British Journal of Dermatology (1989) 120, 665-670.

Combined treatment of psoriasis with acitretinand UVB phototherapy compared with acitretin

alone and UVB alone

J.IEST AND J.BOERDepartment of Dermatology, Deventer Hospitals, Deventer, The Netherlands

Accepted for publication 24 October 1988

SUMMARY

The administration of UVB phototherapy and low-dose acitretin (o 34-0 44 mg/kg bodyweight) was compared with the effect of acitretin alone and UVB phototherapy alone in4t patients with plaque-type psoriasis. Of these patients, 32 received standard UVB photo-therapy without acitretin. The other nine were treated with acitretin and the effect of UVBirradiation (Sylvania UV 21-tubes), applied to one half of the body, was assessed. Clearance wasdefined as 80-100% improvement and this occurred in eight out of the nine patients (89%)treated with acitretin-UVB (ReUVB) and, in two of them (23%), on the untreated side.Clearance occured in 20 ofthe 32 (62 5%) patients given UVB alone. The improvement scorewas significantly higher for the ReUVB side than the acitretin side. Patients treated withReUVB showed a statistically higher therapeutic score (95-100% clearance) than thosereceiving UVB alone. However, taking 80-100% improvement as the criterion, no significantdifference was found. The number of treatments to clearance was significantly less for thepatients treated with ReUVB than for the UVB (19 3 as compared with 24 9). The total UVBdose and the nvimber of minimal erythema doses (MEDs) could be reduced by approximately20% in the ReUVB group relative to the UVB group.

Many treatments have been used for psoriasis, including etretinate (Ro 10-9359). Initially thiswas thought to be a potent and non-toxic drug that was effective as a single agent for thecomplete and permanent suppression of psoriasis. Now it is unlikely that etretinate could berecommended as mono-therapy for plaque-type psoriasis.'-^ Etretinate can be useful in thetreatment of psoriasis in combination with UV radiation. ̂ •''̂ The combination of phototherapywith retinoids (etretinate) has some important advantages in that it increases therapeuticefficacy and mitigates the long-term hazards of UV exposure by reducing the total

Correspondence: Dr J.Boer, Department of Dermatology, Deventer Hospitals, Postbox 5001, 7400 GC Deventer,The Netherlands.

665

666 J.Iest and J.Boer

The major disadvantage of etretinate was the slow elimination ofthe drug, the half-life being84 to 168 days. This is due to the drug being stored in adipose tissue.^ The main derivative oftheethylester etretinate is its hydrolysis product acitretin (Ro 10-1670) and this has a shorter half-life, being eliminated in 2 to 4 days.^ Earlier clinical trials have shown that the therapeuticeffects of acitretin are similar to that of etretinate.^*'® The aim of the present study was tocompare the efficacy of combined acitretin and UVB phototherapy with that of acitretin aloneand UVB alone.

METHODS

PatientsForty-one patients with chronic plaque psoriasis attending the out-patient clinic were includedin this study. These were assigned to one of two regimens; acitretin plus half-body UVBradiation (nine-patients), after informed consent was obtained, and standard total UVBexposure without acitretin (32 patients). The details ofthe patients at the start ofthe study areshown in Table i. Patients included in the study had more than 10% of the body surfaceinvolved in psoriasis; they had discontinued drugs known to affect psoriasis a month beforetreatment and were not applying any preparation, apart from 2% salycylic acid in whitepetroleum. Females of child bearing age were excluded from taking acitretin.

RegimensCombined regimen^ This consisted of a bilateral comparison of an acitretin regimen with and

without standard UVB radiation (nine patients). The choice of which half of the body was to beirradiated was made at random. The combined acitretin plus UVB regimen will be referred to asReUVB.

Acitretin. The drug was administered orally to the nine patients at a daily dose of 30 mg for 2weeks before the start of the half-body UVB therapy and during treatment. The mean dailyacitretin dosage in relation to body weight was o 39 mg/kg (range: o 34 to o 44 mg/kg).

