Mayo ClinicProceedings

VOLUME 68

Efficacy of Vitamin D3 Derivatives in the Treatment ofPsoriasis Vulgaris: A Preliminary Report

ROKEA A. EL-AzHARY, M.D., PH.D., MARGOT S. PETERS, M.D., MARK R. PITTELKOW, M.D.,PAl C. KAO, PH.D., AND SIGFRID A. MULLER, M.D.

SEPTEMBER 1993

The efficacy of 1,25-dihydroxyvitamin D3[1,25(OH)P3] and the new analogue calcipotriene (MC 903)in the treatment of psoriasis was investigated. Eight patients with psoriasis were enrolled in a pilotstudy with systemically administered vitamin D3and were given 1,25(OH)2D3(Rocaltrol; Hoffmann-LaRoche) in dosages from 0.5 Ilg to 2 Ilglday for a 6-month trial. In One patient, the psoriatic plaquesresolved within 2 months after treatment (0.5Ilglday) was initiated. Moderate improvement was notedin one other patient (Lug/day), The serum level of 1,25(OH)2D before treatment was not less than thenormal range of the adult population. Side effects of systemically administered 1,25(OH)2D3included adose-dependent increase in the 24-hour urinary calcium excretion and a decrease in the total number ofplatelets. Seven patients with symmetric plaque-type psoriasis were treated topically with 2 Ilglg of1,25(OH)2D3 in petrolatum. During 3 months of follow-up, mildtlnprovement was noted in threepatients. Five patients in the calcipotriene study were part of a r\tionwide double-blind placebo­controlled trial by Bristol-Myers Squibb. Moderate to marked improvement was noted in the twopatients who received 50 Ilglg of calcipotriene topically. The three patients who received placeboshowed no response. We conclude that a subset of patients with psoriasis responds well to 1,25(OH)2D3'Calcipotriene is efficacious and an excellent alternative to topically applied corticosteroids.

The use of vitamin D3

and its analogues in the treatment ofpsoriasis vulgaris remains controversial. Studies at the cel­lular level have demonstrated that keratinocytes synthesizeintermediates of vitamin D31,2 and are a target for 1,25­dihydroxyvitamin D3[1,25(OH)P3]' which has been shown

From the Department of Dermatology (RA,e,-A.), Mayo Clinic Jackson­ville, Jacksonville, Florida; and Department of Dermatology (M.S.P.,M.R.P., S.A.M.) and Division of Clinical Biochemistry (P.c.K.), MayoClinic Rochester, Rochester, Minnesota.

Information in this article does not imply that Mayo Foundation endorsesthe products of any pharmaceutical firm.

Address reprint requests to Dr. R A. el-Azhary, Department of Dermatol­ogy, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL32224.

to exert a dose-dependent, receptor-mediated inhibition ofproliferation of dermal fibroblasts as well as of keratino­cytes. Furthermore, 1,25(OH)P3 promotes keratinocyte ter­minal differentiation and enhances the formation of thecornified envelope.

Staberg and associates- showed that the serum level of1,25(OH)P in patients with psoriasis was significantlylower than that of healthy control patients matched for ageand sex. Their report suggested that in patients with psoria­sis, the synthesis or metabolism of vitamin D is altered, anoutcome that results in lower levels of vitamin D

3• This

finding, however, has not been verified by other investiga­tors.' Several preliminary clinical studies of the treatment ofpsoriasis with vitamin D

3have shown variable improve-

Mavo Clin Proc 1993; 68:835-841 835 © 1993 Mayo Foundation for Medical Education and Research

836 VITAMIN D, DERIVATIVES IN TREATMENT OF PSORIASIS

ment.>'? Morimoto and colleagues'> reported excellent re­sults with the vitamin D analogue Ia-hydroxyvitamin D3and with I,25(OH)P3 administered either topically (l ug/g)or orally (0.5 ug/g) in the treatment of psoriasis. The serumlevels of calcium were mildly increased but within the nor­mal range in patients who received vitamin D orally. Similarresults were reported by Holick and coworkers. I A recentstudy by Siddiqui and Al-Khawajah" suggested that an oraldosage of I ug of lrr-hydroxyvitamin D3 daily was inef­fective in the treatment of moderate to severe psoriasis.Holick and associates" indicated that up to 2.5 ug of1,25(OH)P3 administered orally each day may be beneficialin treating psoriasis without substantially altering calciumhomeostasis.

