicin and tobramycin Ticarcillin Ciprofloxacin Oral contraceptives and androgen steroids Allopurinol Bromocriptine Amiodarone Ranitidine and cimetidine Metoclopramide Methylprednisolone Protease inhibitors Statins (especially atorvostatin and simvastatin) Danazol Thiazide diuretics Furosemide Warfarin Grapefruit juice Anticonvulsants (carbamazepine, phenobarbitone, phenytoin, and valproate) Rifampicin Rifabutin Isoniazid Octreotide Orlistat Terbenafine Sulfinpyrazone Probucol Troglitazone Ticlopidine Metamizole Selective serotonin reuptake inhibitors (sertraline) Nafcillin St John’s Wort (Hypericum perforatum) Nonsteroidal antiinflammatory drugs Aminoglycosides (gentamycin and tobramycin) Vancomycin Ciprofloxacin Trimethoprim with sulfamethoxazole Clotrimazole and ketoconazole Fibrates Amphotericin B Acyclovir Melphalan Methotrexate Colcichine Cimetidine and ranitidine Continued

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Table I. Cont’d Drugs where cyclosporine affects metabolism, causing increased levels

Treatments where cyclosporine increases carcinogenicity

Digoxin Statins (simvastatin, lovastatin, atorvostatin, and pravastatin) Prednisolone Diclofenac Methotrexate Colchicine Drugs for erectile dysfunction (sildenafil, tadalafil, and vardenafil) Benzodiazepines High cumulative doses of ultraviolet light irradiation Radiotherapy

Renal dysfunction Cyclosporine-induced renal dysfunction is the predominant cause for dermatologist-driven concern, and therefore the lack of embrace of its use by a substantial percentage of the dermatology community. Most persistent renal dysfunction, however, is related to prolonged therapy (ie, longer than 2 years) or doses of greater than 5 mg/kd/day, both of which may result in structural renal changes.31,60-68 Renal dysfunction can be functional or structural. Functional impairment, which may begin soon after commencing treatment, can be subdivided into vascular dysfunction and tubular dysfunction.31,61,64,69 Vascular dysfunction. Vascular dysfunction is caused by vasoconstriction of the afferent glomerular arterioles, leading to increased vascular resistance. This results in a decrease in renal glomerular filtration rate (GFR) and renal blood flow with decreased clearance of creatinine. Tubular dysfunction. Tubular dysfunction is characterized by decreased magnesium reabsorption, decreased uric acid excretion, decreased potassium and hydrogen ion secretion, and distal tubular acidosis. Hypomagnesemia, decreased bicarbonate concentration, hyperuricemia, and hyperkalemia may result.69 There is no loss of urinary concentrating power as is the case with other nephrotoxins.69 Endothelin-1 has been implicated in the vascular dysfunction caused by cyclosporine.70 Patients with psoriasis have higher levels of plasma endothelin, with the highest values occurring in those treated with cyclosporine.71 Both endothelin and cyclosporine mediate vasoconstriction, which may potentiate the nephrotoxic effects of cyclosporine in psoriasis patients. Cyclosporine has also been proposed to cause endothelial dysfunction by increasing production of superoxide,72 decreasing production of nitric oxide in endothelial cells,73 upregulating angiotensin II receptors, and increasing the concentration of

calcium in smooth muscle cells to cause increased sensitivity to vasoconstrictive stimuli.58,74 Acute deterioration related to functional changes is typically reversible on withdrawal of cyclosporine treatment.64 In studies of intermittent short-term therapy in psoriasis (12-16 weeks), renal dysfunction was typically transient. Between 4% and 27% of patients had increases in serum creatinine levels, which returned to normal within 4 weeks75-78 (Table II). A pooled analysis of 10 studies assessing 563 psoriasis patients treated with cyclosporine showed an increase in creatinine of 50% above baseline in 4% and 13% of those taking 2.5 and 5 mg/kg/day, respectively, in the first 12 weeks.79 Intermittent therapy is thought to allow normalization of renal function between courses, thereby minimizing renal toxicity.66 Chronic nephrotoxicity Chronic nephrotoxicity causes an obliterative microvascular renal injury (vasculopathy) and a tubulopathy. Vasculopathy. Vasculopathy comprises glomerular or arteriolar thrombi, arteriolopathy, and interstitial fibrosis with tubular atrophy.80 Thrombi are composed of fibrin or platelets lodged in glomeruli or blood vessels. The arteriolopathy affects vessels in the peripheral vascular tree with up to two layers of smooth muscle. It is characterized by nodular protein deposits in the media consisting of immunoglobulin M and complement (C3 and C1q) which replace necrotic myocytes in the arteriolar wall in a pearl necklace or clover leaf pattern to narrow or occlude the vascular lumen.81 Mucoid thickening of the intimal wall can also occur. This leads to arteriolar hyalinosis, interstitial fibrosis (striped form), tubular atrophy, and glomerular sclerosis (Fig 1). Tubular interstitial fibrosis is associated with an increase in transforming growth factor-beta (TGF-b).58 There may also be an increase in serum factor VIII and antithrombin III in those with cyclosporine-induced vasculopathy.82

