British joiirml of Dcriimlohnitj I9yf-.: 134: 107(1-11)78.

Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3)for the treatment of psoriasis

A.PHREZ, R.RAAB, T.C.CHKN, A.TURNER AND M.F.HOLICK

I'.ndocrine Section of Driuirtmciit of Medicine, Boston University Medical Center. MA, U.S.A.

Accepted Ibr puhlication 26 Odohcr

S u m m a r y Plaque-type psoriasis has been successfully treated with oral ctikitriol. but there has been no long-term Ibilow-up on the safety and efOciicy of this calciotropic hormone for psoriasis. In a single centrestudy, patients were enrolled in an open trial to evaluate the efficacy and safety of oral calcitriol forpsoriasis. Of the 85 patients who received oral calcitriol. HH-()% had some improvement in theirdisease; 2(1-5. 3fT2 and 25-3'Xi, had complete, moderate and slight improvement in their disease,respectively. The mean baseline psoriasis area severity index score (PASI) of 18-4 ± l-() was reducedto 9-7 ±0-8 and 7-8 ± 1 3 after 6 and 24 months on oral calcitrioi therapy. Serum calciumconcentrations and 24h urinary calcium excretion increased by 3-9% and 148-2%. respectively,but were not outside the normal range. Bone mineral density remained unchanged. The clearance ofcreatinine decreased by 1 i-4% from baseline during the tirst fi months of treatment, and thereafter,remained unchanged after 3 years of follow up. An evaluation of creatinine. inulin and para-aminohypurate (PAHi clearance was performed in eight patients. After 5 months on oral calcitriol.there was a 22-5'^. decline in creatinine clearance but no significant changes were observed in eitherinulin or PAH clearance, suggesting that calcitriol alters creatinine metabolism or secretion but doesnot affect renal function. Oral calcitriol is effective and safe for the treatment of psoriasis.

Psoriasis is a hyperproliferative disorder ofthe epidermisaffecting about 1-3% of the world's population.Although there are a variety of therapies for psoriasismost are associated with side-effects. Recently, theactive form of vitamin D;. calcitriol (1.25-dihydroxyvi-tamin D5). and several of its analogues, have beenreported to be therapeutically efficacious for the treat-ment of this disease.' '^ The rationale for using calcitrioland its analogues is based on observations that thishormone inhibited the proliferation of cultured humanand murine keratinocytes."*'' and the fortuitous cliniciilobservation of a patient receiving oral irtlOHjDj forsenile osteoporosis whose psoriasis improved after 10weeks of treatment.' Caleitriol's major physiologicalaction, however, is to enhance the efficiency of theintestine to absorb dietary calcium and to mobilizecalcium stores from bone."^'' Therefore, there remainsconcern that oral calcitriol will be of limited value fortreating psoriasis because of its potent caicaemic effectwhich could cause hypercalciuria. hypercalcaemiH.nephrocalcinosis. ncphrolithiasis and a reduction inbone mineral density (BMD).

Correspondenct-: Dr Holick. Vitamin 1). Skin, .ind lionc Kest-arrliLaboratory. M-HIl i. HO l eist Cotiford Street. U{)st()n UnivcrsilySchool of Medicine. Boston, MA DZllH. U.S.A.

The therapeutic eilicacy and safety of orally adminis-tered calcitriol in treating psoriasis has only beenassessed in few studies.' " These reports have beenconducted for not longer than 7 months:' too short atime to evaluate this drug's long-term effects on psor-iasis, bone mineral density and nephrolithiasis. The goalof this study was to evaluate critically the therapeuticefficacy of oral calcitriol in treating psoriasis, in con-junction with a thorough evaluation of its potentialtoxicity.

Methods

Patients

Eighty-five patients with no other significant iilness (62men and 2 ? women; mean age 46 years: range 1 9-76).with either stable plaque or erythrodermic psoriasisinvolving at least 1 S% of their body surface area,were recruited. They had not responded satisfactorilyto at least one ofthe standard treatments for psoriasis.Women with child-bearing potential not on effectivemethods of contraception, pregnant women andnursing mothers, and patients with hepatic or renalimpairment or idiopathic hypercalciuria. were excluded.

1070 (r^ 1996 British Association of HtTmatologists

ORAL CALCITRIOL IN PSORIASIS 1071

Before enrolment, all patients slopped receiving systemictherapy or phototherapy for their psoriasis for at least50 days, and topical medications, other than blandemollients, for at lenst 14 days.

All patients gave informed consent after a full expla-niition of the details, procedures and potential risks ofthe stndy. The protocol and consent forms wereapproved by the Institutional Review Board of BostonUniversity School of Medicine and an investigationalnew drug application was liled with the Food and DrugAdministralit)n.