A new synthetic analogue of vitamin D3, calcipotriene(Me 903), has properties similar to those of I,25(OH)P3; itpromotes epidermal keratinocyte differentiation but has aless potent effect on calcium metabolism." Furthermore,clinical trials with 50 Ilg/g concentration have shown theefficacy of calcipotriene in the treatment of psoriasis; 13,14 it isreportedly more efficacious than betamethasone valerate."

Our current study had three main objectives: (1) to deter­mine the relative efficacy of both systemic and topical vari­ants of vitamin D3 derivatives in the treatment of psoriasisvulgaris, (2) to ascertain whether the response is related tothe serum level of the hormone, and (3) to assess the meta­bolic abnormalities that may result from high doses of vita­minD3·

METHODSOral Treatment With 1,25(OH)Pf-Eight patients (fivewomen and three men; age range, 28 to 65 years) withpsoriasis from 19 to 40 years' duration participated in theorally administered I,25(OH)P3 study after informed con­sent was obtained. All patients had psoriasis that involvedmore than 25% of the body surface area. Previous treatmentsincluded ultraviolet B, psoralen plus ultraviolet A, etretinate,and topically applied corticosteroids. All previous treat­ments for psoriasis vulgaris were discontinued at least 4weeks before the trial was initiated. Patients were allowed touse a lubricating cream and a corticosteroid cream not stron­ger than 0.05% triamcinolone; dietarily, patients were re­stricted to 800 mg or less of calcium intake per day. Thepatients received I,25(OH)P3 (Rocaltrol; Hoffmann-LaRoche) orally at bedtime; all of them initially took 0.5 ugdaily. If no response was noted by 4 weeks, the dosage wasincreased by 0.5 ug biweekly to a maximal dosage of 2.0 ugdaily. The patients were assessed at 0, 2, 4, 6, and 8 weeksafter treatment was initiated and at 4-week intervals thereaf­ter for a total period of 6 months. Efficacy was determinedby clinical evaluation of the percentage of body surfaceinvolved and by grading the erythema, scale, and thickness

Mayo Clin Proc, September 1993, Vol 68

of the lesions as 0, +1, +2, or +3; these numbers correspondto no improvement or worsening and mild, moderate, ormarked improvement, respectively.

Laboratory studies included a complete blood cell count,serum electrolytes and chemistry group, 24-hour urinarycalcium excretion, and urinalysis. Serum levels of1,25(OH)P before treatment and at 4 months after treatmentwere determined by high-pressure liquid chromatographypurification and a radioreceptor assay based on the methodof Kao and Heser." Patients with major medical problems,including endocrinologic, cardiovascular, liver, kidney, andconnective tissue disease, were excluded from participation.Women of childbearing age were included only if adequatecontraception was maintained throughout the treatment trial.

Topical Treatment. 1,25(OH)P3 Group.-Seven pa­tients with stable, symmetric plaque psoriasis were enrolledin the 1,25(OH)P3 group after informed consent was ob­tained. They were between 22 and 67 years of age and hadhad psoriasis for 6 to 20 years. The I,25(OH)P3 wasobtained from BIOMOL Research Laboratories, Inc. (Ply­mouth Meeting, Pennsylvania) and was formulated at a con­centration of 2llg/g in petrolatum by the Rochester Method­ist Hospital Pharmacy, Rochester, Minnesota. Twice daily,patients applied the active drug to one side of the body andonly petrolatum to the other side. Patients were unaware ofwhich side received the medication. Assessments were per­formed at 2 weeks and at 1, 2, and 3 months thereafter.Patients were allowed to use lubricating creams but nottopically applied corticosteroids, and they were asked torefrain from exposure to sunlight. No laboratory tests weremonitored for this group.

