Intermittent short courses of cyclosporin (Neoral®) for psoriasis unresponsive to topical therapy: a 1-year multicentre, randomized study

Intermittent short courses of cyclosporin (NeoralÒ) for psoriasisunresponsive to topical therapy: a 1-year multicentre,randomized study

V.C.HO, C.E.M.GRIFFITHS,* G.ALBRECHT,² F.VANACLOCHA,³ G.LEOÂ N-DORANTES,§N.ATAKAN,¶ S.REITAMO,** A.JOHANNESSON,²² N.J.MéRK,³³ P.CLARKE,§§

P.PFISTER¶¶ AND C.PAUL¶¶ FOR THE PISCES STUDY GROUP

Division of Dermatology, University of British Columbia, The Skin Care Center, Vancouver General Hospital,

835 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E8*Dermatology Centre, Hope Hospital, University of Manchester, Manchester, U.K.

²Department of Dermatology, Spandau Hospital, Berlin, Germany

³Department of Dermatology, Hospital 12 de Octubre, Madrid, Spain§Departments of Dermatology and Clinical Epidemiology, General Hospital of Mexico, Mexico City, Mexico

¶Department of Dermatology, Hacettepe University, Ankara, Turkey

**Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland

²²Department of Dermatology, VaÈllingby Medical Centre, VaÈllingby, Sweden³³Department of Dermatology, National Hospital, Oslo, Norway

§§Hartington Statistics and Data Management Ltd, London, U.K.

¶¶Central Medical Affairs, Novartis Pharma AG, Basel, Switzerland

Accepted for publication 23 November 1998

Summary We performed a 1-year study to determine whether intermittent short courses of the microemulsion

formulation of cyclosporin (NeoralÒ) could effectively control plaque psoriasis and whether tapering

or abrupt cessation of cyclosporin therapy would in¯uence time to relapse. Four hundred patientswith plaque psoriasis were included in this open, multicentre, randomized study. All patients

commenced cyclosporin at a dose of 2´5 mg/kg daily. Cyclosporin dosage could be increased to a

maximum of 5 mg/kg daily. Treatment was continued until clearance of psoriasis or for a maximumof 12 weeks. Patients were then randomly assigned either to stop cyclosporin abruptly or to have the

dose reduced by 1 mg/kg daily each week until cessation. On relapse, patients were given another

course of cyclosporin. Patients were followed for at least 1 year, during which they could receive asmany treatment courses as necessary. The number of patients who required one, two, three and four

treatment courses was 400, 259, 117 and 26, respectively. The median time to relapse after the end

of the ®rst treatment period was 109 days in the group of patients randomized to stop cyclosporinabruptly and 113 days in patients randomized to taper off cyclosporin (P�0´038). More than 30%

of patients had not relapsed 6 months after having stopped treatment. After each treatment course,

the Kaplan±Meier probability of achieving 75% or more reduction in disease area by day 84 oftreatment was 83%, 76%, 73% and 66%, respectively. Mean serum creatinine concentration and

blood pressure did not show any clinically signi®cant changes over time. Our results show that

intermittent short-course therapy with NeoralÒ, when used in conjunction with topical therapy, iswell tolerated and provides effective control of plaque psoriasis for 1 year. Tapering off cyclosporin on

treatment cessation induces a slight delay in psoriasis relapse.

Key words: cyclosporin, intermittent courses, psoriasis, relapse rate, side-effects.

Psoriasis is a chronic skin disease that can seriously affect

a patient's quality of life.1 Life-long intermittent treat-ment may be required to control the disease.2 Although

topical treatment with corticosteroids, calcipotriol, tar

or dithranol is helpful in controlling mild forms ofthe disease, phototherapy or systemic therapy may be

considered in more severe cases of psoriasis. Systemic

therapies, however, are associated with side-effects that

British Journal of Dermatology 1999; 141: 283±291.

283q 1999 British Association of Dermatologists

Correspondence: Dr V.C.Ho, E-mail: [email protected]

restrict their long-term use. Psoralen and ultraviolet A(PUVA) phototherapy has been associated with an

increased risk of skin cancer.3,4 Hepatotoxicity is a

major limitation to long-term methotrexate use.5

Synthetic retinoids are highly teratogenic and are often

ineffective as monotherapy.6 More recently, cyclosporin

was introduced for the treatment of severe psoriasis.Cyclosporin has been shown to be effective in several

short-term and long-term randomized, controlled stu-

dies.7±12 However, long-term continuous treatmentwith cyclosporin may be associated with nephrotoxicity

and it is recommended that continuous therapy should

not exceed 2 years.13 Intermittent short courses of thenew microemulsion formulation of cyclosporin

(NeoralÒ) may be an effective treatment for psoriasis,

with an improved risk/bene®t ratio.14

To investigate the ef®cacy and safety of intermittent

courses of cyclosporin in psoriasis, we performed an

open, multicentre, randomized study over 1 year inpatients with psoriasis unresponsive to topical therapy.