Proloivl

Kighty-five patients who had at least 1 5% involvementof their hod\- surface were instructed lo ingest no morethan ^00 mg of calcium from their diet in 24 h and werestarted on 0-5 tg of calcitriol (Rocaltrol} at bedtime, aspreviously reported.' Patients had their calcitriolincreased, in increments of 0-5//g every 2 weeks, aslong as the serum and 24 h urinary calcium concentra-tions remained in the normal range. At monthly inter-vals, the patients' lesions were evaluated. A BMDmeasurement of the spine and hip. on a Norland XR-26 dual energy X-ray absorptiometer. were performedtwice a year. The coefllcient of variation of measure-ment of the calibration phantom by this instrumenl was0-40% for the past 3 years. Because of the concern ofincrease risk for nephrolithiasis during caicitriol treat-ment, renal ultrasound studies were Introduced to thestudy protocol. The glomerular filtration rate (CFR) wasevaluated in a representative subset of eight patients bycrealinine clearance (CrCl) and inulin clearance testing.before and at b months during calcitriol therapy. Para-aminohypurate infusion (PAH) was performed in thesame eight patients to assess renal tubular function.

was performed using a global improvement scale (-1 =deterioration. 0 — no change. 1 = mild improvement.2 — moderate improvement and 5 excellent improve-ment). The PASI is a clinical tool which has been usedfor assessing the antipsoriatic efficacy of drugs since1978.' The PASI takes in account the global severityscore and the percentage of body area aflected bypsoriasis.

Laboratorii studies

Samples of venous blood were obtained from patientsbefore and at various intervals during the study. Serumassays for total calcium, phosphorus, creatinine. bloodurea and nitrogen, alkaline phosphatase. albumin.Iransaminases. uric acid, and cholesterol, were per-formed by Smith Kline French Laboratory (Danvers.MA. U.S.A.). Urinary calcium and creatinine were alsoperformed by Smith Kline French Laboratory. Theassays for 1.23{OU)2_U and 2S-()H-1) were performedby competitive binding protein assays as previouslydescribed." '" The intact parathyroid hormone (PTH)and ostcocalcin levels were determined using theNichols Institute l^iagnostics (San Juan Capistrano.CA, I'.S.A.I IRMA PTH and osteocalcin assay kits.Serum and urine inulin and PAH determinations wereconducted according to the procedure described byHigashi and Peters. "

Statistical analysis

Statistical signiticance was assessed within groups bythe two-tailed Student's Mest for paired differences.Results are expressed as the mean ± standard deviation(SD). All results were considered significant atF < ()-()5,

Clinical assessment

Psoriatic lesions were photographed and evaluated bythe investigators who assessed the extent and severity ofthe psoriatic lesions, as previously described. " Thisincluded the psoriasis area and severity index score(PASI), global severity score, and global improvementscale. The severity of the erythema, the plaque thick-ness, and the scaling of the lesions, were evaluatedusing a four-point scale (0 - no lesion. 1 — mild. 2 -moderate and 3 = severe). The global severity scorewas dt'lermined by adding the scores for erythema.scaling and thickness (maximum value - 9). Also, anoverall clinical assessment of each patient's psoriasis

Results

Efficacy of orally administered calcitriol

The baseline global severity score for the patients'lesions ranged from 5 to 9. with a mean value of7-7 ± 1-2. The treatment period ranged from 6months to 3 years. Twenty of 85 patients have beenin this study for 3 years. At tbis time, the mean globalseverity score signiiicantly decreased to 3 2 ±1-9IP < ()-()()0()l). which represents a 58-7 ± 27-9%improvement, Al 6 months, the patients' lesionsshowed signiticant decreases from baseline in erythema.scaling and plaque thickness (JO S ± 28 2%. 37 4 ±

199h British Association of Dermatologisls. British journal oj Dernmtoloyii. I 54. !070-1078

1072 A.PEREZ etal

Etyihema Scaling

Oral caicitrjol

0 12 M 36 0 12 24 36 0 12 24 36Time {monlfisi

ligure 1. Cliiingcs in severity score using oral calcitriol before andduring trcalmcnl art- shown, Vcrlical range bars indicatt- ± slandarJerror of ihe rnt-an (SiiMI. The severity scores during treatment withcalcitriol were stalistically signiticani P < 0-001 in comparison withbaseline values.

29-9% and 3 3 9 ± 32-5%. respectively I IP < OOOOl).This improvement persisted as long as the patientsremained on therapy. At 3fi months (Fig. 1). thepatients' lesions continued showing significantdecreases from baseline in erythema, scaling, andplaque thickness ( 4 ( ) S ± 4 7 9%. 70-8 ± 24 7% and57-5 ± 3 S 9%. respectively) {P < OOOOOl).

