5
474 Guidelines DOI: 10.1111/j.1610-0387.2009.07077.x JDDG | 5 ˙ 2009 (Band 7) © Dt. Dermatologische Gesellschaft • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG •1610-0379/2009/0705 Preamble Cyclosporine is one the important medi- cations for systemic therapy of inflam- matory skin diseases. It is approved for severe forms of psoriasis and atopic der- matitis, but also used “off-label” for many other skin diseases in which it shows high efficacy. Not only patients with skin diseases but also transplant re- cipients and patients with autoimmune disorders treated with cyclosporine con- tribute considerably to the evaluation of its safety. There is extensive literature available on cyclosporine dealing with both experimental and clinical issues. The present recommendations on the treatment of dermatologic diseases with cyclosporine are intended to serve as a practical guide for physicians on choo- sing and performing therapy. 1 Indications In dermatology cyclosporine is approved for the therapy of severe atopic dermati- tis and severe psoriasis vulgaris in adults. The term severe is generally used for pa- tients with widespread skin involvement, high tendency for recurrences and/or in- adequate response to topical therapy. Also, severe reduction in quality of life by the disease can necessitate treatment with cyclosporine. Sufficient experience exists for pati- ents older than 18 years. Reports of successful treatment of children with cyclosporine also exist, especially for those with severe, recalcitrant atopic dermatitis. In most cases cyclosporine should be pri- marily used for induction therapy (up to 6 months) due to its good and rapid ef- fects. On the basis of its safety profile, use in long-term therapy is only indicated in exceptional cases (e. g. when effective therapeutic alternatives are lacking). 1.1 Psoriasis In the S3 guideline “Therapy of Psoria- sis” therapy with cyclosporine is discus- sed in detail. The evaluation was based on 15 studies that fulfilled the criteria of evidence-based medicine. Therapy of psoriasis with cyclosporine is characteri- zed by high efficacy; PASI 75 (at least 75 % improvement of the “psoriasis area and severity index” in comparison to the baseline value) is attained at the end of induction therapy (after 12 weeks) in 50–70 % of patients. It is concluded that cyclosporine is an effec- tive option for systemic therapy of mode- rate and severe psoriasis. Long-term therapy is less recommendable due to the numerous therapeutic alternatives for psoriasis. Combination with topical products in treatment is possible and advisable, as the dose of cyclosporine can be reduced by the simultaneous use of topical vita- min D3 analogues or corticosteroids. In exceptional cases cyclosporine can also be used in the therapy of severe psoriasis in children and adolescents. Cyclosporine can also be used for psoria- tic arthritis, although explicit approval for this indication does not yet exist. 1.2 Atopic dermatitis In the S2 guideline on therapy of atopic dermatitis, the meta-analysis of suitable randomized, controlled studies indica- ted a significant therapeutic effect of cyclosporine. Duration of therapy depends on treat- ment success and tolerability. Here, short-term therapy is frequently suffi- cient; i. e. the dose of cyclosporine is tapered after sufficient improvement (see also 5. Dosages). When required, the treatment cycle can be repeated (interval therapy). When recurrences appear rapidly, continual long-term therapy with the individually to be determined lowest effective dose can be performed. After two years, discontinuation should be attempted. Cyclosporine is also effective in children and adolescents with atopic dermatitis. Data from studies with up to 40 children aged 2 to 16 years exist. 1.3 Further indications For the skin diseases listed in the following, cyclosporine may also be employed. Reports of successful therapy in the scientific literature are well- documented in case reports and small case series. Guideline Cyclosporine therapy in dermatology Ulrich Mrowietz, C. Eberhard Klein, Kristian Reich, Thomas Rosenbach, Thomas Ruzicka, Michael Sebastian, Thomas Werfel Section Editor Prof. Dr. Hans Christian Korting, München

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Page 1: Cyclosporine therapy in dermatology

474 Guidelines DOI: 10.1111/j.1610-0387.2009.07077.x

JDDG | 5˙2009 (Band 7) © Dt. Dermatologische Gesellschaft • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG •1610-0379/2009/0705

PreambleCyclosporine is one the important medi-cations for systemic therapy of inflam-matory skin diseases. It is approved forsevere forms of psoriasis and atopic der-matitis, but also used “off-label” formany other skin diseases in which itshows high efficacy. Not only patientswith skin diseases but also transplant re-cipients and patients with autoimmunedisorders treated with cyclosporine con-tribute considerably to the evaluation ofits safety. There is extensive literatureavailable on cyclosporine dealing withboth experimental and clinical issues.The present recommendations on thetreatment of dermatologic diseases withcyclosporine are intended to serve as apractical guide for physicians on choo-sing and performing therapy.