To de®ne the best treatment cessation method, we

randomly assigned patients either to stop cyclosporinabruptly or to taper off the drug within 4 weeks.

Patients and methods

Study population

Four hundred patients aged 17±81 years (mean 41

years) were enrolled in this multicentre study. To beeligible for the study, patients had to have plaque

psoriasis unresponsive to topical therapies. Women of

child-bearing potential were required to use a medicallyapproved method of contraception throughout the

study. Exclusion criteria included abnormal renal func-

tion (serum creatinine above 10% of the upper limit ofthe reference range), abnormal liver function (bilirubin

or liver enzymes twice the upper limit of the reference

range), hyperkalaemia or hyperuricaemia, a history ofreceiving more than 12 weeks of systemic therapy with

corticosteroids, immunomodulating or cytotoxic drugs

or retinoids, a history of malignancy, acute uncontrolledbacterial, viral or fungal infection, uncontrolled hyper-

tension, clinically signi®cant impairment of haemato-

poietic, cardiovascular and/or cerebral function andconcomitant therapy with nephrotoxic medications.

Before enrolment, all patients stopped receiving systemic

therapy for at least 14 days and PUVA for at least 30 days.All patients gave written informed consent to partici-

pate and the protocol was approved by appropriate

ethics committees or institutional review boards.

Study design

This was a prospective, randomized, open, multicentrestudy lasting 1 year. All patients were advised to con-

tinue their topical treatment at the same dose during

the 2-week screening period. All patients commencedcyclosporin (NeoralÒ) at a total dose of 2´5 mg/kg daily

given in two divided doses. Cyclosporin dosage could be

increased by increments of 0´5±1´0 mg/kg daily to amaximum of 5 mg/kg daily to achieve clearance,

de®ned as 90% or more reduction in the area affected.

Dosage reductions were allowed, in accordance withestablished guidelines,13 for elevated creatinine concen-

trations of more than 30% above baseline or for hyper-

tension. New-onset hypertension was de®ned as systolicblood pressure at least 160 mmHg or diastolic blood

pressure at least 95 mmHg on two or more occasions;

severe hypertension was de®ned as systolic blood pres-sure at least 200 mmHg or diastolic blood pressure at

least 110 mmHg on two or more occasions.15 Treat-

ment was continued until clearance of psoriasis or for amaximum of 12 weeks. Patients who achieved satisfac-

tory clinical response, de®ned as 75% improvement in

disease area, were randomly assigned either to stopcyclosporin abruptly (group A) or to have the dose

reduced by 1 mg/kg daily each week until stopping

within 4 weeks (group B).Patients were followed until relapse, de®ned as when

the investigator and patient deemed that cyclosporin

should be restarted or recurrence of the psoriasis affect-ing 75% or more of the pretreatment disease extent. On

relapse, patients were given another course of cyclo-

sporin, commencing at the dose at which they achievedremission in the previous treatment period. At the end

of each subsequent treatment period, patients had to

stop cyclosporin according to the plan de®ned by therandomization procedure. Patients were followed for at

least 1 year, during which they could receive up to four

treatment courses. Patients were allowed to use the sametopical therapies throughout the study and could

increase or decrease the amount of topical therapy

used as appropriate. Evaluation visits were scheduledon a 2-weekly basis during each treatment period and

then monthly until relapse.

Ef®cacy assessment

Five ef®cacy variables were assessed during the study.

The percentage of the body affected was assessed at eachvisit using the modi®ed rule of nines; scalp and ¯exural

psoriasis were excluded because of dif®culty in accurately

evaluating disease severity and extent at these sites. The

284 V.C.HO et al.

q 1999 British Association of Dermatologists, British Journal of Dermatology, 141, 283±291

severity of the lesions was recorded at each visit usingscores for erythema, in®ltration and desquamation on a

four-point scale in which 0 indicated none, 1 slight, 2

moderate and 3 severe. At the end of each treatmentperiod, the investigator rated the global response to

therapy as cleared, markedly improved, moderately

improved, slightly improved, unchanged, slightlyworsened, moderately worsened or markedly worsened.