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Tubulopathy. Tubular structural changes include isometric vacuolization of the proximal tubule, occasional giant mitochondria in tubular epithelial cells, single cell necrosis, and microcalcification of TammeHorsfall protein in the distal tubule.69 These changes are now rare, with the usage of lower cyclosporine doses. While tubulopathic changes are reversible, vasculopathic changes are maintained in up to half of patients.69,83 There have been many studies of the safety of long-term cyclosporine therapy in dermatology with regard to nephrotoxcity. A prospective study of renal structure and function in psoriatic patients treated with long-term cyclosporine (mean, 3.9 mg/kg/day) for up to 3 years compared 19 psoriatic patients to 38 age-matched transplant donors. Interstitial fibrosis and tubular atrophy were present in all biopsies after 1 year of therapy and became progressive with further treatment.84 These changes were more marked in hypertensive patients but were not strongly correlated to renal function. In a study of renal biopsy specimens obtained from 30 psoriasis patients treated with cyclosporine, no patient treated for 2 years or longer had a normal kidney biopsy specimen, and there was pronounced glomerular sclerosis after 4 years of continuous treatment.85 A study of maintenance cyclosporine for 3.5 years in psoriasis patients showed a moderate degree of interstitial fibrosis and glomerular scarring in two of 14 patients after 2.5 years, with minimal to mild change in all of the remaining 12 patients.64 One year later, there was progression of fibrosis in nine of the 12 patients still enrolled in the study. Similarly, 1 month after drug withdrawal, tubulointerstitial scarring and arteriolopathy was seen in 27% of renal biopsy specimens taken from 15 psoriatic patients who had received cyclosporine (\5 mg/kg/day) for 30 months.67 These patients had marked increases in serum creatinine levels of more than 90% above baseline, and conversely, those showing no increase in serum creatinine levels did not have structural renal changes in 86% of cases. There was no correlation, however, with dose or treatment duration. In a study evaluating eight patients treated with a mean dose of 3.3 mg/kg/day for 5 years, renal biopsy specimens revealed tubular atrophy and arterial hyalinosis in six patients (75%), with interstitial fibrosis and obliteration of glomeruli.62 Again, the best predictor of permanent renal damage was a persistent increase in serum creatinine level 1 month after treatment withdrawal. These studies contrasted to an earlier study in which no relevant cyclosporinerelated structural changes were seen in 14 psoriatic patients taking cyclosporine for a mean of 15 months compared with 16 psoriatic controls.66

Ryan, Amor, and Menter 955

Many studies of long-term cyclosporine treatment have attempted to quantify the optimum dosage and duration of cyclosporine treatment to prevent chronic nephrotoxicity. A study of 192 patients treated with a mean dose of 8.2 mg/kg/day for 13 months for a variety of autoimmune conditions showed renal dysfunction to be dose-related and more common in older patients, and recommended a ceiling dosage of 5 mg/kg/day and a maximum increase in serum creatinine of 30% over baseline based on these results.65 A multicenter study of longterm maintenance therapy with cyclosporine for psoriasis, in which 88 patients were treated for up to 30 months with either 2.5 or 5 mg/kg/day57 followed by a posttreatment period of 3 months showed an increase in serum creatinine of 10% above baseline which occurred in 4.5% of patients. In this study, no association was found between side effects and cyclosporine dose. In a study of 44 patients treated with cyclosporine used for up to 4 years, there was a persistent rise in serum creatinine in 14% of patients, with a mean reduction of 16% in GFR (9% of those treated with\3 mg/kg/day compared with 23% for those treated with [3 mg/kg/day).63 GFR normalized in all cases with discontinuation of cyclosporine.63 In a follow-up study by the same group, renal function was again examined in the seven patients who had remained on cyclosporine for between 9.5 and 11 years.31 All seven patients showed a persistent increase in serum creatinine of greater than 30% over baseline, and four of these had increases of greater than 50%. Similarly, 17% of 181 patients taking 3 mg/kg/day for 6 months (after an induction period of 4 months with 5 mg/kg/day) had an increase in serum creatinine.86 An elevation of serum creatinine of 30% above baseline was reported in 46% of 250 patients treated for 21 months.68 A study of 28 patients reported renal dysfunction in 71% of patients treated with 3.5 mg/kg/day for a median of 55 months, which persisted after discontinuation of the drug in 35% of patients.87 Other risk factors for cyclosporine-induced nephropathy include preexisting or new-onset hypertension, renal conditions, other nephrotoxic medications, older age, and obesity.64,65,88 Recommendations If there is an elevation of serum creatinine of at least 30% over the patient’s baseline value, recorded on two consecutive readings 2 weeks apart, the dose should be reduced by 1 mg/kg/day or by 25% to 50% for a minimum of 4 weeks, even if the value lies within the normal reference range (Fig 2; level IV evidence).11,48-51,65,89 If serum creatinine does not improve after 4 weeks therapy at the reduced dose, cyclosporine should be decreased by another 25% to

Study, study type, dose (mg/kg/day)

No. of patients/ duration

Psoriasis short-term therapy 85/16 wks Ellis et al,164 RCT

3 mg/kg/d 5 mg/kg/d 7.5 mg/kg/d Ho et al,76 randomized PO, 2.5-5 mg/kg/d Ho et al,77 PO, 2.5-5 mg/kg/d Faerber et al,78 MA 1.25 mg/kg/d 2.5 mg/kg/d 5 mg/kg/d Koo et al,8 RNCT, 2.5-5 mg/kg/d Krupp et al,116 MA, 1.25-5 mg/kg/d

AE requiring discontinuation

5% overall

Renal dysfunction

NA

Hypertension

GI side effects

Headache

HyperHyperHyperTremor Paraesthesiae trichosis cholesterolemia triglyceridemia

NA

NA

NA

20% 30% 53% 5%

4% 25% 7% NA

16% 40% 40% 11%

24% 25% 27% 7%

NA

NA

400/\12 wk IT, for 1 y

4%

30%

12%

28% 55% 47% 11% GS

76/\12 wk IT, for 2 y

7%

24%

24%

36% N

49%

NA

NA

NA

NA

NA

597/\12 wk IT

4.1% 5% 14% 9%

3% GS 8% GS 7% GS 17% D/N

1.9% 3.8% 2.3% 26%

NA NA NA 26%

NA NA NA NA

1.2% 0% 4.5% NA

NA NA NA NA

NA NA NA NA

30% D/N 3.8% N, 1.1% V, 2.3% AP, 2% D, 1.1% GS

22% 6.3%

22% 1.1%

NA 11.1%

NA 6.8%

NA 6%

NA 17%

152 MF/24 wks

9%

— 1% 8% 20%

157 OF/24 wks 631/12 wks to 16 mos

5% 5.9%

15% NA

NA

1.8% 3.2% 1.6% 6%

1% 5% 13% 5%

11% 21% 26% 8%

3.7% GS 4.4% GS 5% GS 22% GS

0% 0.5% 5% 3%

1.8% 0.5% 1.7% 2%

0% 1% 0% NA

1% 1% 2% 2%

12% 21% 25% NA

20% 40% 53% 13%

7%

42.5%

8.8%

12% N

30%

NA

18%

17%

NA

NA

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Table II. Adverse events in studies of cyclosporine use (n [ 50 patients) in psoriasis and atopic dermatitis