The mean baseline PASI score was 18 4 ± 1 •(). At 6and 56 months of treatment Ihe mean PASI score wasreduced to 9 7 ±0-8 and 7 ( ) ± 1 3. respectively(P<()()()1) (Fig. 2). Likewise, the overall clinicalassessment showed that 88()% of all patients on oralcalcitriol had some improvement in their disease. Ofthese. 2(f^% had complete clearance. 3(>'2'}ii hadmoderate improvement, and 25- 3% had slight improve-ment. TAvelve per cent of the patients had no change inthe activity of their disease.

Patients with marked erythema as a component oftheir psoriasis often had the most dramatic improve-ment in tlieir disease (Fig. 3). Patients who experiencedmoderate to slight improvement noted decreased scaleproduction. The character ol" the scale often changedand was more tine in nature, the elasticity and com-fortableness of the skin improved, and tliere wasoften improvement in the nails of patients with nailinvolvement.

Effect of oral calcilriol on blood and urine

Patients increased their calcitriol intake in OS //g incre-ments every 2 weeks until their calcium/creatinine

12 18 24

Time (months)

30 36

I igurc 2. Mean values nf Ihe psoriasis area and severity index (I'ASI)scores using oral calcilriol before and during treatment are shown.Verlical range hars indicate mean ± SKM. t'ASI scores duringIrealment with calcilriol were stati.stically signilicant P < 0 01)1 incomparison with baseline values.

ratio in the urine reached OiS (Fig. 4). While thetherapeutic dose range was usually between 1-S and2'5 /jg each night, some patients tolerated up to 4-0/ig/night. The mean calcitriol dose was 2 1 ± (>8//g/nightand 2 4 ± 0-6//g/night at 24 and 3f> months, respec-tively. The circulating concentrations of 1.25(OFI|jI) atM-]2h after the last dose were increased by 19 7 ±35 6% above baseline at 24 months of treatment(P < 0()5) (Table 1). Serum calcium concentrationsincreased 3 9 ± 7 1 % {P<0-0()()5) and 0 7 ± 4 t)%(P = 0-5). at 6 and 36 months, respectively. Themean baseline serum calcium value of 2-39±()-10mmol/1 (9 -56±0 40mg/dl) increased to 2 4 8 ± 0 I 0mmol/l 19 93 ± 0-51 mg/dl) at 6 months during

British A is jcialion of IX'nuatologists. tiritisli journal of Dirmatologii. 1 J4. 11)70- 1078

ORAL CALCITRIOL IN PSORIASIS l ( )7 i

Figure 5. 40-ycar-()ld male with psoriasisfor 15 years. Before (a) and 6 months after2/(g each nighl of oral calcitriol (b).

trecitment (P < 0001) . However, the mean serum cal-cium concentration at 56 months during treatment wassimilar to the baseline value. 2-41 ± ()• 10 mmol/1(9-65 ±0-40 mg/dl) ( P - O S ) . The change in the24 h urinary excretion of calcium from baseline aver-aged a 148-2% increase and the calcium/creatinineratio increased from O i l ± 0 07 to 0-2 3 ± 0 1 (P <0-0002) and ( ) 2 0 ± 0 - l (P<0()()01) at 6 and Jfimonths, respectively. The serum creatinine at 6 and36 months during treatment increased by 11-8% and25-7% from baseline, respectively (P < 0-0005). IntactPTH at 24 months during treatment decreased by32-3 ± 8-1% from baseline (P < 0-01).

Serum osteocalcin determinations in a representativesubset of 10 patients revealed baseline. 7-7 ± 2()ng/ml;6 months. 11-3 ± 2 6ng/ml: 12 months. 15-4±4-7ng/ml: and 24 months. 12-2 ± 4-3 ng/ml. Althoughthere was a trend towards higher levels while on treat-ment, none of the increases reached statistical signifi-cance. The serum values before and after 24 months onoral calcitriol were not significantly different for alkalinephosphatase. 75-2 ± 9'SU/I vs. 74-4 ± 7'9 U/1: alanineaminotransferase 2 4 - 4 ± 1 4 U / l vs. 25-4±l-4U/l ;asparate aminotransferase 324 ± 2 8 U/l vs.3 r 3 ± 2 - 2 U / l ; uric acid 368 7 ± 11 8mmo!/l vs.416 3 ± 5-9mmol/l (62±0-2mg/d l vs. 7 -0±0- l

199f) British Associalion of Dermatologists. Bnti.s7i lounut! of Derrmtoloiitj. 1 34. l()71)-1078

1074 A.PEREZ etal

11^ 10E 9

a> 30Q

SerumCalcium

1,25(OH)2D

Urinarycalcium/creatinineratio

Per centImprovementin Psoriasis

36

Figure 4. Soqut'iice of clinical events overtime. Changes in blood and urine calcium aswell as serum calcitriol concentrations areshown at the same time as the clinicalimprovemenl ot'ciirred.