In addition, patients and physicians evaluated the over-

all ef®cacy of the cyclosporin treatment during thewhole study using a ®ve-point scale as follows: no or

minimal symptoms, considerable improvement, slight

improvement, no improvement, deterioration. For eachpatient at various time points, we also computed a

modi®ed version of the psoriasis area and severity

index (PASI), a global rating that incorporates boththe surface area and the severity index.16 This modi®ed

PASI differs from the original PASI in that a scale of 0±3

instead of 0±4 was used to score disease severity and thehead was not included in the evaluation of disease

extent. The modi®ed PASI score ranges from 0 to 54

instead of 0±72 for the original PASI.

Safety assessment

A complete physical examination was performed on

each patient at the time of enrolment and at thebeginning of each subsequent treatment period. At

each visit, blood pressure was measured by the physi-

cian after the patient had sat for 5 min. Laboratorymonitoring included a complete blood count with differ-

ential at screening and at the beginning of each sub-

sequent treatment period and analysis of bloodchemistry (potassium, uric acid, total bilirubin, alkaline

phosphatase, magnesium, aspartate and alanine amino-

transferases, gamma-glutamyl transferase and choles-terol) at the beginning and end of each treatment

period. The serum creatinine concentration was deter-

mined at each visit. A urine dipstick measurement ofurinary protein and glucose was made at screening and

at the beginning of each treatment period. Any adverse

event during the study, whether or not it was thought tobe related to the study drug, was recorded. At the end of

the study, patients and physicians evaluated the overall

tolerability of cyclosporin during the whole study, usinga ®ve-point scale of very good, good, moderate, poor and

very poor.

End-points

The primary end-point was the time to relapse after the

®rst treatment period, with the main comparison beingbetween the two groups. Secondary end-points were

change from baseline in the psoriasis area, change in

the modi®ed PASI, the global evaluation of responseto therapy and the overall ef®cacy assessed by the

investigator and patient. Secondary end-points were

summarized for all randomized patients at the end ofeach treatment period and at the end of the study.

Statistical analysis

The statistical analysis of the time to relapse after the

®rst treatment period was performed on all randomizedpatients, following an intention-to-treat principle. The

statistical analysis of time to relapse for subsequent

treatment periods was performed on all patients whoreceived at least one dose of the study medication during

that period. Kaplan±Meier estimates of the probability of

remaining relapse-free in each period were presented inlife tables and in cumulative survival plots. The time to

relapse was analysed using a Cox proportional hazards

model, adjusting for the effects of the following covari-ates: age, total surface area of lesions at baseline,

modi®ed PASI at baseline, history of treatment with

phototherapy or systemic antipsoriatic therapy andrandomization group. Statistical tests were two-tailed

and the level of signi®cance was P�0´05. The assump-tion of proportional hazards was tested by including a

time-dependent variable in a model adjusting for the

effects of randomization group only. When the assump-tion of proportional hazards was violated, a piecewise

Cox model was ®tted, by dividing the study period into a

number of time intervals, each of which ful®lled theassumption of proportional hazards. Hazard ratios and

95% con®dence intervals for a model ®tting only the

randomization group were presented for each timeinterval, along with the average hazard ratio and its

95% con®dence interval.

Results

Characteristics of the patients

A total of 400 patients were enrolled in the study at

baseline, of whom 365 (91%) were eligible for random-ization at the end of the ®rst treatment period; 192 were

randomly assigned to stop cyclosporin abruptly (group

A) and 173 were assigned to taper off the drug (groupB). The baseline characteristics of the patients and

reasons for withdrawing from the study before random-

ization are shown in Table 1. No noteworthy differences

INTERMITTENT CYCLOSPORIN FOR PSORIASIS 285


were seen between the treatment groups at baseline.The number of patients who required one, two, three

and four treatment courses was 400, 259, 117 and 26,

respectively.

Time to relapse of psoriasis after cyclosporin cessation

The median time to relapse after the end of the ®rst

treatment period was 109 days in the group of patients

randomized to stop cyclosporin abruptly and 113 daysin patients randomized to taper off cyclosporin within

4 weeks (Fig. 1). The difference was statistically signi-

®cant (P�0´04). Overall, the median time to relapseafter the end of the ®rst treatment period was 112

days. Approximately 45% of the patients had not

relapsed 4 months after having stopped treatment andapproximately 31% had not relapsed 6 months after

stopping cyclosporin. The investigation of the effect of

covariates suggested a statistically signi®cant effect ofphototherapy (hazard ratio 1´53), and systemic therapy

(hazard ratio 1´6), whereas age, total surface area and

modi®ed PASI at baseline did not seem to have an effecton relapse (Table 2). Analysis of time to relapse after the

second and third treatment periods showed that there

was a signi®cant difference between the randomizationgroups up to day 84 (P�0´01 for the second treatment

period; P�0´04 for the third treatment period), but

no signi®cant difference between the randomizationgroups after day 84. Relapse was delayed in the group

of patients tapering off the drug, compared with the

group of patients stopping cyclosporin abruptly. Mediantime to relapse was 60 days in group A and 95 days in

group B after the second treatment period and 52 and

63 days, respectively, after the third treatment period.