Calcipotriene (MC 903) Group.-Five patients wereenrolled in the calcipotriene study after informed consentwas obtained; this group was part of a nationwide placebo­controlled trial by Bristol-Myers Squibb. The patients werebetween 18 and 50 years of age, with psoriasis of 10 to 40years' duration. A 50 ug/g dosage of calcipotriene wasdispensed to patients either as medicated ointment or asplacebo and was to be applied twice daily. Patients werefollowed up during a 2-month period at 1, 2, 4, 6, and 8weeks. No lubricating creams or topically applied cortico­steroids were allowed. Laboratory tests included a completeblood cell count, serum chemistry group, and urinalysis, allof which were performed in the SmithKline laboratories.

RESULTSSystemic Treatment With 1,25(OH)P3'-The responses ofeach of the eight patients who received I,25(OH)P3 orallyare listed in Table 1. At the 0.5 ug/day dosage, one patient(case 5) experienced marked improvement; within 2 monthsafter the initiation of vitamin D3 therapy, the psoriaticplaques had completely resolved (Fig. 1 and 2). This patient

Mayo Clin Proc, September 1993, Vol 68

Table I.-Overall Assessment of Psoriatic Lesions inEight Patients After Oral Administration

of 1,25-Dihydroxyvitamin D3

Improvement*Area of

Dosage Scale,erythema, skin surfaceCase (ug/day) thickness involvement

1.5 0 02 1.0 +1 03 1.0 +2 +14 2.0 0 05 0.5 +3 +36 0.5 +1 07 2.0 0 08 1.0 +1 0

*0 = no improvement; +1 = mild improvement; +2 = moderateimprovement; +3 =marked improvement.

was maintained on 0.25 ug of Rocaltrol for I year until newlesions developed on her fingers and elbows. At the I llg/day dosage, one patient (case 3) had moderate improvement(Fig. 3). The other six patients experienced either mildimprovement or no improvement.

Topical Treatment With 1,25(OHJ!J3'-The effects oftopically applied 1,25(OH)P3 in seven patients withpsoriatic lesions are shown in Table 2. The patients wereassessed by comparing the side that received the activemedication with the placebo-treated side before and during

VITAMIN D3

DERIVATIVES IN TREATMENT OF PSORIASIS 837

treatment. Three patients (cases 2, 3, and 6) had mild tomoderate improvement. The four other patients had nochange in their psoriatic lesions.

Topical Treatment With Calcipotriene.-Of the five pa­tients who were enrolled in the calcipotriene study, tworeceived calcipotriene in the ointment, and the other threereceived placebo. Both patients who received calcipotrieneexperienced moderate to marked improvement. The threepatients who received placebo showed no response. Thepretreatment condition and the response of one patient after8 weeks of treatment with calcipotriene are shown in Figure4.

Serum Level of 1,25(OHJ!J Before and After SystemicTreatment With 1,25(OHJ!J3.-We studied the level of1,25(OH)P in the serum of four patients in the group whoreceived systemically administered 1,25(OH)P3 (Table 3).In all four patients, the serum level of 1,25(OH)P waswithin the normal range (15 to 60 pg/ml for the adult popula­tion) before treatment. At 4 months after treatment, all fourpatients had increased serum levels of 1,25(OH)p. Twopatients (cases 3 and 5) who responded to the treatment (Fig.I through 3) did not have higher levels than two otherpatients (cases 6 and 7) who did not respond.

Abnormal Laboratory Findings During SystemicTreatment With 1,25(OHJ!J3'-The urinary calcium excre­tion in the eight patients who were treated with systemicallyadministered 1,25(OH)P3 is shown in Table 4. Those whoreceived the 0.5 ug/day dosage demonstrated no substan-

Fig. 1 (case 5). Psoriatic plaqueson lower extremities of patient before (A) and 6 monthsafter (B) treatment with 1,25-dihydroxyvitamin D

3, 0.5 ug/day orally.