Psoriasis long-term therapy Christophers et al,55 217/12-36 wks

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RCT 1.25 mg/kg/d 2.5 mg/kg/d 5 mg/kg/d Mrowietz et al,57 RCT,88/6-30 mos 2.5mg/kg/d and 5 mg/kg/d (extension of above study Shupack et al,86 RCT 181/40 wks 5 mg/kg induction for 16wks

PO, 2.5 mg/kg/d for 8 wks, then 2-4 mg/kg/d 106/8-12 wks Czech et al,35 RNCT, 150 mg/d vs 300 mg/d, reducing Schmitt et al,95 MA* 602/6 wks-12 mos

Atopic dermatitis long-term therapy 73/[6 mos Hijnen et al,198 (mean, 1.3 y) R, 2.5-5

17% of 3 mg/kg, 10% of placebo

18%

NA

NA

4%

45.2% 55% 43%

27.4% 10.6% 24%

11.3% N 13.5% N 6%

12.9% 15.3% 11%

8.1% 14.2% 2%

8.1% 1.5% 16%

16.1% 27% 23%

NA

NA

14%

45%

5%

66%

26%

9%

16%

4%

NA

NA

3%

6%

NA

13% GS

NA

NA

NA

NA

NA

NA

Adult, 3.2%/mo; children, 2.5%/mo*

Adults, 1.6%/mo; children 0%/mo*

Adults GS, 18.1%/mo; children GS, 17.5%/mo*

Adults, NA 5.8%/mo; children, 9.1%/mo*

Adults, NA 12.9%/mo; children, 3.1%/mo*

NA

NA

10%

15%

5% N

7%

10%

NA

NA

Adults, 1.6%/mo; children, 0.8%/mo* 16%

1%

7%

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Atopic dermatitis short-term therapy Berth-Jones et al,197 100/48 wks

11%

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1.5/3 mg/kg/d or placebo for 24 wks Laburte et al,68 RNCT 251/21 mos 2.5 mg/kg/d 5 mg/kg/d 122/3-76 mos Grossman et al,88 R, 2.5-5 mg/kg/d

mg/kg/d AE, Adverse event; AP, abdominal pain; CT, continuous therapy; D, diarrhea; GI, gastrointestinal; GS, gastrointestinal symptoms (if not further defined); IT, intermittent therapy; MA, metaanalysis; MF, microemulsion formulation; N, nausea; OF, original formulation for gastrointestinal side effects; PO, prospective open; R, retrospective study; Rev, review; RCT, randomized controlled trial; RNCT, randomized noncontrolled trial; V, vomiting. *In the metaanalysis by Schmitt et al,95 adverse events were calculated as % of patients/month of treatment

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958 Ryan, Amor, and Menter

Fig 1. Cyclosporine-induced chronic nephropathy. Note the interstitial fibrosis (arrow) with adjacent tubular atrophy. (Periodic acideSchiff stain; original magnification, 310.)

50%. If creatinine remains elevated at this stage, cyclosporine should be discontinued. Treatment should not be recommenced until the serum creatinine has returned to less than 10% above the patient’s baseline value. If creatinine rises 30% over baseline again on reintroduction of cyclosporine, the drug should be permanently withdrawn. If serum creatinine lies outside the normal reference range but remains less than 30% above baseline for a given patient, there may be underlying preexisting renal impairment and caution should be exercised. Measurement of the GFR is recommended at least annually for those on long-term treatment,48-50 because secretion of creatinine in the renal tubules can increase in cyclosporine-induced nephropathy, making the interpretation of serum creatinine levels less reliable.90 Cyclosporine-induced nephropathy has been reported in patients with normal serum creatinine levels.91 As discussed in part I of this review, there is a discrepancy between guidelines from the United States and those from Europe with regard to recommended duration of continuous treatment to prevent chronic nephrotoxicity. In the United States, a maximum of 1 year of treatment is recommended by the American Academy of Dermatology, while guidelines published by the British Association of Dermatology and the European Association of Dermatology and Venereology recommend a ceiling of 2 years.11,48-51 In general, if cyclosporine is administered at a dose of 5 mg/kg/day or less and patients’ serum creatinine levels are carefully monitored to ensure that they do not increase to more than 30% above baseline, renal side effects will be fully reversible after discontinuation of the drug.75,79,81 Hypertension There is a wide variety in the reported incidence of new-onset hypertension with cyclosporine treatment, ranging from 0% to 57% in different studies

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(Table II). Studies of short-course cyclosporine therapy show a low incidence of new-onset hypertension, ranging from 0% to 24%, which is typically reversible on dose reduction or with the use of antihypertensive medications.76 In studies of longterm treatment, hypertension is more frequent. In a study by Mrowietz et al,57 8% of patients had an elevated blood pressure as determined by an increase of at least 10% of either systolic or diastolic pressure, while 3.5% showed an increase in blood pressure in the posttreatment phase.57 In a pooled analysis of 10 studies, 10.6% of patients had new-onset hypertension that was not dose related (10% of those taking 2.5 mg/kg/day and 11.9% taking 5 mg/kg/day).79 The lack of relationship between dose of cyclosporine and frequency of hypertension has been shown in other randomized studies.55,68,92 This suggests that there is a subset of patients with increased individual sensitivity to cyclosporine who are susceptible to hypertension even at low doses. For this reason, it has been proposed that cyclosporine-induced hypertension should be managed by antihypertensive therapy rather than dose reduction.79 Initiating or monitoring antihypertensive therapy may be another reason why dermatologists have been resistant to embrace cyclosporine in their clinical practices. In another study of long-term therapy in 122 patients the median time to development of hypertension was 55 months.88 The onset of hypertension in this group was shown to be bimodal, with a peak during the first 9 months of therapy and again after 36 months. In the pooled analysis by Feutren et al,79 a significant increase in diastolic blood pressure was detected after 1 month of treatment compared to controls, but no further increase was seen between months 1 and 3. There was no significant difference between mean blood pressure at baseline and at 3 months posttreatment. Longer-term studies have shown the persistence of hypertension posttreatment in up to 35% of patients.87 There appears to be a lower incidence of new-onset hypertension in studies of short-term cyclosporine treatment in adults with atopic dermatitis compared with studies of psoriasis (Table II). Although this may reflect a younger mean age in the cohort of patients recruited to atopic dermatitis studies, psoriasis patients may have a higher inherent risk of developing hypertension because of an increased incidence of obesity and the metabolic syndrome and therefore hypertension.93,94 In a large systematic review and metaanalysis of 15 studies of cyclosporine in atopic dermatitis, seven studies showed no newly diagnosed hypertension, with five of these studies being in adults only.95 In the pooled analysis of adults alone, there was a 1.6% incidence per month of newly diagnosed hypertension.

