Arch Dermatol 2012 Bailey

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EVIDENCE-BASED DERMATOLOGY: REVIEW

SECTION EDITOR: MICHAEL BIGBY, MD; ASSISTANT SECTION EDITORS: OLIVIER CHOSIDOW, MD, PhD;ROBERT P. DELLAVALLE, MD, PhD, MSPH; DAIHUNG DO, MD; URB GONZALEZ, MD, PhD;

CATALIN M. POPESCU, MD, PhD; HYWEL WILLIAMS, MSc, PhD, FRCP

Combination Treatments for Psoriasis

A Systematic Review and Meta-analysis

Elizabeth E. Bailey, MD, MPH; Elisabeth H. Ference, MD, MPH; Ali Alikhan, MD;Meghan T. Hession, MD; April W. Armstrong, MD, MPH

Objective: To summarize the current state of evidencefor combination topical and systemic therapies for mildto severe psoriasis.

Data Sources: We performed a systematic search forall entries in PubMed, CINAHL, Cochrane Review, andEMBASE related to combination treatments for psoria-sis through July 2010.

Study Selection: We included randomized controlledtrials thatreportedproportion of disease clearance or meanchange in clinical severity score (or provided these datathrough communication with study authors) for effi-cacy of a combination treatment for psoriasis comparedwith 1 or more corresponding monotherapies.

Data Extraction: Study data were extracted by 3 inde-pendent investigators, withdisagreement resolvedby con-sensus. The proportion of patients who achieved clear-ance, definition of clearance, means and standarddeviations for baseline disease symptom score and finaldisease symptom score, and major design characteris-tics were extracted for each study.

Data Synthesis: Combination treatments consisting ofvitamin D derivative and corticosteroid, vitamin D de-rivative and UV-B, vitamin A derivative and psoralenUV-A, vitamin A derivative and corticosteroid, vitaminA derivative and UV-B, corticosteroid and hydrocolloidocclusion dressings, UV-B and alefacept, and vitamins A

and D derivatives were more effective than 1 or moremonotherapies using the likelihood of clearance as theoutcome. Blinding status and potency of the corticoste-roid treatment used were significant sources of hetero-geneity between studies.

Conclusions: The results demonstrate the need foradditional long-term trials with standardized outcomemeasures to evaluate the efficacy and adverse effects ofcombination therapies for psoriasis and highlight thepossible effects of trial design characteristics onresults.

Arch Dermatol. 2012;148(4):511-522.Published online December 19, 2011.doi:10.1001/archdermatol.2011.1916

WITH AN INCREASING

number of topicaland systemic treat-ments available forpsoriasis, choosinga

therapy often depends on multiple factors,including disease severity, patient prefer-ence, practitioner experience, and medicalinsurance.1-3 Combination topical thera-

pies are frequently used in clinical practicefor patients with mild to moderate psoria-sis, whereas systemic combination treat-ments are reserved for patients with recal-citrant disease. Data from a number ofclinical trialssuggestthatcombinationthera-pies may have greater efficacy, tolerability,and, perhaps, fewer combined adverse ef-fects comparedwith monotherapies.4,5How-ever, to our knowledge, no comprehen-sive meta-analysis has been performed to

synthesize data on combination therapy inpsoriasis; such a meta-analysis will be use-ful in guiding evidence-based practice forclinicians. We applied meta-analysismeth-ods to various combinations of topical andsystemic therapies and analyzed and sum-marized efficacy data for combinationtherapy compared with monotherapy regi-mens for psoriasis.