838 VITAMIN D3

DERIVATIVES IN TREATMENT OF PSORIASIS Mayo elin Proc, September 1993, Vol 68

Fig. 2 (case 5). Psoriatic plaques on upper extremities of patient before (A) and 6 months after (B) treatmentwith 1,25-dihydroxyvitamin D" 0.5 ug/day orally.

tially abnormal laboratory findings. At the 1 ug/day dosageand higher, most patients had an increase in 24-hour urinarycalcium excretion. The platelet counts of two patients de­creased to 102,000 and 148,000/dl in comparison with the

counts before treatment-148,000 and 184,000, respec­tively. Only one patient (case 4) experienced an increase inliver enzymes; this patient's serum level of aspartateaminotransferase also increased mildly (36 Ulliter) (nor-

Fig. 3 (case 3). Psoriatic plaques on midback of patient before (A) and 6 months after(B) treatment with 1,25-dihydroxyvitamin Dr I ug/day orally,

Mayo Clin Proc, September 1993, Vol 68

Table2.-0veraIl Assessmentof Psoriatic Lesions in, Seven Patients After Topical Application

of 1,25-Dihydroxyvitamin D/

Improvement]

AreaofAge Scale, erythema, skin surface

Case (yr) thickness involvement

I 22 0 +12 39 +1 +13 22 +1 +24 52 0 05 32 0 06 67 +1 +27 27 0 0

*Patients applied2 ug/g of 1,25-dihydroxyvitamin D3inpetrolatum

to plaques on one side of body and only petrolatum to similarplaques on other sideof body.

to = no improvement; +1 = mild improvement; +2 = moderateimprovement; +3 =marked improvement.

mal, 12 to 31). Subjectively, no patient reported any sideeffects.

The relationship of the serum levels of calcium and totalurinary excretion of calcium to the dose of 1,25(OH)P3 inone patient (case 7) is shown in Figure 5. The serum level ofcalcium was not affected appreciably by increasing the dos­age from 0.5 ug/day to 2 ug/day. The 24-hour urinarycalcium excretion increased in a dose-dependent manner,however, to more than sixfold the value before treatment.Use of the medication was discontinued, and the level re­turned to normal within 2 weeks.

DISCUSSIONThe beneficial response to vitamin D

3analogues in patients

with psoriasis has been reported in several clinical studies.

VITAMIN D3

DERIVATIVES IN TREATMENT OF PSORIASIS 839

Initially, Iu-hydroxyvitamin D3 reportedly diminished ex­tensive psoriasis.' Other studies showed that 1,25(OH)P3'the active variant of the vitamin, is also efficacious, whetheradministered topically or orally, in the treatment of psoriasisvulgaris. 1,5.6

Our results show that systemically administered1,25(OH)2D3 was very beneficial in one patient, whosepsoriatic plaques completely resolved within 2 months aftertreatment was initiated. This patient was maintained on thelow dosage of 0.25 ug/day of vitamin D3for I year; no sideeffects occurred. Another patient experienced moderate im­provement at a dosage of I ug/day, Patients who receiveddosages of more than I ug/day had an increase in 24-hoururinary calcium excretion. We were unable to confirm theresults of Holick and colleagues,11 who found that dosages of1,25(OH)P3 as high as 2.5 ug/day were not only beneficialin the treatment of psoriasis but also safe, without alteringcalcium homeostasis. In the current study, all patients whoreceived dosages of I /lg/day or more had an increase in 24­hour urinary calcium excretion without appreciable changein the serum level of calcium. Therefore, we do not recom­mend using 1,25(OH)P3 at dosages of more than I ug/day.If the I ug/day dosage is used to treat psoriasis, the 24-hoururinary calcium excretion should be monitored closely. Fur­thermore, complete blood cell counts should be performed tomonitor for decreases in platelet count, as noted in two ofourpatients.

The serum level of vitamin D3 did not correlate withactivity of disease, and it was not an accurate predictor ofwhich patients would respond to treatment. None of ourpatients had a serum level of 1,25(OH)P that was below thenormal range of that for healthy people. This finding con­trasts with the results of Staberg and coworkers,' who founda 35% decrease in the levels of 1,25(OH)P in patients with

Fig. 4. Psoriatic plaques on abdomen of patient before (A) and 8 weeks after (B) treatment with calcipotriene, 50 /lg/g appliedtopically twicedaily.