Table I. Changes in the hlood and urine variables before and during ireatment. Values are expressed as conventional units. Conversion factors forobtaining international units ISI) arc as follows: serum cakium |>()-25l. crealinine | x884) , alkaline phosphatase I >:(l(n f>fi7|. 1.2S(()Hl>DI x2-4). 25-OH-D (x2-49), PTH I x 11. 24-h-urine calcium |x{)()25) and creatinine I x « S 4 |

Number of patientsDose l/ig/night)Serum

Calcium

Creatinine

AlkalinL' phosphatase

1,25(OH),D(15-fiOpg/mn25-OH-D(tO-55ng/mhPTH (IRMAI(IO-65pg/inl)

UrineCalcium(O-3OOmg/24h)Creatinine(O-6-I-8g/24h)Calcium/creatinine ratioCreatinine clearance(8K-128 ml/mill per l-73m-|

Mean ± SD.NA - not available.*P < 0-001 baseliiiL- vs. treatment

Baseline

880

9^6 ±0-5

1-0 ±0-2

82.0 ±24-5

4() '4± t 6 4

J l - 8 ± I8'4

2 ! -0± 14-8

165-4 ±95'fi

1-T ±0-(S

0-12 ±() '0r103-8 ±4(M

time.

h months

881-8 ± :)'4

9-9 ± ;)'5*

1-1 ± :)-3*

8O-i±28.S

49'1 ± 14'9

35 '8± 19-8

NA

268-S £ M7-4*

1-i ± |)-5

0-24 ± 0 ' l *81-6± i3'4*

12 months

511-9_LO'5

9.9±()-5 '

M±0-3'

87-1 ±27-h

5(,.2±2 3-O-

32'0±20-8

NA

29M ± 148-1*

t-3±O-4

O-24±( ) ' r79'6± 2H-7'

24 months

262-1 ±0-8

9-8 ±0-5'

l ' 2 ± ( ) - r

92-3± 32-J

44-1 ± 12'2

37-2 ± Uv8

12-4 ± 9-7*

281-5 ± 1 J4-9*

l'5±()-5

0-23 ± 0 - 1 '80-8 ± 35-5'

3h months

202-4 ± 0 6

9-7±0'4*

l-3±O-3-

95-8±48 ' l

NA

NA

NA

273'9± 37-7'

1-4 ±0-6

() .2()±(>r80-9 ± 59-5*

•r, 199fi British Associalioii of Dcrmatiilogists. British joiirim! of Dernkitolo<!y. 1 J4. 1070-1078

O R A L C A L C I T R I O L IN P S O R I A S L S 1 0 7 6

m g / d l ) : a n d choles te ro l • ) -J5 ± 0 - 1 2 m m o l / l vs. 5 - 2 8 ±()'()3 m m o l / l ( 2 0 6 - 8 ± 4 -5 m g / d l vs. 2 0 V 7 i 1-2 m g / d l ) .

Studies for nephrolithiasis

Patients who were on oral Ciilcitriol therapy or wereintroduced into the stttdy lind renal ultrasound per-formed semi-annually to determine the presence ofkidney stones. Of the 55 palients st tidied for a tota!period of 34.617 patient days, two had positive renalultrasounds for kidney stones. Both stones were radio-opaque while on treatment. One case had a positiveriglit kidney echogenic signal for a kidney stone on hisfirst ultrasound study. As he did not have an ultrasoundbefore treatment, we could not determine if this was anew .onset. His calcium/creatinine ratio range wasbetween 0-04 and ()-3 and his serum calcium rangedbetween 9'8 and 10'4 mg/dl. No changes occurred inthe size or number of kidney stones in his follow-upultrasound studies while on oral calcitriol 3-0^(g/nightfor 4" 5 years. The second case was a patietit with anormal baseline kidney ultrasound. After receiving upto 2-2 5/(g/night for 20 months, her renal ultrasoundshowed a small echogenic foci on the upper pole of herright kidney, consistent with a kidney stone or fibrotictissue. The patient agreed to continue treatment withoral calcitriol for another year. While on treatment withcalcitriol. her calcium/creatinine ratio was between ()• 1and {) 4 and her sertim calcium was between 9-7 and10-8 mg/dl. When the patient developed hyper-calcacmia. oral calcitriol treatment was discontinued.A 2-year Ibllow-up revealed that her renal ultrasoundremained unchanged and the patient has been asymp-tomatic. Renal ultrasound studies were negative in theother 5 3 patients who have been taking a dailycalcitriol dose of 2 4 ± 0 6 /tg for up to 5 years.