METHODS

We conducted a systematic search of PubMed(using MeSH and free-text terms), CochraneReview, CINAHL, and EMBASE for random-ized clinical trials of psoriasis combinationtherapy, most recently updated in July 2010.Searches performed are listed in eAppendix 1(http://www.archdermatol.com). A total of 2213potentially relevant reports were initially iden-

Author Affiliations:Department of Medicine,Brigham and Womens Hospital,Boston, Massachusetts(Dr Bailey); Department of

OtolaryngologyHead and NeckSurgery, NorthwesternUniversity (Dr Ference), andDepartment of Medicine, SaintJoseph Hospital (Dr Hession),Chicago, Illinois; andDepartments of Dermatology,Mayo Clinic, Rochester,Minnesota (Dr Alikhan), andUniversity of California, Davis,School of Medicine, Sacramento(Dr Armstrong).

ARCH DERMATOL/ VOL 148 (NO. 4), APR 2012 WWW.ARCHDERMATOL.COM511

2012 American Medical Association. All rights reserved.at LEO Pharma, on April 16, 2012www.archdermatol.comDownloaded from
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tified; among them, 129 randomized controlled trials met studyinclusion criteria (Figure 1).

Study inclusion criteria were (1) useof between-patient (par-allel group), crossover, or left-right design; (2) designs with pa-tient self-randomization by lesion if they were a left-right designwithout the presence of multiple plaquestreated with more than2 different therapeutic combinations; and (3) reported measuresofeffectiveness andinclusion ofat least10studyparticipants. Thesecriteria were modeled after those used in the Cochrane ReviewbyMasonetal.6 Studies were not limited by disease severity,area

of involvement, skin area treated, or type of psoriasis.All data were extracted by at least 2 of 3 independent in-vestigators (E.E.B., E.H.F., and M.T.H.) using a standardizedextraction form with disagreements resolved by consensus be-tween investigators. Study design and population characteris-tics were extracted. All corticosteroid treatments were catego-rizedby potency using the criteriaoutlined by Jacob andSteele.7

The proportion of patients who achieved clearance, the defi-nition of clearance used, means and standard deviations of thebaseline disease symptom score, andfinal symptom score werealso extracted. For any study in which any of the aforemen-tioned outcomes data were not available, additional data wererequested from the original study investigators.

Baseline psoriasis severity was defined as mild, mild to mod-erate,moderate, moderate to severe, or severe(see eAppendix2).A trial was classified as following an intention-to-treat analysis ifall subjects who were randomized to a treatment arm and re-ceived study drug or placebo were included in theefficacy analy-sis. Patients whowere lost to follow-upor whostopped using thestudy drug could not be excluded from the efficacy analysis.

The primary outcome of this study was the number of sub-jects who experienced disease clearance as defined by the in-dividual study investigators, analyzed by therapeutic combi-nation type. This outcome was adapted from a similar outcomemeasure used in the systematic review by Griffiths et al.8 Theproportion of patients with disease clearance was measured ona risk difference scale, which was calculated as the risk of clear-ance in the combination group minus the risk of clearance inthe monotherapy group. A random-effects model with inversevariance andDerSimonian andLaird weighting was used to ac-count for within-study and between-study variability, which

does not assume that the studies are homogeneous in patientpopulation or study characteristics.

When sufficient data were available, we also reported thestandardized mean change in the clinical severity score (suchas the Psoriasis Area and Severity Index, the Psoriasis SeverityIndex, or other symptom severity scores used in the includedtrial) as a secondary outcome. If multiple measures were used,the measure used as the primary outcome measure for theorigi-nal study was used. This analysis was performed for any sub-group in which more than 1 study reported sufficient data tocalculate a mean change in disease score and standard devia-tion foreach arm. These results were pooledfrom thetrials usinga standardized mean difference statistic in a random-effectsmodel with Cohen d weighting.9

Heterogeneity testing for the primary outcome was per-

formed using the I2

statistic,and meta-regression was used to de-termine whether studyduration,dosage/treatment potency, typeof randomization, blinding,use of intention to treat,baseline dis-ease severity, presence of past treatment failure inclusion crite-ria, number of dropouts, and number of adverse events pre-dictedbetween-studyvariation.All predictors thatweresignificantat P=.05 wereused in a furthermultivariatemeta-regression,and,if a predictor was significant after controlling for all other pre-dictors, subgroup analyses were performed. Subgroup analyseswere also performed for any known significant differences be-tweenstudies within a treatment subgroup based on type of dis-ease treated or the treatment used. Forgroups with more than 2