1 IndicationsIn dermatology cyclosporine is approvedfor the therapy of severe atopic dermati-tis and severe psoriasis vulgaris in adults.The term severe is generally used for pa-tients with widespread skin involvement,high tendency for recurrences and/or in-adequate response to topical therapy.Also, severe reduction in quality of lifeby the disease can necessitate treatmentwith cyclosporine. Sufficient experience exists for pati-ents older than 18 years. Reports ofsuccessful treatment of children withcyclosporine also exist, especially for

those with severe, recalcitrant atopicdermatitis. In most cases cyclosporine should be pri-marily used for induction therapy (up to6 months) due to its good and rapid ef-fects. On the basis of its safety profile, usein long-term therapy is only indicated inexceptional cases (e. g. when effectivetherapeutic alternatives are lacking).

1.1 PsoriasisIn the S3 guideline “Therapy of Psoria-sis” therapy with cyclosporine is discus-sed in detail. The evaluation was basedon 15 studies that fulfilled the criteria ofevidence-based medicine. Therapy ofpsoriasis with cyclosporine is characteri-zed by high efficacy; PASI 75 (at least75 % improvement of the “psoriasis areaand severity index” in comparison to thebaseline value) is attained at the end ofinduction therapy (after 12 weeks) in50–70 % of patients. It is concluded that cyclosporine is an effec-tive option for systemic therapy of mode-rate and severe psoriasis. Long-term therapyis less recommendable due to the numeroustherapeutic alternatives for psoriasis.Combination with topical products intreatment is possible and advisable, as thedose of cyclosporine can be reduced bythe simultaneous use of topical vita-min D3 analogues or corticosteroids. In exceptional cases cyclosporine can alsobe used in the therapy of severe psoriasisin children and adolescents.

Cyclosporine can also be used for psoria-tic arthritis, although explicit approvalfor this indication does not yet exist.

1.2 Atopic dermatitis In the S2 guideline on therapy of atopicdermatitis, the meta-analysis of suitablerandomized, controlled studies indica-ted a significant therapeutic effect of cyclosporine.Duration of therapy depends on treat-ment success and tolerability. Here,short-term therapy is frequently suffi-cient; i. e. the dose of cyclosporine is tapered after sufficient improvement(see also 5. Dosages). When required,the treatment cycle can be repeated (interval therapy). When recurrences appear rapidly, continual long-term therapy with theindividually to be determined lowesteffective dose can be performed. Aftertwo years, discontinuation should beattempted.Cyclosporine is also effective in childrenand adolescents with atopic dermatitis.Data from studies with up to 40 childrenaged 2 to 16 years exist.

1.3 Further indicationsFor the skin diseases listed in the following, cyclosporine may also be employed. Reports of successful therapyin the scientific literature are well-documented in case reports and smallcase series.

Guideline

Cyclosporine therapy in dermatologyUlrich Mrowietz, C. Eberhard Klein, Kristian Reich, Thomas Rosenbach, Thomas Ruzicka, MichaelSebastian, Thomas Werfel

Section EditorProf. Dr. Hans Christian Korting,

München

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Guidelines 475

© Dt. Dermatologische Gesellschaft • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG •1610-0379/2009/0705 JDDG | 5˙2009 (Band 7)

Very good response is reported for: • Pustular psoriasis• Palmoplantar pustulosis (PPP)• Psoriatic erythroderma• Pyoderma gangrenosum• Severe, recalcitrant dyshidrotic hand

and foot dermatitis

Good response is reported for:• Chronic urticaria• Extensive lichen planus • Behçet disease*• Chronic actinic dermatitis, actinic re-

ticuloid

Cyclosporine is also a good option for: • Bullous pemphigoid • Pemphigus vulgaris• Epidermolysis bullosa acquisita*• Dermatomyositis• Recalcitrant, severe, generalized prurigo*For the treatment of Behçet disease andepidermolysis bullosa acquisita, higher do-ses of cyclosporine (> 5 mg/kg) were admi-nistered than for the other indications.