to 79 S± 14-3ml/min per 1 75m-: / ' <0 ( )01 ) . TheCrCI calculated at 2. 5. 4. 5 and 6 months did not differsignificantly from the CrCI obtained during the inulininfusion period (79-4 ± 25-7ml/min per 1'7 3 m*"). Theinulin clearance remained unchanged: 95-8 ± 32 9 ml/min per 1-73 ni" at baseline and 101 (S ± 351 ml/minper 1-73 m^ after 6 months of calcitriol therapy.

PAH infusion was also performed in the same eightpatients in order to assess the maximum tubular secre-tion of PAH (Tm PAH). Tni PAH did not changebetween pretreatment and 6 months of calcitriol treat-ment: Tm PAH 899-6 ± 6 1 6 74 and 753 4 ± 3 1 1 9mg/min. respectively (P - 0-5). There was no signiti-cant change in the urinary protein concentrations fromhaseline and at 6 months during calcitriol treatment.169-7 ±66-0 and lOfv 3 ± 76-8 mg/24 h. respectively( F - 0 - 2 8 ) .

/://('(•( of oral cakitriol therapy on hone iniiwral tiensity

Patients who were begun on calcitriol therapy werefollowed semi-annually for their BMU of their lumbarspine (L2-L4) and femoral neck. The mean baselineBMD of spine and hip in the women was 1()95 ± 0()30and OS92 ± ()()29g/cm". respectively. Follow-upBMD 2 years later dtiring calcitriol therapy showedmean spinal and hip values of 1-120 ± O'()57g/cm"and 0-842 ± 0-052 g/cm". respectively. The mean BMDof spine and hip for the men at baseline wereM 0 8 ±0-027 and 0-907 ± 0-02()g/cm-. respect-ively. After 2 years on calcitriol therapy, they main-tained a BMD of spine and hip of 1-1 30 ± 0-046 and0-908 ±0-052 g/cnr. respectively. At 12 and 24months, the changes in BMD of the hip and spine forboth sexes at all ages were not statistically significantlydifferent from baseline values.

Effect of oral calcitriol iherapy on nhmerular filtration rate Discussion

CrCI at 6 and 36 months decreased by 13-4 and 1 3- 3';,,,respectively, from the baseline value (/' < OOOOl)(Table 1). Creatinine and inulin clearances were per-formed before and at 6 months of therapy in a group ofeiglit patients. The age range of this group of subjectswas 24-55 years (mean ± SD = 38-5 ± 10-5 years).CrCI decreased hy 2 3-3 ±6-0% (P < 0-001) after 2months of therapy when the calcitriol dose was l -4±0- 3 //g/night. The CrCI remained unchanged during thenext 4 months of treatment in spite of increasing thedaily calcitriol dose to 2-7 ± 0 3/ig/night. After 6months, the CrCI decreased by 24-{}% (114-7± 35-5

Several clinical studies have demonstrated a beneficialresponse of psoriasis to calcitriol and several of itsanalogues including lo-hydroxyvitamin D5. ealcipo-triene and 1.24-dihydroxyvitamin ~ ' Calcitriolis a natural hormone thai is responsible for regulatingcalcium and bone metabolism. Only a few short-termstudies have been conducted to evaluate the efficacy oftopical and oral calcitriol. These short-term studies havesuggested that calcitriol can be an effective therapy forthe treatment of psoriasis. i 2 . 1 5 - 17 Oral calcitriol hasbeen used for the past 1 "> years to treat renalosteodystrophy.*^ There have heen no reports of oral

British Association of Denniitologists, British journal of Dcniuitolojjii, 1 J4,

107(1 A.PHRE/ ('( (ll.

caicitriol causing hepatic failure or having any adverseefiects on the skin. However, there is concern thcttherapeutic doses of oral calcitriol taken Ibr prolongedperiods of time for the treatment of psoriasis, could havesignificant undesirable side-effects on calcium and bonemetabolism.