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Fig 2. Management of cyclosporine-induced renal dysfunction.

Fig 3. Management of cyclosporine-induced hypertension.

Recommendations Earlier studies evaluating adverse effects of cyclosporine used thresholds of 160 mm Hg and 95 mm Hg to define systolic hypertension and diastolic hypertension, respectively. Subsequently, the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure have decreased the reference ranges used to define prehypertension (120-139/80-89 mm Hg) and hypertension ([140/90 mm Hg).96 Patients with psoriasis in particular are known to be at increased risk of cardiovascular morbidity and mortality94; it is important to monitor blood pressure regularly (eg, weekly self-monitoring) and institute appropriate management as soon as there is evidence of cyclosporine-induced hypertension.48-50 The current guidelines recommend a dose reduction of 25% to 50% if possible or the introduction of antihypertensive therapy (Fig 3; level IV evidence).48-50 Because there appears to be no correlation between the onset of hypertension and cyclosporine dose, the introduction of antihypertensives in the first instance may be more appropriate. Calcium channels blockers of the dihydropyridine

class, such as amlodipine or isradipine, are the antihypertensives of choice in cyclosporine-mediated hypertension because of their vasodilating effect on the afferent arteriole, which may confer protection against nephropathy.97-99 Verapamil and diltiazem should be avoided because they interfere with serum cyclosporine levels, while nifedipine can potentiate the gingival hypertrophy caused by cyclosporine. There have been reports of angiotensin-converting enzyme inhibitors causing a decrease in GFR in cyclosporine-treated hypertensive patients, although other studies have shown perindopril to be equally effective as amlodipine in lowering blood pressure without affecting GFR or effective renal plasma flow.100-102 The use of thiazide diuretics may lead to increased nephrotoxicity.103 Potassium-sparing diuretics should also be avoided, because cyclosporine can increase serum potassium. Malignancy potential The increased risk of malignancy associated with long-term cyclosporine use in transplant populations is well described.104,105 In this population, however,

960 Ryan, Amor, and Menter

multiple immunosuppressive agents are frequently used in concert, resulting in higher levels of immunosuppression. Experimental studies have shown that cyclosporine is not genotoxic but causes dosedependent tumor promotion.106,107 In skin tumor models, cyclosporine has been shown to enhance the induction of skin tumors by ultraviolet irradiation.108 The increased risk of malignancy has been attributed to potent immunosuppression, but other direct effects have also been observed. Cyclosporine increases formation of reactive oxygen species which promotes transformation to malignancy.109 In mice studies, cyclosporine increases the synthesis of TGF-b, interleukin-6 (IL-6), and vascular epidermal growth factor (VEGF) in tumor cells, resulting in increased tumor growth, metastasis, and angiogenesis.110 Another study showed that cyclosporine induces invasiveness of nontransformed cells by a cell autonomous mechanism, which is blocked by monoclonal antibodies to TGF-b.111 Cyclosporine can also inhibit DNA repair by inducing apoptosis in activated T cells.110 In a study of 1252 psoriasis patients treated for a mean duration of 1.9 years with low-dose cyclosporine (2.7-3.1mg/kg), there was a six-fold increase in cutaneous squamous cell carcinomas (SCCs) after a 5-year follow-up period.112 The risk increased with longer duration of therapy ([2 years), with the increased incidence being seen solely in those with a previous history of PUVA treatment. Another nested cohort crossover study of 28 patients who had been treated with PUVA followed by cyclosporine showed a seven-fold increase in risk of SCC after treatment with cyclosporine compared to before first use of the drug.113 Six of the 842 psoriasis patients studied in the Sandoz Pharma study114 developed malignant or premalignant skin lesions, almost all of whom had been treated previously with PUVA, ultraviolet B light, or methotrexate. Another case report described eruptive keratoacanthomas and nodular basal cell carcinoma in psoriasis patients treated with cyclosporine.115 In view of this increased risk of cutaneous SCC, current guidelines suggest that narrowband ultraviolet B light should be used as a first-line agent when considering phototherapy, so that cyclosporine remains a future treatment option. If PUVA is used, the number of lifetime treatments should be limited to fewer than 200. Immunosuppression should not be used concurrently with phototherapy or directly before or after PUVA; immunosuppressants should be avoided in those with a high cumulative dose of PUVA or a previous history of SCC or melanoma.48-50 Studies in transplant recipients have shown an increased risk of lymphoma. There was no increase,

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however, in the occurrence of lymphomas in the 1252 psoriasis patients described by Paul et al.112 In the Sandoz Pharma study,114 three of the 842 psoriasis patients developed benign cutaneous lymphoproliferative disorders, another developed a B-cell lymphoma, and one a cutaneous T-cell lymphoma. The benign cutaneous lymphoproliferative disorders and B-cell lymphoma regressed rapidly on withdrawal of cyclosporine. There have been isolated case reports of the development of B- and T-cell lymphomas in psoriasis patients treated with cyclosporine.116-119 It is important to note, however, that psoriasis causes a state of chronic overactivation of the immune system with a higher incidence of lymphoma and other malignancies than the normal population.120,121 Cyclosporine has been shown to promote EpsteineBarr virus (EBV) transformation of human peripheral blood lymphocytes.122 One report described the development of EBV-associated lymphoproliferative disease after long-term cyclosporine use, with spontaneous regression on stopping the drug, strongly suggesting causality.123 Other lymphoproliferative disorders, such as hairy cell leukemia and Waldenstrom macroglobulemia, have been reported.124 Although there have been multiple case reports of solid tumors in patients on cyclosporine therapy in the literature,125 there was no increase in the incidence of solid tumors in the psoriasis study by Paul et al.112 In the Sandoz Pharma study,114 five of the 842 patients (0.7%) developed solid organ tumors, which were considered unlikely to be cyclosporine related by the investigator or reporting physician. Remarkably, an immunoprotective effect against certain tumor types has been suggested by large case-control studies of patients suppressed with cyclosporine in combination with other immunosuppressive agents, with a decreased odds ratio of rectal and breast cancers.126,127 Neurologic side effects The neurologic side effects of cyclosporine include headaches, tremor, seizures, psychosis, paraesthesias, and sleep disturbance. Headache occurs in up to half of patients, while parasthesias and tremor occur in up to 40% and 26% of patients, respectively (Table II). Paraesthesia and tremor often occur in the first weeks of treatment and improve without reduction of the dose, with hypomagnesemia suggested as a possible cause.115,128 Pseudotumor cerebri has been reported in several pediatric patients taking cyclosporine.129-131 In particular, tetracyclines should not be used to treat cyclosporine-induced acne because this increases the possibility of developing this complication. Three young female patients in our department