Ef®cacy analysis

For all of the ef®cacy variables studied, an improvementwas seen in all treatment periods over the course of the

study. The mean area of skin involved at baseline

was 25%. This had reduced at the end of treatmentperiods 1, 2, 3 and 4 to 4%, 2´6%, 4´4% and 4´5%,

respectively. Similar results were observed with the

modi®ed PASI: at the last treatment visit, the mean

286 V.C.HO et al.


Group A Group B

(abrupt cessation) (tapering off) Total

Patients (n) 192 173 400

Age (years) 41 6 13 40 6 13 41 6 13Male/female ratio (%) 59 : 41 61 : 39 62 : 38

Weight (kg) 77 6 15 77 6 16 77 6 16

Psoriasis duration (years) 15 14 15

Psoriatic area (% total) 24 6 20 25 6 20 25 6 20Modi®ed PASI score 13 6 9 14 6 8 14 6 9

Previous treatment (% patients)

phototherapy 42 45 42

systemic therapy 19 19 19Patients withdrawing before

randomization [n (%)] 35 (9)

Reason for withdrawal (n)adverse event 10

protocol violation 5

medication ineffective 7

other 13

Where applicable, data are mean 6 SD.

Table 1. Patient demographics, baseline

clinical characteristics and withdrawals

before randomization

Figure 1. Time to relapse after the ®rst treatment period (Kaplan±

Meier survival estimate: proportion of patients who have not relapsed).

Group A: abrupt cessation; group B: tapered cessation of cyclosporin.

score had improved by 82%, 78%, 70% and 74% afterthe ®rst, second, third and fourth treatment periods,

respectively. Improvement was noted within 4 weeks of

therapy, with a mean decrease in modi®ed PASI of 50%of baseline by that point (Fig. 2). The percentage of

patients achieving satisfactory clinical response at day

84 was 83% after the ®rst treatment period, 76% afterthe second treatment period, 73% after the third treat-

ment period and 66% after the fourth treatment period

(Fig. 3). According to the physicians' global evaluation,the percentages of patients who were cleared or mark-

edly improved at the end of treatment periods 1, 2, 3

and 4 were 87%, 85%, 82% and 92%, respectively. Onthe assessment by the investigators and patients of

overall ef®cacy of cyclosporin therapy throughout the

study, more than 85% of the patients had considerableimprovement in their psoriasis or had no or minimal

symptoms. There was good agreement between physi-

cians' and patients' evaluation of the overall ef®cacy ofcyclosporin therapy.

Time to clinical response, cyclosporin dosage and durationof therapy

Patients were treated with cyclosporin at an initial totaldaily dose of 2´5 mg/kg daily in the ®rst treatment

period. The median time to achieve satisfactory clinical

response in the ®rst treatment period was 68 days and

the mean 6 SD cyclosporin daily dose was 3´3 6

1´1 mg/kg. For the second, third and fourth treatment

periods, the median time to achieve a satisfactory

response was 70, 74 and 63 days, respectively. Themean 6 SD cyclosporin daily dose at time of satisfactory

response was 3´4 6 0´9, 3´9 6 0´9 and 4´0 6 0´8 mg/

kg, respectively. The mean duration of therapy overallwas 80 days in the ®rst treatment period, 81 days in the

second treatment period, 75 days in the third treatment

period and 64 days in the fourth treatment period. Onaverage, patients randomized to taper off cyclosporin

received the agent for 11±23 days more than patients

randomized to abrupt cessation. For the entire 1-yearstudy period, the mean number of days on cyclosporin

treatment was 160 days overall, 161 days for group A

and 176 days for group B.

Safety analysis

Adverse events considered by the investigators to be

probably or de®nitely related to the study medication

were reported by 50% of patients. Paraesthesia (11%),nausea (11%), hypertrichosis (7%) and headache (5%)

were the four most frequently observed adverse events

(excluding serum creatinine changes and hypertension).



Table 2. Multiple regression analysis offactors predicting time to relapse after the

®rst treatment period

Covariates Hazard ratio 95% con®dence intervals P-value

Age 0´998 0´989, 1´007 0´6402Total surface area of lesions 1´011 0´993, 1´029 0´2481

Modi®ed PASI at baseline 0´985 0´946, 1´025 0´4546

Phototherapy (yes vs. no) 1´532 1´196, 1´961 0´0007

Systemic therapy (yes vs. no) 1´597 1´182, 2´157 0´0023Randomization group (B vs. A) 0´772 0´605, 0´986 0´0379

Figure 2. Change in modi®ed psoriasis area and severity index during

the ®rst on-treatment and off-treatment period. Data are mean 6 SD.