The study of S5 patients using oral caicitriol revealedthat 88-0% of patients had improvement in the activityof their disease. Although this was an open study, ali ofthe patients initiaiiy participated in a 2-month doubiebiind right/left-sided topicai calcitrioi study. Ofthe 8 5patients who had no signiticant change in the activity oftheir psoriasis for up to S years, the areas not treatedwith caicitriol ointment had no change in tiie activity ofthe disease in83-3%of the patients: lS-S%and 1-2% ofthe patients had either siight improvement or deteriorti-tion in their disease, respectiveiy.'^

The patients were instructed to iimit their calciumintake to no more than SOOmg a day and were givencalcitrioi each night. As long as the urine calcium/creatinine was <O-55 and serum calcium was <2-6mmol/l (<10 4mg/dl), the dose was increased every 2weeks in increments of ()-5//g. The average dose forthese patients was 2 4±0f-)/ig with some patienistaking up to 41)//g each night. Some of the patientshave been taking oral caicitriol for up to 5 years. Ananaiysis oflhc blood chemistry profile showed that oralcalcitriol therapy did not aiter biood cholesteroi. uricacid or iiver function tests. Not surprisingiy. the 24 hexcretion of caicium increased by approximately 148'li.but was usually not outside the normal range. When apatient's calcium/creatinine ratio rose above 0-35. itwas often due to the patient inadvertently ingestingmore than 8{)()mg of dietary calcium. A reduction inthe caicium intake and a decrease in the calcitriol doseof 0-5//g for 2 weeks caused the calcium/creatinine toreturn to below 0-iS. 'I'he serum caicium increased by3-6% but was not outside of the normal range and therewas the expected compensatory decline in the serutnPTH levels.

Despite the signiticant increase in the urinary cai-cium excretion, only two patients were found early inthe study to have radio-opaque kidney stones. We havefollowed the other 5 5 patients with normal renal ultra-sounds, some of whom have been receiving orai caici-triol for more than 5 years. It has been estimated thaiabout 12% of the US popuiation wili suffer a kidntystone sometime in their life. ' It is recognized thatpatients with psoriasis have an increased risk of devci-oping kidney stones because of the marked increasedproliferative activity of their epidermis which results in

increased excretion of uric acid. This, in combinationwith an increase in the caicium concentration in theurine, may predispose some patients to ncphroiithiasis.None of tiie patients on orai caicitrioi showed anyciinicai or diagnostic signs of soft tissue calcificationincluding nephrocalcinosis or calcification ofthe bloodvessels.

It is well known that calcitrioi or in-hydroxyvitaminI); therapy causes a 10-20% decline in CrCi in patientswith moderate chronic renal faiiure.""' "" An evaiua-tion of CrCI in our patients after b and 36 months ontherapy demonstrated a 13-4% decline. The urinaryprotein excretion did nol significantiy change frombaseline in the patients who received orai calcilrioisuggesting that signiticant giomerular damage hadnot occurred. A representative subset of patients whowere started on caicitrioi therapy had their CrCi. PAHand inuiin clearance determined before and 6 monthswhiie on orai caicitriol therapy. Inulin. a fructose poly-saccharide. is iiltered but neither reabsorbed norsecreted and its ciearance is equai to the GER.' "'" '' Incontrast, creatinine is filtered and secreted by thekidney; and therefore. CrCI is not a true measurementof GFR."^ In humans witii normai renal function, theclearance of creatinine overestimates inulin clearanceby 13-7%."' which is in agreement with our results.The inuiin ciearance in our patient subset at f) monthsdid not differ from baseiine values. These results clearlydemonstrate that, although caicitriol altered CrCl. it didnot affect GER as measured by inulin clearance. Thisobservation is similar to the observation by Bertoli ct a/.""who showed that inuiin ciearance was not altered inpatients with moderate renai faiiure on calcitrioltherapy. An evaiuation of renal tubular function, asmeasured by the clearance of PAH in the same subsetof patients, also showed no significant differences whencomparing baseline vaiues with vaiues after (i monthsof caicitriol therapy. These observations demonstratethat the orai caicitriol-induced decrease in creatininesecretion is not due to either tubuiar damage or func-tion. It may be that calcitriol alters the secretion and/ormetaboiism of creatinine causing the observed increasein serum creatinine and decrease in CrCi.

Caicitriol is considered to be one of the more potentcalciotropic hormones on bone because it is responsiblefor mobiiizing stem cell monocytes to becomeosteoclasts.^"' *" Indeed, one of the major biologicalfunctions of calcitriol is to mobiiize caicium stores frombone to maintain serum calcium levels within thenormai range. Our semi-annual analysis of tbe honemineral density ofthe hip tmd spine of bolb men and

1996 British Association ofDermatologists, Brilisli jounml of Dennalology. i 34, 1(170-1078

ORAL CALCITRIOL IN PSORIASIS 1077

women aged 19 through 7(i did not show any statisti-cally significant difference of the BMD for up to 2 years.An analysis of inlraindividuai chanj^es in the BMD, withtime, also did not reveal any significant changes (datanot shown). Our analysis of serum osteocalcin levels in10 representative patients showed a trend towards anincrease which is consistent with calcitriol's knownstimulatory effect on osteohlasls. As we did nolobserve any significant decrease in the BMD. even inour older patients, the calcitriol may offer the additionalIx'neiit of protecting age-related bone loss as haspreviously been reported.'"