UVB regimen. The ReUVB and UVB groups (9 and 32 patients, respectively) were treatedsimilarly with suberythema doses of UVB. All patients received the first dose of between 30-50% of their minimal erythema dose (MED). With the second treatment the dose increment wasgiven according to a standard schedule;^'' however, the arms and legs did not receive additional

TABLE I. ReUVB vs. UVB; population characteristics

No. of malesMean age, year ± SDAge range, yearMean duration of psoriasis, year 1 SDMean extent of psoriasis ± SD (% body surface)Mean minimal erythema dose (MED) + SD (mjoules/cm^)

ReUVB(n = 9)

7437 ±14-5

20-6412 9 1 1 1 6

17-2 ±8-7146 7 + 44 0

UVB(n = 32)

1942 0+ 144

13-6916 9112 4161 ± 7 0

1373 + 52-9

ReUVB indicates acitretin plus UVB.

Acitretin and UVB treatment of psoriasis 667

UV exposure. After the 23rd and subsequent treatment, the dose of UVB was held constant. Ifany area of skin became red and sore, the next irradiation was omitted. If only mild symptomsoccurred then the preceding dose of UVB was used. Patients were allowed to miss, at the most,one treatment in any 2-week period.

For both groups, the endpoint was taken as clearance of the psoriasis or no furtherimprovement in two successive weeks after a maximum of 30 UVB exposures.

Evaluation of results (ReUVB and UVB groups)The patients were evaluated before treatment and at two-weekly intervals. The two sides of thebody were compared and evaluated and the lesions plotted and graded according to a systemused in earlier trials."-'^ Scaling and induration were graded from o (none) to 8 (very marked),and these scores were used to determine the percentage of overall improvement relative to thepatient's status on entry into the study. The therapeutic effect was graded as follows: o = 0% to24%; + I = 25% to 49%; + 2 = 50% to 79%; + 3 = 80% to 95%; and + 4 = > 95% clearance oflesions.

In the nine patients on the combined ReUVB regimen, blood chemistry studies, completeblood cell counts, and urinalysis were done at the start of the study, after i month, and at the endof the study. Several of these laboratory investigation (ESR, liver function tests, cholesterol andtriglyceride determinations) were repeated after 2 and 8 weeks of treatment.

The Chi-square test. Student's J-test and the Signed Rank test were used for statisticalanalysis.Light sourceThe UVB source was a Waldmann UV-iooo cabin with 26 Sylvania F 75/85 W UV-21fluorescent lamps. Ultraviolet B spectral irradiance measurements were made with a Radio-meter with a WBS 320 sensor (International light. Inc., Dexter Industrial Green, Newbury,MA, U.S.A. model IL700). The intensity of wavelengths in the 280-320 nm band at a distanceof 20 cm was i 56 mW/cm^. The spectral distribution of the UV-21 lamps and the method usedfor light-dose control has been described elsewhere.'^

TABLE 2. Acitretin plus UVB (ReUVB) vs. acitretin alone; results of clearing treatment

Patientno.

I

2

345678

9t

Extent ofpsoriasis at entry(% body-surface)

10

30152510

10

3010

15

No. oftreatments

1521

15232 2

24161812

Total UVBdose (J/cm^)

6-1

9 48 2

1 6 5

8-78 03 86 57-8

No. ofMEDs toclearing

32

974286728432

5426

Grading*(oto

ReUVB

+ 4+ 4+ 4+ 3+ 4+ 3+ 4+ 4+ 1

+ 4)

Acitretin

+ 3+ 3+ 2+ 2+ 1+ 2+ 2+ 20

MED = minimal erythema dose; Acitretin: daily dose 30 mg.*P = o 012; signed rank test.t Dropped out of treatment (combination of treatment failure and side effects).

668 J.Iest and J.Boer

RESULTS

There was no significant difference between the ReUVB and UVB alone groups at the start ofthe study. The severity of their psoriasis and the MED values were similar in the two groups(Table i). The results of treatment of the patients for the left-right comparison betweenReUVB and acitretin alone are shown in Table 2. One patient stopped treatment after 12irradiations because of being unable to tolerate the adverse effects of acitretin. Seven out of ninepatients (78%) received a score of +2 or +3 for the side treated with acitretin alone, with aclearance of 50% to 95%. On the ReUVB side, clearance (grades +3 and +4) was achieved ineight out of nine patients (89%) with a mean number of 19 irradiations as against two out of ninepatients (23%) on the side given acitretin alone in the same period (mean 63 weeks). However,acitretin therapy alone never gave complete clearance in any of the patients. The highest scoreobtained was + 3 in two patients (Nos. i and 2). Two other patients (Nos. 4 and 6) received a + 3for the ReUVB side and + 2 for the acitretin side after 23 and 24 UVB irradiations, respectively,but after that neither side showed any further improvement in either of them. After furthertreatments, up to 30 UV exposures, their scores were still exactly the same.