840 VITAMIN 03

DERIVATIVES IN TREATMENT OF PSORIASIS

Table 3.-Serum Level of 1,25-Dihydroxyvitamin Din Four Patients Before and 4 Months After

Systemic Administration of 1,25-Dihydroxyvitamin D3

Serum level*(pg/ml)

Dosage Before AfterCase (ug/day) treatment treatment

3 1.0 40 515 0.5 34 706 0.5 63 857 2.0 41 95

*In our laboratories, normal range of values for adult population is15 to 60 pg/ml.

psoriasis in comparison with control subjects. Other investi­gators" have been unable to confirm the results of Stabergand associates. Furthermore, the patients who responded toorally administered 1,25(OH)P3 did not have a higher se­rum level than those who did not respond. Therefore, weconclude that the serum level of 1,25(OH)P does not corre­late with the activity of disease.

Our results do not confirm the possibility that patientswith psoriasis have decreased ability to synthesize1,25(OH)2D ,.

Three patients in the topically treated group experiencedimprovement; however, the response was slow, and onlymild improvement occurred during 3 months of therapy.Prolonged treatment to 6 months or higher concentrationsmay have induced substantial improvement similar to that

Mayo Clin Proc, September 1993, Vol 68

Table 4.-Urinary Calcium Excretion in Eight Patients AfterSystemic Administration of 1,25-Dihydroxyvitamin D3

Urinary calciumDosage excretion*

Case (ug/day) (mg/24 h)

I 1.5 3412 1.0 4683 1.0 4544 2.0 5095 0.5 1866 0.5 2627 2.0 6398 1.0 166

*Normal range of values for 24-hour urinary calcium excretion is25 to 300 mg/24 h.

achieved with calcipotriene. Concentrations of1,25(OH)2D3' such as those used for calcipotriene, have re­portedly offered improved benefit.':":" The use of higherconcentrations of 1,25(OH)P3 is limited, however, becausethe cost for the current study would have been prohibitive.

Calcipotriene in 50 ug/g doses was effective in resolvingpsoriatic lesions. The two patients who receivedcalcipotriene showed moderate to marked improvementwithin 2 months after initiation of treatment, and no sideeffects were noted.

CONCLUSIONA subset of patients seems to respond to orally administered1,25(OH)P3' If the use of systemically administered1,25(OH)P3 is contemplated in patients in whom other

650 J::

'#.

e-coo

400

300

200

100

o

ElllD Serum Ca++

~ 24-hr urinary Ca++

Notreatment

1.0 1.5...

Fig. 5. Effect of increasing systemic doses of 1,25-dihydroxyvitamin 03

onserum level of calcium (Ca") and 24-hour urinary calcium excretion in patientwith psoriasis (case 7). Baseline values: serum level of calcium, 9.2 mg/dl; 24­hour urinary calcium excretion, 169 mg/dl. vit = vitamin.

Mayo Clio Proc, September 1993, Vol 68

therapies have failed, the dosage should be restricted to Illg/day or less, and regular laboratory monitoring should includedetermination of 24-hour urinary calcium excretion. Mostpatients tolerate the drug. The new derivatives of activevitamin D analogues, including calcipotriene, offer the ad­vantages of topical usage and, hence, fewer calcium-relatedmetabolic abnormalities. Furthermore, they provide an al­ternative to topically applied corticosteroids.

ACKNOWLEDGMENTWe thank Raffaela A. Blomberg for coordinating the study,Edward S. Mansfield for pharmaceutical preparation, andCharlene M. Graff for secretarial assistance. Thecalcipotriene was provided by the Bristol-Myers SquibbCompany.

REFERENCESI. Holick MF, Smith E, Pincus S. Skin as the site of vitamin D

synthesis and target tissue for 1,25-dihydroxyvitamin D3

.