2213 Potentially relevantreports identifiedthrough databasesearch

463 Reports examined forstudy design basedon abstract or full textif abstract unavailable

129 Randomized controlledtrials reviewed byinvestigators forinclusion criteria

1750 Ineligible entries

1128

508111

3

Not related to psoriasiscombination treatment efficacyDuplicatesNot in EnglishUnable to retrieve full textthrough Columbia or HarvardLibrary Systems

334 Not RCTs

157

76

7523

3

Prospective nonrandomized trials(1 treatment arm)Review articles/conferenceproceedingsCase seriesRetrospective medical recordreviewsMeta-analyses

29 RCTs excluded based on design16

7

32

1

Head-to-head active arms>2 Plaques treated with multipletreatments


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studies, we performed Egger and Begg tests for publication bias

and sensitivity analyses to investigate the implications of indi-vidual study exclusion and study year. A P value of less than .05was considered statistically significant. All analyses were per-formed withcommercially availablesoftware(STATA,version 10;StataCorp LP, College Station, Texas).

RESULTS

Fifty trials wereused in theclearanceefficacyanalysis, whichyielded66 combinationvs monotherapyarmsbecausesev-eral studies included multiple monotherapy or combina-tion arms. The 66 arms included efficacy analysis on 8325trial subjects. Ten trials were used in standardized meandifference analysis forchange in clinical severity score, in-

cluding11 combination vs monotherapy arms.These analy-ses included results from 1728 trial subjects. Vitamin D de-rivative and immunomodulator combination therapy wasnotincludedforsummary analysis because of a lack of simi-larity between immunomodulator treatments. Combina-tion therapies consisting of coal tar derivative and UV-Band of tar treatment and coal tar derivative were not in-cluded in the analysis owing to a lack of sufficient data foranalysis. These studies are included in eTables 1, 4, and 5.No publication bias was apparent based on the Begg andEgger tests for any treatment combination or overall, al-

though many subgroups had a small number of studies,

which limited bias ascertainment. Study year did not havea significant effect on study results foranytherapeutic sub-group.

VITAMIN D DERIVATIVE COMBINATIONS

Vitamin D Derivatives and Corticosteroid

Twelve randomized controlled trials examined the effi-cacy of vitamin D derivativecorticosteroid combina-tions (eTable 1).10-21 Two studies examined the treat-ment of only nail or scalp psoriasis and were not used inthe statistical analysis.16,21 Of the remaining 10 studies,

7 had sufficient data reported to be used in an analysisof clearance efficacy,11,13-15,17-19 and 2 of these 7 studieshad sufficient data to analyze efficacy by disease sever-ity score reduction.11,15

A total of 4593 subjects underwent analysis in these7 trials, with 151 dropouts in the combination arm and276 dropouts in the monotherapy arms. Compared withvitamin D derivative monotherapy, combination vita-min D derivativecorticosteroid therapy led to a 22% in-creased likelihood of clearance (95% CI, 12%-33%)(Figure 2). This effect was robust to the removal of in-

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Risk Difference

Vitamin D derivative + corticosteroid vs vitamin D derivative

Kaloh and Kishimoto,11 2003

Kaufmann et al,13 2002

Kragballe et al,15 2004 (vitamin D for 4 weeks)


Kragballe et al,14 1998 (betamethasone valerate)

Kragballe et al,14 1998 (clobetasone butyrate)