Figure 3. Cumulative remission rate at each visit during each treat-

ment period. (Remission is de®ned as 75% improvement in psoriasis

area.)

Most adverse events were mild to moderate and re¯ected

the known side-effect pro®le of cyclosporin. Five (1´2%)patients (one from group A, four from group B) devel-

oped transient palmar and/or plantar pustular psoriasis

lesions on one occasion upon withdrawal of cyclosporin.The severity was considered as mild in two patients,

moderate in two patients and severe in one. In none of

these patients was this event considered serious enoughto lead to study discontinuation. A total of 15 serious

adverse events were reported in 11 patients (3%) during

the study. Of these, two serious adverse events inone patient (severe myalgia and paraesthesia) were

considered to be probably or de®nitely related to study

medication. Thirty-three patients (8%) discontinued thestudy because of adverse events; 23 events in 16 (4%) of

these patients were considered to be probably or de®-

nitely related to the study drug. These included asthenia(n�1), hypertension (n�3), headache (n�1), para-

esthesia (n�4), gastrointestinal disorders (n�6),

serum creatinine increase (n�2), musculoskeletalsymptoms (n�3), confusion (n�1), infection (n�1)

and pruritus (n�1).

The mean serum creatinine concentration remained

stable throughout the study, with no clinically signi®-cant increases (Fig. 4). Although slight increases in

mean serum creatinine concentration of 5±14% over

baseline occurred during cyclosporin treatment, theconcentrations returned to baseline within 1 month of

cyclosporin cessation (Fig. 4). The mean 6 SD percen-

tage increase in serum creatinine concentration overbaseline at the beginning of the second, third and fourth

treatment periods was 2´2 6 13´1%, 1´7 6 11´6% and

1´8 6 15´1%, respectively, re¯ecting the absence ofcumulative deleterious effects of intermittent treatment

with cyclosporin on renal function. Two patients (0´5%)

withdrew from the study because of elevation of serumcreatinine. The percentage of patients who did not

experience any clinically signi®cant increase in serum

creatinine (>30% increase from baseline) during treat-ment with cyclosporin was 90% during the ®rst treat-

ment period, 82% during the second treatment period,

80% during the third treatment period and 73% duringthe fourth treatment period. The number and percen-

tage of patients experiencing clinically signi®cant

increases in serum creatinine during the whole studyare presented in Table 3. Most of these patients had a

moderate rise of 30±50% above baseline on one or two

occasions. During the 1-year period, 32 patients (8%)had three or more rises in serum creatinine of more

than 30% above baseline. The number of patients withelevation of serum creatinine of more than 30% above

baseline during the off-treatment periods was 37, com-

pared with 120 during treatment, indicating reversibil-ity of serum creatinine changes on cyclosporin cessation

(Table 3).

The mean systolic and diastolic blood pressureremained stable throughout the study (Fig. 5).

Increased variability in blood pressure was observed in

the fourth treatment period, most probably because ofthe small number of patients treated during that period

288 V.C.HO et al.


Figure 4. Change in serum creatinine concentration from baseline.Data are mean 6 SD.

Patients with serum creatinine increase [n (%)]

Increases (n) 31±50% increase 51±100% increase >100% increase

On treatment

0 309 (78´0) 369 (93´2) 390 (98´5)1±2 69 (17´4) 22 (5´6) 6 (1´5)

$ 3 18 (4´5) 5 (1´3) 0 (0)

Off treatment0 283 (90´4) 307 (98´1) 312 (99´7)

1±2 27 (8´6) 6 (1´9) 1 (0´3)

$ 3 3 (1´0) 0 (0) 0 (0)

Table 3. Number and percentage of patients

with increased serum creatinine

concentrations from baseline during the

study

(Fig. 5). New-onset hypertension was observed in 45

patients (12%). Only one patient (0´3%) experienced

severe hypertension. Initiation of antihypertensivemedication during the study was required in 21 patients

(5%) receiving cyclosporin. A reduction in cyclosporin

dosage due to raised blood pressure occurred in 26patients (7%). Three patients (0´75%) discontinued

the study because of hypertension.Global assessment at the end of the study showed that

more than 89% of patients and physicians considered

the overall tolerability of cyclosporin treatment to bevery good or good. Overall tolerability was rated as poor

or very poor by 3% of patients and by 4% of physicians.