2 ContraindicationsThe following restrictions apply totherapy with cyclosporine:

Absolute contraindications:• Significant renal impairment (excep-

tion: nephrotic syndrome)• Uncontrolled hypertension• Uncontrolled infections• Relevant malignancies (as well as hi-

story of malignancy; exception: basalcell carcinoma)

• Simultaneous phototherapy

Relative contraindications:• Significant hepatic impairment• Pregnancy and lactation• Simultaneous use of substances

which interact with the metabolismof cyclosporine.

In patients with high cumulative UV ex-posure and/or severe actinic skin da-mage, cyclosporine should be used onlyif close clinical control is insured. Beforetherapy the patient must be informedabout adequate sun protection measures.

3 Drug interactionsTherapy with cyclosporine can lead tovarious drug interactions. The decisionfor therapy with cyclosporine in a patientreceiving the drugs named in the follo-wing must be carefully considered by thephysician. Changing the concomitant

therapy (e. g. changing the calciumchannel blocker or the antibiotic) mayhelp prevent interactions. Cyclosporine can delay the metabolismof other drugs. This can increase the toxicity of substances such as digoxin,colchicines, lovastatin, simvastatin andprednisolone. Depending on the type of interactionwith cyclosporine, three groups of drugscan be differentiated, of which the mostimportant examples are listed below.

A. Drugs that by inhibiting thecytochrome P450 system can lead tohigher levels of cyclosporine:• Calcium channel blockers (diltiazem,

nicardipine, verapamil)• Azole antifungal agents (ketoconazole,

fluconazole, itraconazole)• Macrolide antibiotics (e. g. erythromycin)• Doxycycline• Allopurinol• Oral contraceptives • Metoclopramide• Ranitidine

B. Drugs that by stimulating thecytochrome P450 system can lead to lower cyclosporine levels:• Anticonvulsants (carbamazepine, phe-

nobarbital, phenytoin)• Rifampicin• Metamizole• Ticlopidine• Octreotide• Preparations containing St. Johns-wort

C. Drugs that can impair renal functionduring cyclosporine therapy:• Non-steroidal antiinflammatory drugs

(e. g. diclofenac)• Antibiotics (aminoglycosides, cipro-

floxacin, clotrimazole)• FibratesGrapefruit juice by interacting with thecytochrome P450 system can inhibit themetabolism of cyclosporine. In order toprevent unavoidable effects on cyclospo-rine levels, grapefruit juice should beavoided during therapy with cyclospo-rine. The moderate inhibition of predni-solone metabolism by cyclosporineusually is not relevant clinically. Increa-sed occurrence of myopathy is possiblewith simultaneous use of statins.

4 Side effectsDuring therapy with cyclosporine the fol-lowing side effects might occur (Table 1).

Frequency and severity of these side ef-fects are usually dependent on dose andduration of therapy and are reversible af-ter discontinuation. Persistent renalstructural abnormalities can appear afterlong-term use. Patients older than55 years develop side effects such as di-sturbed renal function and hypertensionmore frequently. Long-term therapy with immunosup-pressive drugs such as cyclosporine in-creases the risk of cutaneous malignancies(especially squamous cell carcinomas).From the therapy of transplant recipi-ents with cyclosporine, an increased riskof lymphoma is known. In a study on1200 psoriasis patients treated for amean duration of 1.9 years with low-dose (< 5 mg/kg) cyclosporine in a fol-low-up period of 5 years, a 6-fold in-crease in the skin cancer risk, usuallysquamous cell carcinomas, but no in-creased occurrence of malignant lym-phomas was observed.

5 DosagesInitial doseThe initial dose, depending on disease severity, lies between 2.5 and 5 mg/kg/day(divided into a morning and evening administration). This also applies tochildren.

Dose adjustmentA dose adjustment may be necessary forthe following reasons: • Successful response to therapy

Dose reduction to an individual mainte-nance dose. To achieve this the cyclos-porine dose can be reduced in steps of0.5–1.0 mg/kg/day in two-week inter-vals (alternatively 50 mg every 4 weeks).