Ortonne et al,17 2004

Papp et al,18 2003

Ruzicka and Lorenz,19 1998Overall: I2=92.3%; P


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dividual studies. There was significant heterogeneity be-tween studies, indicating a statistically significant differ-ence in outcomes between individual studies (I2=92.3%[P .001]). There was some variation in the potency ofthe topical corticosteroid used, with 5 studies using class1 corticosteroids,11,13,15,17,18 2 studies using class 2 corti-costeroids,14,19 and 1 study arm using class 3 corticoste-roids.14 The corticosteroid class used introduced signifi-cant heterogeneity (P=.04)(Figure 3). When the resultswere stratified by corticosteroid class, patients had a 28%increased likelihood of disease clearance using a class 1

corticosteroid combination(95%CI,16%-41%)and a 14%increased likelihood of disease clearance using a class 2corticosteroid combination (95% CI, 5%-22%) com-pared with vitamin D derivative monotherapy. Use of aclass 3 corticosteroid in combination with a vitamin Dderivative didnot lead to increaseddisease clearancecom-pared with vitamin D derivative monotherapy. Combi-nation therapy with any corticosteroid class decreaseddisease severity by 1.52 units of standard deviation (95%CI, 2.56 to 0.48) more than the vitamin D derivativemonotherapy arm (data not shown).

Compared with corticosteroid monotherapy, vita-min D derivativecorticosteroid treatment led to a 20%increased likelihood of clearance (95% CI, 15%-24%)

(Figure 2). There was no significant heterogeneity be-tween studies within the group (I2=0.0% [P=.84]).

Vitamin D Derivatives and UV-B

Eight randomized controlled trials examined the effi-cacy of combined vitamin D derivativeUV-B (UV-B)therapies (eTable 1).22-29 Of these 8 studies, 4 had suffi-cient data to be used in comparative analysis of clear-ance efficacy of combination therapy to UV-B mono-therapy,24,26-28 and 2 of these 8 studies had sufficient data

to be used in analysis of clearanceefficacy compared withvitamin D monotherapy23,24; thus, 5 studies in total wereused in clearance efficacy analysis. Two studies hadsufficient data to be used in analysis of efficacy by dis-ease severity score reduction compared with UV-Bmonotherapy.26,28

A total of 493 subjects underwent analysis in these 5studies,with 19 dropouts in thecombination therapy armsand 20 dropouts in the monotherapy arms. ComparedwithUV-Bmonotherapy,vitamin D derivativeUV-Bcom-bination therapy did not lead to a statistically signifi-

cant increase in the likelihood of clearance (11%; 95%CI, 2% to 24%) (Figure 2). There was a statistically sig-nificant effect when the study by Molin et al24 or the oneby Ramsay et al26 was removed from the analysis, whichboth had null results in the original studies. There wasno significant heterogeneity among studies (I2=56.9%[P=.07]). There were no significant differences in re-duction of disease severity scores after vitamin D deriva-tiveUV-B combination therapy compared with UV-Bmonotherapy (0.92; 95% CI, 3.86 to 2.02).

Two studies had sufficient data to compare clearanceefficacy of combination therapy with vitamin D deriva-tive monotherapy.23,24 Compared with vitamin D deriva-tive monotherapy, vitamin D derivativeUV-B combina-

tion therapy ledto a 34% increasedlikelihood of clearance(95% CI, 22%-47%) (Figure 2). There was no signifi-cant heterogeneity between studies (I2=11.5% [P=.29]).

VITAMIN A DERIVATIVE COMBINATIONS

Vitamin A Derivatives and PsoralenUV-A

Seven trials examined theefficacy of vitamin A derivativepsoralen-UV-A (PUVA) combinations (eTable 2).30-36 All7 studies had sufficient data to be used in an analysis of