Calcilriol, when used topically, is a safe and effectivetherapy Ibr ihe trealmenl ol psoriasis. " Oral admin-istration of calcitriol rather than topical should beconsidered in widespread plaque psoriasis. Most patientswere pleased with the continued gradual decrease inscale produtlion. erythema and plaque thickness.Furthermore, oral therapy caused significant improve-ment in how patients felt about their skin (more flexible,less itching) as well as improvement in their nails.Calcitriol therapy was found to be most effective inpatients with erythrodermic psoriasis or psoriasisvulgaris with minimal plaque thickness. Patients withpustular psoriasis and guttate psoriasis with thickplaques were less likely to respond. Patients afllietedwith psoriatic arthritis also noted signiticant improve-ment in their symptoms. Patients with psoriasis whodo not suffer from idiopathic hypercalciuria or havemild renal failure are more likely to tolerate this drugwithout any signiiicant consequences. It is recom-mended that for patients on oral calcitriol blood andurine calcium levels be monitored on a frequentschedule and yearly renal ultrasound be performed.

2 Morimolo S. Yoshikiiwii K. Kozukii T i'( al. An open sludy ofvilamin D- trt-alnicnl in psoriasis vulgaris. Br / n-rnuttot 1985;

IS

Acknowledgments

We are grateful for the help and support of J.McNeil.Diane [oyce-Otis and Dr T.Dunzendorfer. We appreciatethe generosity of i)rs M.llskokovic and C.Sekaran fromHoffmann-La Roehe for the caleitriol that was used inthis study. A special thank you to all of the patients whoparticipated in the study. Supported by NIH GeneralClinical Research Center Grant # MOl RRO()533-25and NIH grant ROl DK 43690.

References1 Smith EL. t'ini'iis SH. Ponoviui I,. Holick MF. A novel approach for

iho cviiliialion iind Ire aim (.'ill of psoriasis. ()r;il or topii^al use ofl.J5-dihydroxyvilamin !)( ciin IH" a safe and cffeftivt' ttierapy furpsoriasis. I Am Aaiil Dfitiuitol I9SS 19: S l ( i - 2 S .

Krajiballf K. BfLk HI. Sogiiard H. Improvi-monl of psoriasis bylopiail vilamin I)s analogue (ML'SOJ) in a double blind sludy. BrJDenmUfl 198S; 119: 22 J- iO.Kato T. Kokugo M. Tcriii T. 'ranami M. Successful trealmenl ofpsoriasis with lopical application ol active vitamin D-, analogue. 1alpha, 24-dihydroxychoiecakiliTol. Br / DcniuitoJ l^Sli: 115:4 3 1 - i .

Smith EL. Walworth NC, Holick MF. KITcct of 1 alpha, 25-dihydroxyvitamin \)<, on the morphologic and biochemical differ-enliation of cultured human epidermal keratinotytes grownserum free conditions. / Invest Di'niuilnl 198(i: 86: 709-14.Hosomi j , Hosoi J. Abe E el ill. Regulation of terminal differentia-lion of cultured mouse epidermal cells by 1 alpha, 2S-dihydroxy-vilamin 1);. Emtocniiohuin 19S}: 11 J: 1950-7.Morimolo S. Kumahara Y. A patient with psoriasis cured by 1-alpha-hyilroxyvitamin I),. Mi-d j Osakii Uiiiv I98S: JS: 51-4.DeLiica H, The vitamin I) story: A collaborative effort of basicscience and clinical medicine. iASEH I 1988: 2: 114- id.Holick MF. Vitamin I): Biosynthesis metabolism and mode ofaction. In: Kiiiiochnohgii (IVGroot L|. Besser M, Burger HI'., eds).Philadelphia: WB Saunders 1989: 9((2-2(i.

Fredricksson T, Pettorsson 11. Severe psoriasis: Oral therapy with anew retinoid. licnmitohtiiai 1978: 1 S7; 2J8-44 .Chen Tt", Turner AK, Holick MF. Methods for the determination ofthe circulating concentrations of 25 liydroxyvitainin I). / ,'V(((rlim-hcm 1990: I: J15 - I9 .