• Inadequate response to therapyIncrease dose (to a maximum of5 mg/kg/day)

• Development of hypertensionAntihypertensive therapy (recommen-ded: isradipine, amlodipine; beware ofnifedipine, verapamil, diltiazem);perhaps dose reduction (e. g. initiallyby 25 %).

• Elevation of serum creatinine by atleast 30 % over the individual baselinevalue determined in at least 2 succes-sive blood samples at an interval of2 weeks. Dose reduction (e. g. by 25 % for atleast 4 weeks)

If blood pressure and/or serum creati-nine normalize treatment with the

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reduced cyclosporine dose may be continued.If blood pressure and/or serum creati-nine are still elevated under the reduceddose after 4 weeks, cyclosporine must bediscontinued.

6 Therapy monitoringBefore starting cyclosporine therapy in-dividual baseline values must be determi-ned (Table 2).The pretreatment examination includesthe following parameters:• History of organ dysfunction and ma-

lignancies• Physical examination including ins-

pection of the skin • Indications of ongoing infections• Blood pressure measurement (at two

different times)

Before the start of therapy molluscumcontagiosum, condylomata and multiplewarts should be eliminated. During therapy with cyclosporine thementioned tests should be performed af-ter week 2, week 4 and then in monthlyintervals. During long-term therapy withcyclosporine, the control intervals can be2 months if the drug is well-tolerated.Routinely determining creatinine clea-rance provides no advantage to serumcreatinine measurements with regards tomonitoring renal function during cyclos-porine therapy.To evaluate therapeutic response in pati-ents with dermatologic diseases, measu-ring the trough blood levels of cyclospo-rine is usually not necessary, as there is nocorrelation to therapeutic response andrenal function parameters. Measuring the

level can be done to assess compliance orthe effects of a possible drug interaction.

6.1 VaccinationsDuring treatment with cyclosporine, vaccinations with dead vaccines are notrecommended because of the possiblelack of or weakened vaccination response.Live vaccines are contraindicated in func-tionally significant immunosuppression.For vaccination, interruption of therapytwo weeks before and 4–6 weeks after theprocedure is recommended.

7 Therapy strategiesToday two therapy regimens are differen-tiated:Short-term interval therapyIn short-term interval therapy treatmentwith cyclosporine is continued until a

Table 1: Side effects of cyclosporine therapy.

Organ system

Kidney/cardiovascular

Liver/ gastrointestinal

tract

Nervous system/musculature

Metabolism/electrolytes

Skin Blood

Veryfrequent> 10 %

None None None None None None

Frequent> 1 %,< 10 %

Renal functiondisturbances, irreversible kidney damageduring long-term therapy

Gingiva hyper-plasia, gastroin-testinal upset

Tremor, fatigue,headache, burningsensations onhands and feet

Increased lipidsserum

Hypertrichosis None

Sporadic> 0.1 %,< 1 %

None Gastric ulcers Convulsions

Weight gain,hyperglycemia,hyperuricemia,hyperkalemia,hypomagnese-mia

Acne Anemia

Rare> 0.01 %,< 0.1 %

Ischemic heartdisease

Pancreatitis

Motor polyneuro-pathy, myopathy,visual, acousticand central motordisturbances

None Pruritus Leukopenia,thrombocytop -enia

Very rare< 0.01 %

None None None None None

Microangiopa-thic hemolyticanemia, hemo-lytic uremic syndrome

Individualcase reports

Colitis Papilledema

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vast improvement of the skin disease hasoccurred. Subsequently, the dose is tape-red and treatment is continued with ano-ther medication after discontinuation ofcyclosporine. In the event of a possibledeterioration of cutaneous findings,therapy with cyclosporine can be re-initiated.

Long-term therapySevere forms of psoriasis, atopic dermati-tis or other chronic skin diseases with astrong tendency to recur can be treatedwith cyclosporine continually for a longperiod of time. In this case the individualadjustment of the dose is particularly im-portant, so that the lowest possible doseof cyclosporine is used. In long-term therapy regular determina-tion of renal function parameters is ofspecial importance. In long-term therapyan elevation of serum creatinine by> 30 % can be expected in up to 50 % ofpatients, which is usually dose-dependentand reversible upon discontinuation.After therapy for two years, an attempt atdiscontinuation should be made.