There was good agreement between physicians' andpatients' evaluation of overall tolerability of cyclosporin

therapy.

Discussion

This study shows that intermittent treatment with shortcourses of cyclosporin (NeoralÒ) in conjunction with

topical therapy can adequately control plaque psoriasis

that was previously unresponsive to topical therapyalone. More than 80% of the patients in this study

achieved satisfactory clinical response in a median

duration of treatment of about 10 weeks at a meancyclosporin dose of 3±4 mg/kg daily. About 71% (283 of

400) of the patients required only one or two courses of

treatment with cyclosporin during the 1-year periodand 29% (117 of 400) required three or four courses of

treatment. Similarly satisfactory clinical response was

achieved after each treatment course and no reboundeffect was observed after cessation of cyclosporin therapy.

One criticism of the trial might be that, because of the

study design, only cyclosporin-responders (at the end ofthe ®rst treatment period) were allowed to continue in

the trial. However, because more than 90% of the

patients who enrolled were cyclosporin-responders,the selection process is unlikely to have had much

impact on our ®ndings.

An important observation in this study is that onecourse of cyclosporin of 12 weeks or less can lead to

sustained remission of plaque psoriasis in some patients,

similar to one course of PUVA or methotrexate. After the®rst treatment period, more than 40% of patients had

not relapsed 4 months after the end of treatment and

approximately one-third of patients had not relapsed6 months after having stopped cyclosporin. The faster

relapse after treatment periods two, three and four is

likely to be due to the selection of patients who havemore severe or refractory disease. The selection of

patients with refractory disease may also account for

the increase in cyclosporin dose requirement in thesubsequent treatment periods.

We have demonstrated that tapering off cyclosporin

on treatment cessation induces a slight delay in theoccurrence of psoriasis relapse. The median time to

relapse was lengthened by between 4 days and 35

days in patients who tapered off cyclosporin. Thismodest advantage of a longer remission must be counter-

balanced by the disadvantage of the longer treatment

duration in this group. Patients randomized to taper offthe drug received on average 11±23 more days of

cyclosporin. As the bene®t of the tapering proceduremay be questioned, the decision in clinical practice to

taper or not to taper a second or subsequent course of

cyclosporin should be individualized according to thepatient's clinical response to prior cyclosporin treatment,

such as the rapidity or severity of relapse.

Multiple regression analysis also identi®ed a history ofphototherapy or systemic treatment as an independent

variable associated with earlier relapse. However, the

baseline disease extent and modi®ed PASI score did notcorrelate with time to relapse. There are two possible

explanations for these ®ndings. (i) Patients who had

previously received phototherapy or systemic therapymay have more resistant disease. Disease resistance may

be a better predictor of relapse than the PASI score. This

is in accordance with early studies with cyclosporin,which suggested that cyclosporin was less effective in

the subgroup of patients who had received previous

treatment with other systemic drugs, such as metho-trexate or retinoids.17 (ii) Baseline disease extent and

modi®ed PASI score are poor indicators of the true

disease severity.The relapse rate was lower and the time to relapse

was longer in our study compared with those previously

reported in studies with cyclosporin. In a double-blind



Figure 5. Change in systolic (ÐÐ) and diastolic (± ±) blood pressure

from baseline. Data are mean 6 SD.

study of maintenance treatment with cyclosporin after a16-week open clearing phase, the relapse rate at the end

of the 24-week follow-up was 84% in the placebo group

vs. 42% in the cyclosporin-treated group, with a mediantime to relapse of 42 days.12 In another double-blind

study involving 20 patients with severe psoriasis, the

mean time to relapse after stopping treatment was 7weeks and only one patient had not relapsed at the end

of the 4-month follow-up.11 The likely explanation for

the differences between our study and previous ®ndingsis that the patients included in previous cyclosporin

studies had more severe or more resistant psoriasis. This

is in agreement with the ®ndings of Berth-Jones et al.14

and Higgins et al.18 who showed a lower rate of relapse

and a longer remission after cyclosporin treatment in

patients with less severe forms of psoriasis. As pre-viously pointed out by Higgins et al.18 the relapse rate

after cyclosporin treatment is similar to that observed

with other therapies, such as phototherapy or metho-trexate. Most probably, psoriasis resistance or severity

determines the time to relapse, rather than the therapy.

Another possible explanation for our ®ndings may bethat we used the new microemulsion formulation of

cyclosporin (NeoralÒ), which is known to produce a

more rapid response and higher remission rate than theearlier formulation of cyclosporin.19

Intermittent treatment with cyclosporin was gener-ally well tolerated. The type of side-effects observed in

the present study was comparable with those reported

in previous studies on psoriasis. Hypertension occurredin 12% of patients and only one patient (0´3%) experi-

enced severe hypertension during the 1-year period.