There was always a difference of at least one grade between the ReUVB side and the sidetreated with acitretin alone. A score was available for each side (ReUVB vs. acitretin). Analysisofthe paired scores over eight patients showed a significant difference in favour ofthe ReUVBside (signed rank test, P = o-ot2). Table 2 also shows the individual data on extent of thepsoriasis, total UVB dosage, and MEDs to clearing; the mean values of these three parametersare given in Table 3.

Side-effects occurred in all nine patients on acitretin but were generally mild. Cheilitisoccurred in all nine and several patients complained of a stuffy nose, nose bleeds, itchy eyes and,in one patient each, there was hair loss, a decrease in libido and, in another, depression. In twopatients, the plaques of psoriasis enlarged and became more inflamed during the first 2 weeks oftreatment with acitretin. A substantial improvement occurred in one patient with psoriatic naildystrophy. All patients had normal baseline values of serum cholesterol and triglycerides. Inone patient there was an elevation of cholesterol. Of the six patients who developed alteredtriglyceride levels, four had high and two had low levels. All these changes during the trial weretemporary and reverted to normal. There was no reason to withdraw acitretin in any ofthe casesbefore the end of the study.

TABLE 3. ReLTVB vs. UVB; treatment outcome and dosimetry

Outcome

No. clearedNo. of treatments for clearing*Dose at first treatment* (mj/cm^)Dose at final treatment* (mj/cm^)No. of MEDs at final treatment*Total UVB dose to clearing* (J/cm^)No. of MEDs to clearing*

ReUVB(n = 9)

8 (88-9%)i9-3 + 3-7t657 ±245847 ± 2796 2 ± 2 0

84 + 3762-4125 8

UVB(« = 32)

20 (62-5%)249 +5 8t634 + 37563612824-8+ 1-8

I I I ±6-478-8±3i 6

ReUVB indicates acitretin plus UVB.* Mean ± Standard deviation; MED: Minimal erythema dose.t P < o o i , Student's r-test.

Acitretin and UVB treatment of psoriasis 669

TABLE 4. ReUVB vs. UVB; improvement scores atthe end of the clearing treatment

Response of ReUVB, No. (%) UVB,No. (%)psoriasis % (" = 9) (" = 32)

96-100

80-95

50-79

0-49

6(67)

2(22)

—

I (II)

6(188)

14 (43-7)8(25)

4(12-5)

/ ' = o 035, Chi-square test.ReUVB indicates acitretin plus UVB.

The doses of UVB given to patients in the ReUVB and UVB groups are shown in Table 3.The differences were not statistically significant. The number of irradiations in the ReUVBgroup was significantly lower than that in the UVB group (P<oo i , Student's t-test). Theproportion of cleared patients (80-100% improvement) differed widely but not significantlybetween the two groups, i.e., 89% (8/9) for the ReUVB group compared with 62 5% (20/32) forthe UVB group (Table 3). If, however, the psoriatic response is further subdivided into fourgroups (Table 4), the therapeutic score for the ReUVB group is significantly higher than that forthe UVB group (P = o 035, Chi-square test). It appears that the majority of the patients treatedwith ReUVB scored the highest grade of improvement (95-100% clearance of lesions). Incontrast, the majority of UVB treated patients scored one grade lower (80-94% clearance oflesions). If the psoriasis response is divided into three groups (0-79%, 80-95%, and 96-100%),the difference between the therapeutic scores of the two groups is more pronounced (P = o 019,Chi-square test).

DISCUSSION

The oral retinoid etretinate has been reported to be an effective agent in combination with UVBphototherapy.^*'* This drug has a major drawback in that its terminal elimination half-life isvery long because of storage in adipose tissue.^ This means that, because of the teratogenic effectof etretinate, pregnancy has to be avoided for at least 2 years after stopping the drug. Acitretin,the hydrolysis product of etretinate, has a terminal elimination half-life of only 2-4 days.*̂ Trialsusing acitretin as a monotherapy for psoriasis showed similar side-effects and the sameefficacy^* as reported for etretinate therapy.