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have developed pseudotumor cerebri as a result of this combination, one of whom required a ventriculoperitoneal shunt. The condition is rapidly reversible on withdrawal of cyclosporine, so prompt diagnosis is necessary to prevent permanent visual deficits. Seizures have also rarely been reported, and those with a history of epilepsy should be warned that cyclosporine can lower the seizure threshold. The risk of seizures is increased in those taking high doses of prednisone, prednisolone, or methlyprednisolone. Cyclosporine levels in those on antiepileptic therapy may also be lower than expected because of upregulation of the cytochrome P450 system (Table I). Cyclosporine has rarely been reported to cause a reversible posterior leukoencephalopathy, consisting of headache, hypertension, seizures, cortical blindness, and other visual abnormalities with characteristic magnetic resonance imaging changes.132 There have been four reports of cyclosporine-induced Parkinsonism.133 A study using a magnetic resonance spectroscopyebased metabonomic approach to evaluate the effect of cyclosporine on rat brain cell metabolism showed a significant decrease in high-energy phosphate metabolism and a reduction in intracellular concentrations of neurotransmitters, such as glutamate and N-acetyl-asparate (NAA) in rat brain cells.134 Gastrointestinal side effects The reported incidence of gastrointestinal side effects, such as nausea, vomiting, diarrhea, or flatulence, varies considerably (Table II). In the pooled analysis by Krupp et al,114 nausea, abdominal pain, diarrhea, vomiting, and gastrointestinal complaints were seen in 3.8%, 2.3%, 2%, 1.1%, and 1.1%, respectively. Hyperbilirubinemia also occurs in up to 30% of patients.50 This is generally dose related and, in the absence of other abnormalities of liver function, does not require further evaluation.49 It is believed to be a consequence of competitive inhibition of transport between bilirubin and cyclosporine rather than direct hepatotoxicity.86 An increase in transaminases occurs in up to 30% of patients.50 If serum bilirubin or transaminases rise to twice the normal value, a dose reduction of 25% is necessary.50 An increased incidence of cholelithiasis has been reported in renal and cardiac transplant recipients treated with cyclosporine compared with those treated with alternative immunosuppressants.135 Gingival hyperplasia Gingival hyperplasia is caused by fibrous hyperplasia and has been reported in up to 30% of patients on cyclosporine, with a higher incidence reported in

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Fig 4. Cyclosporine-induced gingival hyperplasia.

children (Fig 4).136,137 The pathogenesis is uncertain but it is often associated with poor oral hygiene. Plaque control and the removal of local irritants have been shown to be of benefit.138 Genetic heterogeneity also seems to play an important role in its development.136 Complications include functional difficulties, disfigurement, and increased caries.136 Onset tends to be during the first 3 to 6 months of treatment. Treatment with metronidazole resulted in complete resolution in one series of four patients.139

Cutaneous side effects A study examining cutaneous side effects of cyclosporine therapy in 67 renal transplant patients revealed hypertrichosis in 60%, epidermal cysts in 28%, keratosis pilaris in 21%, acne in 15%, folliculitis in 12%, and sebaceous hyperplasia in 10%.140 There is considerable variability in there reported incidence of hypertrichosis (Table II). Hypertrichosis was reported in 6.8% of patients in the study by Krupp et al,114 23% in that of Grossman et al88 and in 54% in a study by Griffiths et al.141 This side effect is more cosmetically unacceptable for women with darker hair. The etiology is unknown with no evidence to suggest an alteration in endocrine status.115 Cyclosporine modulates protein kinase C expression and translocation in hair epithelial cells and promotes proliferation of these cells.142 Cyclosporine also prolongs human hair growth in vitro.143 Most other cutaneous side effects also affect the pilosebacous unit, with studies suggesting that the follicular epithelium is more sensitive to cyclosporine than the interfollicular epithelium.142 Acneiform eruptions or worsening of preexisting acne vulgaris are common with cyclosporine.144 As previously mentioned, tetracyclines should not be used to treat acne because of the increased risk of pseudotumor cerebri. In a study of intermittent therapy in 400 psoriasis patients, transient palmar and/or plantar pustular psoriasis occurred in 5 patients on

962 Ryan, Amor, and Menter

withdrawal of cyclosporine but was not serious enough to warrant study discontinuation in any patient.76 Infections Despite its immunosuppressive effects, infectious side effects with cyclosporine are rare and seldom severe. In controlled studies, there was no difference in the frequency of infections between those taking cyclosporine compared with etretinate or placebo. If spontaneous recovery did not occur, treatment of the infection or withdrawal of the drug led to resolution.115 A review of 2 decades of safety data of cyclosporine in dermatology patients suggested no increased risk of opportunistic infections or tuberculosis reactivation.125 Because cyclosporine has been reported to cause the reactivation of latent tuberculosis infection in higher doses used in transplant recipients, and because cyclosporine is an immunosuppressant, the National Psoriasis Foundation recommends screening for latent tuberculosis infection before initiation of cyclosporine treatment (level of evidence IV).145,146 Management of infection while taking cyclosporine depends on the pathogen and the severity of infection. Bacterial or fungal infections should be treated with appropriate antibiotic therapy as soon as they are detected. Commencement of cyclosporine should be delayed until the resolution of active herpes simplex in those with atopic dermatitis, and withdrawal should be considered if there is evidence of dissemination, to reduce the risk of eczema herpeticum.51 Other side effects Fatigue, lethargy, and flu-like symptoms are commonly reported. Musculoskeletal symptoms such as joint pain and muscle aches are reported in 10% to 40% of patients.50 Hyperlipidemia Hyperlipidemia (particularly hypertriglyceridemia) during cyclosporine treatment is well described.55,57,115,147,148 The package insert reports hypertriglyceridemia ([750 mg/dL) in 15% of patients and hypercholesteremia ([300 mg/dL) in less than 3% of patients.49 In the study by Mrowietz et al,57 an increase in triglycerides 30% above baseline was observed in 12.5% of patients. Another study investigating the effect of 5 mg/kg/day of cyclosporine on serum fasting lipids showed an increase of more than 30% in cholesterol and triglycerides in 18% and 50% of patients, respectively, seen after just 2 weeks in both, with no further significant change noted throughout the course of treatment.148 This study showed no