The most serious side-effect associated with long-termcyclosporin therapy is renal impairment.20 The risk of

developing renal damage with cyclosporin has been

associated with both dose and duration of therapy.20±

22 The percentage increase in serum creatinine concen-

tration above baseline during cyclosporin therapy has

been shown to be the best predictor of cyclosporin-induced renal dysfunction.21,23 Up to 2 years' cyclo-

sporin therapy for psoriasis has been shown to be

associated with a good safety pro®le, provided guidelinesfor treatment are observed and persistent increases in

serum creatinine concentration of more than 30%

above baseline are avoided.13,20 In our study, both theseverity and the frequency of serum creatinine changes

appeared to be less pronounced than those observed in

previous long-term studies of continuous cyclosporintreatment in psoriasis. In a 12-month study of 209

patients on continuous maintenance treatment,24 42%

of patients experienced an increase in serum creatinine

concentrations of more than 30% above baseline, com-pared with 30% of patients in our study. In the study by

Grossman et al.25 on the long-term safety of continuous

cyclosporin treatment, 14% of patients had to discon-tinue treatment because of cyclosporin-related side-

effects, compared with 4% in our study. We believe

that the better safety pro®le in our study is related tothe intermittent nature of the treatment, which allows

time for recovery, and the overall reduced time of

exposure to cyclosporin.In conclusion, this study indicates that intermittent

therapy with cyclosporin adequately manages plaque

psoriasis unresponsive to topical treatment. By reducingthe exposure to the drug, intermittent treatment should

help minimize undesirable side-effects associated with

long-term continuous use of cyclosporin. The results ofour study in patients with psoriasis unresponsive to

topical therapy show that, after one 12-week treatment

course with cyclosporin, the median time to relapse is112 days. Approximately one-third of patients had long-

term relapse-free intervals after the ®rst treatment

course. Although intermittent treatment with cyclo-sporin has been proven to be suitable for most of the

patients studied, in a minority of patients suffering from

recalcitrant forms of psoriasis, continuous or nearlycontinuous treatment was required to obtain good

control of their psoriasis. Alternation with otherforms of systemic treatment may be considered in the

long-term management of this small subgroup of

patients.

Acknowledgments

This study was sponsored by Novartis Pharma AG,

Basel, Switzerland. The members of the Psoriasis

Intermittent Short Courses Ef®cacy of SandimmunNeoral (PISCES) study group are: Canada: V.C.Ho,

W.Gulliver, S.Murray, R.Cloutier, D.Sauder, G.Sibbald,

K.Papp, M.Sunderland, D.SoulieÁres, P.Draga. Finland:M.Nuutinen, S.Reitamo, H.Granlund, P.Erkko, A.Remitz,

M.Kartamaa. France: J.P.Ortonne, J.J.Guilhou, S.Belaich,

O.Reigneau. Germany: G.Albrecht, E.G.Jung, W.B.Schill,E.SchoÈpf, T.Luger, J.Knop, M.BraÈutigam. Mexico: G.LeÂon-

Dorantes, C.Rosado, R.G.Plata. Norway: N.J.Mùrk,

J.R.Bjerke, D.E.Hatun, I.Helland. Spain: F.Vanaclocha,A.Aliaga Boliche, A.Garcia Diez, J.Escudero, M.Alepuz.

Sweden: A.Johannesson, B.Wilson Clareus, P.Holm,

T.Arvidsson. Switzerland: J.H.Saurat, J.Tinguely.Turkey: N.Atakan, G.OÈ zarmagan, Z.Nefesoglu. U.K.

C.E.M.Grif®ths, J.Berth-Jones, H.Lewis, D.Kemmett,

M.Good®eld, P.V.Harrison, S.George, C.Haliburn, R.Keefe,

290 V.C.HO et al.


A.Beard, M.Sumner. Novartis Pharma AG, Switzerland:C.Paul, P.P®ster, N.King, E.Stebler.

References

1 Finlay AY, Coles EC. The effect of severe psoriasis on the quality of

life of 369 patients. Br J Dermatol 1995; 132: 236±44.

2 Spuls PI, Witkamp L, Bossuyt PMM, Bos JD. A systematic review of

®ve systemic treatments for severe psoriasis. Br J Dermatol 1997;137: 943±9.

3 Stern RS, Laird N, Melski J et al. Cutaneous squamous-cell

carcinoma in patients treated with PUVA. N Engl J Med 1984;

310: 1156±61.4 Stern RS, Nichols KT, VaÈkevaÈ LH. Malignant melanoma in patients

treated for psoriasis with methoxsalen (psoralen) and ultraviolet A

radiation (PUVA). The PUVA Follow-Up Study. N Engl J Med 1997;336: 1041±5.