Seven of the nine patients (78%) in our study treated with acitretin alone, had animprovement score of 50% to 95%. This is comparable with the results obtained by Kingston etal.,'' who reported 50% improvement or more in 18 out of 21 patients (86%). We used a dailyacitretin dose of 30 mg, based on a previous trial that found doses higher than 30 mg a day did notgiven better results and that the side-effects were more severe.^

In our study the mucocutaneous side-effects of acitretin were mild, and there were fewabnormal laboratory values. This is in agreement with other studies.^* In general, the UVBexposures applied in the ReUVB group were well tolerated.

The combination of acitretin and UVB phototherapy was markedly more effective than UVBphototherapy alone. Clearance (80-100% improvement) amounted to 89% for the ReUVB

670 J.Iest and J.Boer

group compared with 62-5% for UVB alone. ReUVB had therapeutic advantages over UVB.The number of irradiations was significantly lower (19 3 vs. 24.9), which is a mean reduction of56 irradiations or a difference of almost 2 weeks in the duration ofthe treatment period. Thetotal UVB dose was also lower for the ReUVB group, although this difference is not significant(84 vs. I l l J/cm^). The results of this trial are similar to those of an earlier trial in whichetretinate instead of acitretin was combined with phototherapy for the treatment of psoriasis.'^

The combination of acitretin and UVB phototherapy is effective during the initial phase ofphototherapy. The influence of retinoids on the duration of remission after withdrawal of thedrug is still not clear. Continuation of a low dose of retinoid during the maintenance phase doesnot seem advisable.' Perhaps the role of retinoids is limited to the maintenance treatment ofpatients with severe psoriasis for whom therapy with UVB alone would require excessivelyfrequent exposures of UV radiation.''̂

ACKNOWLEDGMENT

The authors wish to thank Dr J.Hermans ofthe Department of Medical Statistics, UniversityHospital, Leiden for the statistical analyses.

REFERENCES

1 Morison WL. Etretinate and psoriasis. Arch Dermatol 1987; 123: 879-81.2 Lowe NJ, Roenigk H, Voorhees JJ. Etretinate—Appropriate use in severe psoriasis. Arch Dermatol 1988; 124:

527-8.3 Orfanos CE, Steigleder GK, Pullman H, Bloch PH. Oral retinoid and UVB radiation: A new, alternative treatment

for psoriasis on an out-patient basis. Acta Derm Venerol (Stockh) 1979; 59: 241-4.4 Boer J, Suurmond D. Combined UVB phototherapy and low dosage oral retinoid (Ro 10-9359) for psoriasis

responding inadequately to UVB alone. In: Retinoids. (Orfanos CE et al. eds), Berlin: Springer-Verlag, 1981;439-42.

5 Fritsch P, Honigsmann H. Combination phototherapy—A critical appraisal. In: Current Problems Dermatology(Honigsmann H, StingI G, eds). Vol. 15. Basel: Karger, 1986; 238-53.

6 Paravicini U, Camenzind M, Gower M et al. Multiple dose pharmacokinetics of Ro 10-1670, the main metabolite ofetretinate (Tigason). In: Retinoids: New trends in research and therapy (Saurat JH, ed), Basel: Karger, 1985; 289-92.

7 Kingston TP, Matt LH, Lowe HJ. Etretin therapy for severe psoriasis. Arch Dermatol 1987; 123: 55-8.8 Lassus A, Geiger JM, Nyblom M et al. Six months treatment of severe psoriasis with etretin (Ro 10-1670). Br J

Dermatol 1987; 117: 333-41.9 Geiger JM, Ott F, Bollag W. Clinical evaluation of an aromatic retinoid, Ro 10-1670, in severe psoriasis. Curr Ther

Res 1984; 35; 735-40.10 Adrian RM, Parrish JA, Momtaz TK, Karlin MJ. Outpatient phototherapy for psoriasis. Arch Dermatol 1981; 117:

623-6.11 Boer J, Hermans J, Schothorst AA, Surrmond D. Comparison of Phototherapy (UV-B) and Photochemotherapy

(PUVA) for clearing and maintenance therapy of psoriasis. Arch Dermatol 1984; 170: 52-7.12 Schothorst AA, Boer J, Surrmond D, Kenter CAC. Application of controlled high dose rates in UV-B phototherapy

for psoriasis. Br J Dermatol 1984; n o : 81-7.13 Boer J, Piscaer P. Retinoid (etretinate) and phototherapy combined for psoriasis. In: Abstracts of Anglo-Nordic

Symposium: long-term treatment of psoriasis. Helsinki, Finland, September 26-27, 1986; IV: 36.