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effect on high-density lipoprotein levels. A study by Grossman et al147 showed a 50% increase in triglyceride levels in seven out of eight psoriasis patients, which peaked after 1 month of treatment and suggested a correlation between hypertriglyceridemia and previous retinoid use, a finding that was refuted in a subsequent study.149 Hyperlipidemia normalizes on discontinuation of the drug.86 Hyperlipidemia has been suggested to contribute to accelerated atherosclerosis in renal transplant patients.150 With the current knowledge that the incidence of metabolic syndrome and cardiovascular morbidity is increased in severe psoriasis, this side effect needs to be actively managed in psoriasis patients. While no studies have examined the incidence of cyclosporine-induced hyperlipidemia in atopic dermatitis patients, it would be interesting to compare the incidence of hyperlipidemia between these two population groups. Recommendations If hyperlipidemia develops and cyclosporine therapy is maintained, a lipid-lowering diet should be introduced (level IV evidence). If this is not successful, the dose of cyclosporine should be reduced or a lipid-lowering agent should be commenced. Because cyclosporine decreases the clearance of statins, rhabdomyolysis may occur in patients taking concomitant statin therapy.151 Vigilance is important in detecting this rare but potentially fatal drug interaction. Patients should be instructed to report symptoms such as muscle pain or weakness, dark-colored urine, or generalized malaise immediately, and serum creatinine phosphokinase should be monitored after commencement of the drug. There have also been reports of nephrotoxicty and renal failure when fibrates have been used with cyclosporine in transplant recipients.152 Other laboratory abnormalities One of the advantages of cyclosporine compared to other immunosuppressant therapies is the lack of myelosuppression relating to treatment. A slight normochromic, normocytic anemia, however, may be observed,115,153 and microangiopathic hemolytic anemia and thrombocytopenia have also rarely been reported.49 Renal dysfunction can lead to hypomagnesemia, hyperuricemia, and hyperkalemia. One study showed hyperuricemia (2.6% of patients) and hypomagnesemia (8.8%) to be doserelated, while hyperkalemia (0.5%) was not related to dose or treatment duration.115 Hypomagnesemia has been reported in 5% to 15% of patients and should be treated with oral magnesium supplements (beginning at 200 mg magnesium daily and

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Table III. Guidelines for pretreatment assessment and monitoring Investigation

Details

Full history

Previous infections: TB, hepatitis B/C; history of hypertension, kidney disease, liver disease, or malignancy; full medication history, which should be repeated at every subsequent visit Blood pressure Baseline (2 separate measurements, should be \140/90 mm Hg); taken again at weeks 2, 4, 6, and 8, then monthly Physical examination Actinic damage/cutaneous malignancies; herpes simplex; viral warts Serum creatinine Baseline (mean of 2 separate fasting measurements; if discrepancy of [10%, repeat again);taken again at weeks 2, 4, 6, and 8, then monthly Blood urea nitrogen Baseline and at weeks 2, 4, 6, and 8, then monthly Complete blood cell count Baseline, then monthly Potassium Baseline, then monthly Bilirubin, liver enzymes Baseline, then monthly Fasting lipid profile Baseline, then monthly Uric acid Baseline, then monthly Magnesium Baseline, then monthly Urinalysis Baseline, then monthly Tuberculin test Baseline Glomerular filtration rate After 1 y of continuous therapy Screening Programs Cervical, breast, and colon cancer screening as per national guidelines Vaccinations Annual pneumococcal and influenza vaccinations

increased as needed), with adherence monitored.50 Studies in rats have shown that magnesium supplementation may prevent chronic cyclosporine nephropathy by adjusting nitric oxide synthase activity.154 Hyperuricemia should be treated with a low purine diet and sufficient fluid intake.50 Hyperkalemia in the setting of normal renal function can occur and is most likely caused by tubular dysfunction and secondary hypoaldosteronism.155 If fluid intake and a low potassium diet do not restore normal serum potassium levels, dose reduction is necessary.50 Increased levels of serum alkaline phosphatase (ALP) have been reported in up to 8% of psoriasis patients undergoing treatment, generally in the setting of normal liver function tests.115 This is likely related to an increase in the bone isozyme of ALP, caused by changes in bone metabolism. Cyclosporine has been shown to cause mild osteoblastic proliferation and matrix mineralization activity, as reflected by increased serum alkaline phosphatase in renal transplant patients with normal parathyroid hormone levels.156

MONITORING Key points d

Blood pressure and blood urea nitrogen and serum creatinine levels should be measured at baseline, weeks 2, 4, 6, and 8, and then monthly thereafter

d

d

d

Level of evidence

IV

Patients should be instructed regarding dental care commencing treatment and attend their dentist at 6-month intervals to monitor for gingival hypertrophy National malignancy screening programs should be adhered to Vaccination should take place before the initiation of treatment where possible

Screening and history Before beginning cyclosporine treatment, patients should be screened with a careful history, examination, and baseline laboratory investigations (Table III). In particular, a history of malignancy, renal dysfunction, hypertension, current infections, or a history of previous PUVA phototherapy should be elicited. A full medication list should be recorded, including over the counter preparations. The physical examination should include measurement of blood pressure at two time points and an assessment of the skin for actinic damage and skin cancers. Initiation of treatment should be deferred until active herpes simplex lesions have resolved, particularly in the atopic dermatitis population. If possible, viral warts should be treated before beginning a course of cyclosporine. Patients should be instructed regarding careful dental hygiene and to visit their dentist at 6-month intervals to monitor for gingival hypertrophy. The need for contraception should be discussed with women of child-bearing age and a pregnancy test performed if indicated. Specifically, cyclosporine can reduce the efficacy of