5 Roenigk HH Jr, Auerbach R, Maibach H et al. Methotrexate in

psoriasis: consensus conference. J Am Acad Dermatol 1998; 38:

478±85.6 Paul C, Dubertret L. Etretinate and acitretin: strategy for use and

long-term side effects. In: Psoriasis (Roenigk HH Jr, Maibach HI,

eds), 3rd edn. New York: Marcel Dekker, 1998: 671±83.

7 Ellis CN, Gorsulowsky DC, Hamilton TA et al. Cyclosporin improvespsoriasis in a double-blind study. JAMA 1986; 256: 3110±16.

8 Van Joost T, Bos JD, Heule F, Meinardi MMHM. Low-dose cyclo-

sporin A in severe psoriasis. A double-blind study. Br J Dermatol

1988; 118: 183±90.9 Ellis CN, Fradin MS, Messana JM et al. Cyclosporin for plaque-type

psoriasis. Results of a multidose, double-blind trial. N Engl J Med

1991; 324: 277±84.10 Christophers E, Mrowietz U, Henneicke HH et al. Cyclosporin in

psoriasis: a multicenter dose-®nding study in severe plaque psor-

iasis. The German Multicenter Study. J Am Acad Dermatol 1992;

26: 86±90.11 Ellis CN, Fradin MS, Hamilton TA, Voorhees JJ. Duration of

remission during maintenance cyclosporin therapy for psoriasis.

Relationship to maintenance dose and degree of improvement

during initial therapy. Arch Dermatol 1995; 131: 791±5.12 Shupack J, Abel E, Bauer E et al. Cyclosporin as maintenance

therapy in patients with severe psoriasis. J Am Acad Dermatol

1997; 36: 423±32.

13 Berth-Jones J, Voorhees JJ. Consensus conference on cyclosporin Amicroemulsion for psoriasis, June 1996. Br J Dermatol 1996; 135:

775±7.

14 Berth-Jones J, Henderson CA, Munro CS et al. Treatment of

psoriasis with intermittent short course cyclosporin (Neoral). Amulticentre study. Br J Dermatol 1997; 136: 527±30.

15 Gross F, Pisa Z, Strasser T, Zanchetti A. Management of Arterial

Hypertension. Geneva: World Health Organization, 1984.

16 Fredriksson T, Pettersson U. Severe psoriasisÐoral therapy with anew retinoid. Dermatologica 1978; 157: 238±44.

17 Zachariae H, Steen Olsen T. Ef®cacy of cyclosporin A (CyA) in

psoriasis: an overview of dose/response, indications, contraindica-tions and side-effects. Clin Nephrol 1995; 43: 154±8.

18 Higgins E, Munro C, Marks J et al. Relapse rates in moderately

severe chronic psoriasis treated with cyclosporin A. Br J Dermatol

1989; 121: 71±4.19 Koo J for the OLP302 Study Group. A randomized, double-blind

study comparing the ef®cacy, safety and optimal dose of two

formulations of cyclosporin, Neoral and Sandimmun, in patients

with severe psoriasis. Br J Dermatol 1998; 139: 86±93.20 Zachariae H. Long-term use of cyclosporin in dermatology. Arch

Dermatol 1996; 132: 692±4.

21 Feutren G, Mihatsch MJ. Risk factors for cyclosporin-inducednephropathy in patients with autoimmune diseases. International

Kidney Biopsy Registry of Cyclosporin in Autoimmune Diseases. N

Engl J Med 1992; 326: 1654±60.

22 Powles AV, Hardman CM, Porter WM et al. Renal function after 10years' treatment with cyclosporin for psoriasis. Br J Dermatol

1998; 138: 443±9.

23 Pei Y, Scholey JW, Katz A et al. Chronic nephrotoxicity in psoriatic

patients treated with low-dose cyclosporin. Am J Kidney Dis 1994;23: 528±36.

24 Laburte C, Grossman R, Abi-Rached J et al. Ef®cacy and safety of

oral cyclosporin A (CyA; Sandimmun) for long-term treatment of

chronic severe plaque psoriasis. Br J Dermatol 1994; 130: 366±75.

25 Grossman RM, Chevret S, Abi-Rached J et al. Long-term safety of

cyclosporin in the treatment of psoriasis. Arch Dermatol 1996;132: 623±9.



Documents

Intermittent short courses of cyclosporin (Neoral®) for psoriasis unresponsive to topical therapy: a 1-year multicentre, randomized study