Chen TC. Turner AK. Holick MF, A methmi for the determinationof the circulating eoneeiitrations of 1.25-dihydroxyvitamin D./ Niilr B»N7i('ni 1990: 1: i2()-7.Higashi A. Peters L A rapid colorimetric method for the determi-nation of inulin in plasm and urine.//^jfiC/ifi Med 195t): JS:47S-82.Morimoto S. Kumahara Y. A patient with psoriasis cured by 1alpha-hydroxyvitamin Ui. Mi'd I Osaka Uiiiv 1985: J5: 51-4.Morimoto S, Yoshikawa K. Psoriasis and vitamiii tlj, A review ofour cxpcncncc. Arch DiTinalol 1989: 125: 2 J1-4.el-A/hary RA. Peters MS. Pittelkow MR i-t a!. Efficacy of vilamin Djderivatives in the treatment of psoriasis vulgaris: n preliminaryreporl. Mayo am hw 199 5: dS: 8 i 5 - 4 1 .

Holick MF. Will 1.25-dihydroxyvitamin I),, MC 90 i and theiranalogues herald a new pbarmacologic era for the treatment ofpsoriasis? Arch Dtrmtilnl 1984: 125: l h92-7 .Holick MF, Active vitamin I) compounds and analogues: A newtherapeutic era for dermatology in the 21st Century. Miup CliiiProc 1993:68:925-7 .

Curhan CC. Willett WC. Rimm EB. Stampfer MJ. A prospectivestudy of dietary calcium and other nutrients and the risk ofsymptomatic kidney stones, N Eiifil J Meil 199J: 328: 8 J i - 8 .Nordi[i, HT'C Vitamin-I) analogues and renal function. Uiticet1978: ii: 1259-M),

Christiansen C. Rodbro P. Christenson MS ct al. Deterioration ofrenal function during treatment of chronic renal failure with1.25-dihydroxytholecalciferol. himn 197«: ii: 700-J .Neilsen H, Romer RK, Meisen F ct iil. I alpha hydroxyvitamin Djtreatment of non-tlialyzed patients with chritnic renal failure.Effects on bone mineral metabolism and kidney function, i'linNcrltrol 1980: U : H) i -8 .

Christiansen C. Rcnlbro P, Christensen MS ft ill Is 1.25-dihydroxy-cholecalciferol harmful to renal function in patients with chronicrenal failure? Clin EmUHrinol 198 i: 15: 229- ib.

199() Brilisb Association of Dermatoiogists, lirilisli joiiriiiil nf . 114. 11)70-11)78

1078 A.PERE2 et al.

24 BerUili M l.uiscltii G. RiiffattI A et al. Renal funttion duringfiilcitriol ihcrapy in chronic renjii fiiikire. Chn \ephrol 1940: J {:ys- l( l2.

25 Pitts RV. Pluisiolociy of the Kidney and Body Fluids. Chka^o: Yt'iirBook Publishers. Iiic:. 196S; 62-70.

26 Smith H. Clearances Involving Tubular Excretion: Endonenoiis Cre.htiniiie Chroinogen Clearance in the Kidney: Structure nnd fiim-tio'i.New York: Oxford Universily Press. 1951: 190-4.

27 Bauer ]H. Brooks CS. Burcli R\. C'liuiciil iipprtiisal of crciftinineclearance us ;i measLiremenI of glomerular fikralion rate. Am jKidimiDis 19S2:2: J57-46.

28 Molina E. Herrera ). Rodrigucz-lturiic B. Thi' renal fiuictitin:ilreserve in health and renal disease in school age fhildre. Kidney I.it1988; 34: 809-16.

29 Merke J. Klaus G. Hugd I) et al. No 1.25-dihydroxyvitiimin I);receptoni on osleoclasts of calcium-deticient chicken tiespile

demonstrable receptors on circuialini; inoiiocyles. / Chn Invest19Hh: 77: 512-14.

30 Bar-Shavit Z. 'reitelbaurii SI,. Kintsina P ft id. Induction of mono-cytic differentiation and rt'sorption by 1,25-dihydroxyvitamin D^.Proc \at! Aead Sii VSA 1983: 80: 5907-11.

!1 Zerwekh JE, Sakhaee K. Pak CYC. Shorl-term 1.25-dihydroxy-vitamin Dj tidministration raises serum osteocalcin in patientswith ptistmenopausal osteoporosis. / Chn Endocrinol Metnh I9S5:60: 615-17.

52 Tilyard MVV. Spears GFS. Thomson I). Doi-ey S. Treatment ofpostmenopausal osteoporosis with calcitrio! or calcium. ,\' Eniil /Med 1992: 326: 357-62.

5 3 Huckins D. Feison DT. Hoiick M. Treatment of psoriatic arthritiswith oral 1,25-dihydroxyvitamin f),: A pilot study. ArthritisRheum 1990: 33: 1723-7.

© 1996 British .Xssociation of Dermatologists. British Journal of Dernuitoloiiy. 134. 1070-1078