Arch Dermatol 1987; 123:1677-16832. Hosomi J, Hosoi J, Abe E, Suda T, Kuroki T. Regulation of

terminal differentiation of cultured mouse epidermal cells byI a,25-dihydroxyvitamin D3" Endocrinology 1983;113:1950-1957

3. Staberg B, Oxholm A, Klemp P, Christiansen C. Abnormalvitamin D metabolism in patients with psoriasis. Acta DermVenereol (Stockh) 1987; 67:65-68

4. Guilhou 11, Colette C, Monpoint S, Lancrenon E, Guillot B,Monnier L. Vitamin D metabolism in psoriasis before andafter phototherapy. Acta Derm Venereol (Stockh) 1990;70:351-354

5. Morimoto S, Yoshikawa K, Kozuka T, Kitano Y, Imanaka S,Fukuo K, et al. An open study of vitamin D

3treatment in

psoriasis vulgaris. Br J Dermatol 1986; 115:421-4296. Morimoto S, Yoshikawa K. Psoriasis and vitamin D

3: a

review of our experience. Arch Dermatol 1989; 125:231­234

7. Kato T. Rokugo M, Terui T, Tagami H. Successful treatmentof psoriasis with topical application of active vitamin D

3

VITAMIN D3

DERIVATIVES IN TREATMENT OF PSORIASIS 841

analogue, 1a,24-dihydroxycholecalciferol. Br J Dermatol1986; 115:431-433

8. Siddiqui MA, A1-Khawajah MM. Vitamin D3 and psoriasis:a randomized double-blind placebo-controlled study. JDermatol Treat 1990; 1:243-245

9. Van de Kerkhof PCM, Van Bokhoven M, Zultak M,Czarnetzki BM. A double-blind study of topical 1a,25­dihydroxyvitamin D

3in psoriasis. Br J Dermatol 1989;

120:661-66410. Henderson CA, Papworth-Smith J, Cunliffe WJ, Highet AS,

Shamy HK, Czarnetzki BM. A double-blind, placebo-con­trolled trial of topical I,25-dihydroxycholecalciferol in pso­riasis. Br J Dermatol 1989; 121:493-496

11. Holick MF, McCarthy E, Joyce-Otis D, Pochi P, Bhawan J.Long-term effects of orally and topically administered 1,25­dihydroxyvitamin D

3on calcium and bone metabolism in

healthy young and middle-aged male and female adults whosuffer from psoriasis: 1,25-dihydroxyvitamin D

3heralds an

exciting new pharmacologic era for testing psoriasis [ab­stract]. J Bone Miner Res 1989; 4(Suppl):S298

12. Binderup L, Bramm E. Effects of a novel vitamin D analogueMC 903 on cell proliferation and differentiation in vitro andon calcium metabolism in vivo. Biochem Pharmacol 1988;37:889-895

13. Kragballe K, Beck HI, Segaard H. Improvement of psoriasisby a topical vitamin D

3analogue (MC 903) in a double-blind

study. Br J Dermatol 1988; 119:223-23014. Kragballe K. Treatment of psoriasis by the topical applica­

tion of the novel cholecalciferol analogue calcipotriol (MC903). Arch Dermatol 1989; 125:1647-1652

15. Kragballe K, Gjertsen BT, de Hoop D, Karlsmark T, van deKerkhof PCM, Larke 0, et al. Double-blind, right/left com­parison of calcipotriol and betamethasone valerate in treat­ment of psoriasis vulgaris. Lancet 1991; 337: 193-196

16. Kao PC, Heser DW. Simultaneous determination of 25­hydroxy- and 1,25-dihydroxyvitamin D from a single sampleby dual-cartridge extraction. Clin Chern 1984; 30:56-61

17. Holick MF. Will 1,25-dihydroxyvitamin D3

, MC 903, andtheir analogues herald a new pharmacologic era for the treat­ment of psoriasis? [editorial]. Arch Dermatol 1989;125:1692-1697

18. Ashenfelter A, Coutinho J, Gwo J, Zultak M, ArmstrongR. Calcitriol cream in the treatment of psoriasis: efficacy andsafety considerations. Presented at Fifth International Psoria­sis Symposium; 1991 JullO-14; San Francisco, California