8 End of therapyTreatment with cyclosporine can be dis-continued abruptly without the risk of a

rebound phenomenon. Stepwise reduc-tion (tapering) of therapy can possiblydelay a rapid recurrence. In the following situation discontinua-tion of cyclosporine therapy may be indi-cated:• Insufficient or absent response to

therapy after 12–16 weeks• Development of side effects that per-

sist despite dose reduction • Development of severe infections• Development of malignancies• Pregnancy during therapy (only in ex-

ceptional cases where cyclosporine is theonly treatment option and positive be-nefits outweigh possible risks, can treat-ment be continued during pregnancy.Pregnancy must then be considered ahigher risk pregnancy and be monitoredon an interdisciplinary basis).

In children special circumstances (plan-ned vaccinations, exposure to potentiallyinfectious children) may necessitate aninterruption or discontinuation oftherapy with cyclosporine.

9 Transition from cyclosporine toother therapiesAfter discontinuation of cyclosporine othermedications or therapeutic measures canusually be started without temporal delay.

When transitioning to a biologic due toinsufficient effectiveness of cyclosporine,overlapping therapy for several weeks maybe possible to avoid a rapid recurrence.In transitioning due to side effects, thespecific safety profile of cyclosporinemust be taken into consideration to avoid increased toxicity of the subsequent me-dication.

9.1 Transitioning from other therapies to cyclosporineCyclosporine should not be used within4 weeks after discontinuing acitretintherapy. After long-term PUVA therapy, cyclospo-rine should not be used, as an increasedskin cancer risk exists for this combination.

10 Combination therapyTherapy with cyclosporine can be com-bined well with topical treatments. Thefollowing combination therapies act syn-ergistically:

Cyclosporine• with topical corticosteroids• with anthralin (in psoriasis)• with vitamin D3 analogues (in psoriasis)

Further, cyclosporine can be combinedwith the following therapies:• Balneotherapy (without UV therapy,

in psoriasis and atopic dermatitis)• Salicylic acid (in psoriasis)• Topical products containing urea• Emollients

Cyclosporine should not be combined withthe following medications or therapeuticmeasures:• Photo- or photochemotherapy• AcitretinIn individual cases a combination of cy-closporine with methotrexate, mycophe-nolate mofetil or mycophenolic acid orfumaric acid esters can be successful.Due to possible interactions, intensivemonitoring of therapy may be necessary.No sufficient experience exists on thelong-term combination of cyclosporinewith biologics.

Procedure in creating consensusDeveloped by the consensus conferencecyclosporineScientific chairman: Prof. Dr. UlrichMrowietz, KielParticipants: Prof. Dr. C. EberhardKlein, Heidenheim; Prof. Dr. Kristian

Time (weeks)

Diagnostics Beforetherapy

2 4 8 12 16

Blood count* x x x x x x

Liver parameters** x x x x x x

Electrolytes*** x x x x x x

Serum creatinine x x x x x x

Urea x x x x x x

Urinalysis x x x x x

Uric acid x x x x x

Cholesterol/triglycerides **** x x x

Magnesium***** x x x

Table 2: (modified according to Nast et al., 2006).

*Erythrocytes, leukocytes, thrombocytes**Transaminases, GGT, AP, bilirubin***Sodium, potassium****Fasting value!*****Only in the event of muscle cramps

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Reich, Hamburg; Priv. Doz. Dr. ThomasRosenbach, Osnabrück; Prof. Dr. Thomas Ruzicka, Munich; Dr. MichaelSebastian, Mahlow; Prof. Dr. ThomasWerfel, Hannover (all Germany)Completed: September 2008Level: S1Valid: until October 2011

Correspondence toProf. Dr. Ulrich MrowietzDepartment of Dermatology, Venereology and AllergyUniversity Clinic of Schleswig-Holstein,Campus KielSchittenhelmstr. 7D-24105 Kiel, GermanyTel.: +49-431-597-1508/1512Fax: +49-431-597-1543E-mail: [email protected]

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