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progesterone-containing contraceptives, so alternative birth control methods should be considered.50 Patients should also be counseled regarding the need for longterm sun protection in view of the higher incidence of skin cancer in those taking cyclosporine. Baseline laboratory investigations Fasting serum creatinine should be measured in a standardized manner on at least two separate occasions (fasting [12 hours, in the morning, no preceding strenuous exercise), and repeated again if there is a discrepancy of more than 10 mol/L between these measurements.11,48-50 The average of these two values then serves as the baseline serum creatinine against which subsequent treatment values are compared. Baseline laboratory investigations should also include a complete blood count, blood urea nitrogen (BUN), potassium, bilirubin, liver enzymes, uric acid, magnesium, fasting lipids, and urinalysis for proteinuria.11 Regular follow-up investigations Blood pressure, BUN, and serum creatinine should be measured at weeks 2, 4, 6, and 8, and then monthly thereafter, with more frequent readings if there are abnormal measurements.11,48-50 Measurements of the complete blood cell count, potassium, uric acid, fasting lipids, bilirubin, liver enzymes, and magnesium should be taken initially monthly and thereafter pending the course of therapy (2-month intervals, possibly). Patients should be weighed at every visit. Annual investigations The GFR should be assessed annually for the small number of patients who are treated continuously for more than 1 year.48-50 There should be full compliance with national screening programs for cervical, breast, and prostate cancers. Cyclosporine serum concentrations Cyclosporine serum concentrations are typically monitored in transplant patients to avoid toxicity caused by high concentrations and to minimize possible organ rejection caused by low concentrations. In practice, this has not been adopted or shown to be of benefit in monitoring efficacy or toxicity in dermatology patients.57,157,158 No difference was detected between mean cyclosporine trough levels measured using specific monoclonal or nonspecific polyclonal radioimmunoassay in relation to efficacy or renal dysfunction. It can be used, however, if there is a query regarding patient adherence to treatment or to detect cyclosporine levels above the recommended dosing range.159

DECEMBER 2010

Vaccinations Live vaccination is contraindicated while on cyclosporine.11 There have been numerous studies of immunologic response to inactivated vaccines in transplant recipients treated with cyclosporine. Pneumococcal vaccination with a 23-valent vaccine in transplant recipients treated with cyclosporine has been shown to be equally effective as in controls, while immune response to influenza vaccination is significantly reduced although not completely abolished.160,161 It has been suggested that this differential response is related to T-cell independent antibody production against polysaccharide antigens in the pneumococcal vaccine.160 Immune response to hepatitis B vaccination is impaired.162 The response to standard diphtheria and tetanus booster vaccination in pediatric renal transplant recipients treated with cyclosporine is comparable to healthy children.163 Vaccination should take place before the initiation of treatment where possible, and although response may be suboptimal,11,49 annual vaccination with pneumococcal and influenza vaccines is advocated.11 Delayed-type hypersensitivity reactions to skin-test antigens are reduced by cyclosporine, and so the interpretation of tuberculin skin testing is unreliable in those undergoing treatment.164,165 As a result, Mantoux testing is recommended before initiation of cyclosporine.11

PREGNANCY Key points d

d

d

Cyclosporine crosses the placental blood barrier and is a category C drug in pregnancy Pregnancy registries show no increase in the risk of teratogenicity, although there were trends towards low birth weight and prematurity Cyclosporine is excreted in breast milk

Cyclosporine has been labeled as a category C drug by the FDA Pregnancy Labeling Task Force (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). Cyclosporine has been shown to passively cross the placental blood barrier to achieve 10% to 50% of the maternal plasma concentration.166 The administration of 25 mg/kg of cyclosporine to female Lewis rats resulted in characteristic drug-induced pathologic changes in the mother and a high incidence of fetal mortality, while a dose of 10 mg/kg was not fetotoxic.167 Animal studies have not shown increased malformation rates, but in utero exposure to cyclosporine in rabbits

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induced a nephron reduction that led to systemic hypertension and progressive chronic renal insufficiency in adulthood.168 As controlled studies in humans cannot ethically be performed, we must look to pregnancy registries to evaluate the safety of cyclosporine in pregnancy. The majority of our safety data comes from analyses of pregnancy outcomes in transplant recipients, which have concluded that there is no evidence of teratogenicity.50,169,170 A metaanalysis of 410 patients in 15 studies (6 with control groups) showed no statistically significant increase in the incidence of congenital malformations, preterm delivery or low birth weight associated with cyclosporine exposure during pregnancy, although there were definite trends towards low birth weight (prevalence, 43%) and prematurity (prevalence, 56%).169 A report on 629 pregnancies in patients treated with cyclosporine for transplantation collected by the Sandoz international database showed a higher incidence of prematurity and low birth weight, as would be expected with conventional immunosuppressive therapy, but the rates of fetal loss and malformation were within the normal range for the general population.170 A 12-year follow-up of 175 children exposed to cyclosporine in utero showed a 16% incidence of mental developmental delay.171 This was attributed to the high incidence of prematurity in the group. A study of seven children exposed to cyclosporine in utero showed a transient minimal effect on fetal immune development, with normal immunoglobulin and complement levels on serologic testing, and normal seroconversion in response to vaccination. The authors concluded that children exposed in utero are unlikely to be at risk of immunodeficiency or autoimmunity.172 Another study examined six infants born to female kidney transplant recipients who had received cyclosporine and methylprednisolone throughout their pregnancies.173 This showed a disturbance of the maturation and development of T cells, B cells, and natural killer cells, which was apparent up to 1 year of age. While there were no clinical signs of immunosuppression, the authors suggested that conventional vaccinations should be delayed in these infants. Despite the aforementioned study showing nephron reduction in rabbits exposed to cyclosporine, there appears to be no nephrotoxic effect in children exposed to cyclosporine in utero.174 Cyclosporine trough levels decrease with pregnancy because of the increased volume of distribution and increased metabolism.175 Because of the unique state of immunologic tolerance afforded by pregnancy, however, a significant proportion of dermatoses improve during pregnancy, making increases in cyclosporine dosages seldom necessary.

Lactation Mothers taking cyclosporine have been advised not to breastfeed because of concerns regarding immunosuppressive effects in the neonate (level IV evidence).11,48-50,176 Cyclosporine is excreted in breast milk, with a wide variation in the milk-tomaternal serum concentration ratio, depending on the time of sampling and maternal dose.177 To date, evidence on the safety of breastfeeding during cyclosporine therapy is limited to two small case series and two case reports. No adverse events related to maternal cyclosporine treatment during lactation have been observed in these reports, and cyclosporine concentrations in the blood of the infants were undetectable with the exception of one infant.177,178 While this is reassuring, evidence concerning the safety of breastfeeding is limited and still inconclusive.

PEDIATRIC USE Key points d

d

There is decreased bioavailability of cyclosporine in children Children are less susceptible to cyclosporineinduced nephropathy than adults

Cyclosporine has been used in transplant recipients as young as 1 year of age with no serious adverse effects. The safety and efficacy of both intermittent and continuous cyclosporine therapy in children for the treatment of atopic dermatitis for up to a year at doses of up to 5 mg/kg/day has also been shown (Table II).179-182 No randomized controlled trials have been performed for pediatric psoriasis, but cyclosporine is often used in the treatment of severe psoriasis in this age group.183 Children are less susceptible to cyclosporineinduced nephropathy than adults.65,81,95 This may be because of decreased sensitivity to cyclosporine, higher clearance, or decreased bioavailability of the drug. For a given reduction in renal function, however, the incidence of renal vasculopathy is the same. A metaanalysis of cyclosporine use in atopic dermatitis suggested that although the effectiveness was similar in adults and children, tolerability was better in children than in adults.95 In the pooled analysis, only 2.5% of children had an increase in creatinine of more than 30% per month of treatment and no children developed hypertension. Discussion and our personal 25-year experience of cyclosporine usage The Baylor University Medical Center (Dallas, TX) has large liver, renal, and bone marrow transplant units. We have been fortunate to have had a close

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working relationship with their physicians, resulting in our usage of cyclosporine for more than 25 years, particularly for severe psoriasis and atopic dermatitis of all age groups. With the advent of biologic therapies, our use of cyclosporine has changed significantly over the past seven years. Cyclosporine is now typically used as a ‘‘rescue’’ or ‘‘induction’’ therapy for periods of up to 6 months because of its rapid onset of action and considerable efficacy. A small subset of patients, particularly the pediatric population, is still treated with maintenance therapy for periods of up to 1 year. Intermittent therapy in psoriasis—with inevitable flares and disappointed, frustrated patients—has become a regimen of the past. In recent years, there have been significant therapeutic advances in psoriasis. Today, the majority of psoriasis patients can expect to achieve prolonged clearance or nearclearance of their disease with the currently available systemic or biologic agents. Similarly, there have been advances in the treatment of pyoderma gangrenosum with biologic agents. New, highly effective, biologic and nonbiologic immunomodulatory agents are in clinical development for the treatment of chronic idiopathic urticaria.184 Progress in the treatment of atopic dermatitis has been more limited, but systemic agents such as azathioprine, methotrexate, interferongamma, and mycophenolate mofetil are now more commonly used. There is now a greater appreciation of the importance of disease-related quality of life for dermatologic conditions and the importance of a psychosocial approach to management. Many dermatologic conditions, especially psoriasis and atopic dermatitis, can cause significant psychological and emotional stress for both patients and their families, especially in the younger population groups, with an increased prevalence of depression and poor selfesteem.185-187 Quality of life can be impaired to a similar extent as is seen in chronic diseases such as diabetes mellitus and coronary heart disease.188-190 Quality of life instruments are increasingly being used to further inform clinical decision making, but a poor correlation has been seen in both psoriasis and atopic dermatitis between objective, clinician-determined clinical extent and subjective, patient-driven quality of life scores.190,191-194 What constitutes ‘‘significant disease’’ varies considerably among patients.195,196 While some patients may be intolerant of even a minor amount of skin disease, others are unperturbed by what many clinicians may consider severe disease. To allow a patient to achieve clearance, raise their expectations, and then subject them to relapse, albeit to a lesser disease extent, in order to be treated with another course of intermittent therapy may be highly distressing for

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patients. Having experienced remission, sometimes the first in many years, patients live in fear of return of their disease, and the prospect of relapse can cause significant and unnecessary anxiety. As a result, we personally do not recommend the use of repeated courses of ‘‘intermittent therapy’’ with cyclosporine for psoriasis, but rather its use as a rescue agent for significant flares of psoriasis with continuation of the previous drug or initiation of another agent as the cyclosporine is tapered. In the treatment of atopic dermatitis, particularly in pediatric and adolescent patients, we will frequently recommend continuous rather than intermittent therapy for up to a year for a more consistent control of disease and resultant improvement in quality of life, especially in younger patients. Rotational therapy with azathioprine or methotrexate may also minimize toxicity while allowing a more stable disease course.

CONCLUSION In summary, since its advent in 1972, cyclosporine has played a very valuable role, not only in the treatment of many dermatoses but also in the expansion of our knowledge of the immunopathophysiology of many dermatologic conditions. Its serendipitous discovery in 1979 for psoriasis changed the entire field of psoriasis research from that of a hyperproliferative, keratinocyte-driven disorder to that of an ‘‘immune-driven’’ disease, paving the way for the subsequent biologic revolution in psoriasis. Because of its rapid onset of action and marked efficacy, cyclosporine is particularly useful in the treatment of significant flares of cutaneous disease—especially psoriasis and atopic dermatitis— that are unresponsive to other therapies, and also as a bridging agent during the induction of other maintenance agents. With a growing armamentarium of therapeutic alternatives, intermittent therapy should no longer be necessary and long-term treatment with cyclosporine is only advocated in exceptional cases. In these patients, combination or rotational therapy can be used to minimize cumulative dosage and long-term side effects. In general, however, treatment for more than 1 year should be avoided where possible. Side effects are dose dependent, related to the duration of therapy, and reversible on discontinuation once treatment guidelines are followed and careful monitoring is practiced. Cyclosporine is a drug in common use in our clinical practice and one we are very comfortable with, provided that the aforementioned guidelines are closely followed. It is a drug that should be an integral part of our therapeutic armamentarium and be considered for broader use by the dermatologic community.

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We thank Drs Stacy Hinson and Nesrin A. Onur for their histopathologic image of chronic cyclosporine-induced nephropathy, and Cristina Martinez for her technical support.

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