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Risk Difference

Class 1

Kaloh and Kishimoto et al,11 2003

Kaufmann et al,13 2002



Ortonne et al,17 2004

Papp et al,18 2003

Subtotal: I2=93.0%; P


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the clearance efficacy of combination therapy comparedwith PUVA monotherapy, and 2 studies had sufficientdata to analyze the clearance efficacy of combinationtherapy compared with vitamin A derivative mono-therapy.30,33 No studies provided sufficient data to ana-lyze efficacy by the reduction of disease severity score.All studies used oral vitamin A derivative treatments incombination with PUVA. Four studies used etreti-nate,30,31,33,34 2 studies used acitretin,35,36 and 1 study used

beta carotene.32

A total of 265 patients were enrolled in these 7 trials.There were 15 dropouts from the combination arms and13 dropouts from the monotherapy arms. Compared withPUVA monotherapy, vitamin A derivativePUVA com-bination treatment led to a 22% increased likelihood ofclearance (95% CI, 7%-38%) (Figure 4). This effect wasrobust to the removal of individual studies. There wassignificant heterogeneity, indicating statistically signifi-cant differences between individual study results(I2=59.3%[P=.02]). The blinding status of the study in-

troduced significant heterogeneity (P=.048), adjustingfor intention-to-treat status (Figure 5). When resultswere stratified by blinding status, patients using combi-nation therapy in the unblinded studies had a 35% in-creased likelihood of clearance (95% CI, 16%-55%),whereaspatients using combinationtherapyin the double-blinded studies were not more likely to experience dis-ease clearance compared with PUVA monotherapy (6%;95% CI, 8% to 20%).

Additional analyses were performed, stratified by typeof psoriasis (Figure 6) and with the removal of the studyby Macdonald et al32 in which beta carotene was used.Among patients with palmoplantar pustulosis and hy-perkeratotic psoriasis of the palms and soles, those usingcombination therapy had a 50% increased likelihood ofclearance compared with those receiving monotherapy(95% CI, 26%-74%). Patients with all other types of pso-riasis were not more likely to experience disease clear-anceusing combinationtreatment thanwhenusing mono-therapy (15%; 95% CI, 1% to 31%). Additional results

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Risk Difference

Vitamin A derivative + PUVA vs PUVA

Lauharanta et al,30 1981

Lawrence et al,31 1984

Macdonald et al,32 1984

Matsunami et al,33 1990

Parker et al,34 1984

Saurat et al,35 1988 (acitretin)

Saurat et al,35 1988 (etretinate)

Tanew et al,36 1991

Overall: I2=59.3%; P=.02Vitamin A derivative + PUVA vs vitamin A derivative



Overall: I2=0.0%; P=.68

Vitamin A derivative + corticosteroid vs vitamin A derivative

Christiansen et al,37 1982

Green and Sadoff,39 2002 (betamethasone dipropionate, cream 0.05%)

Green and Sadoff,39 2002 (diflorasone diacetate, cream 0.05%)

Green and Sadoff,39 2002 (diflorasone diacetate, ointment 0.05%)

Green and Sadoff,39 2002 (fluocinonide, ointment 0.05%)

Green and Sadoff,39 2002 (fluticasone propionate, ointment 0.005%)

Green and Sadoff,39 2002 (mometasone furoate, ointment 0.1%)

Lebwohl et al,40 1998 (fluocinolone acetonide, cream 0.01%)

Lebwohl et al,40 1998 (fluocinonide, cream 0.05%)

Lebwohl et al,40 1998 (mometasone furoate, cream 0.1%)

Poulin,42 1999

Overall: I2=53.9%; P=.02

Vitamin A derivative + UV-B vs UV-B

Green et al,43 1992

Koo et al,44 2000

Ruzicka et al,46 1990

Overall: I2=42.9%; P=.17

0.45 (0.18 to 0.72)

0.50 (0.18 to 0.82)

0.10 (0.48 to 0.28)

0.50 (0.14 to 0.86)

0.33 (0.06 to 0.61)

0.1 (0.12 to 0.37)

0.03 (0.30 to 0.23)

0.07 (0.16 to 0.30)

0.22 (0.07 to 0.38)

13.13

11.46

9.70

10.31

12.93

14.27

13.44

14.74

100.00

0.50 (0.24 to 0.76)

0.40 (0.01 to 0.79)

0.47 (0.25 to 0.69)

69.26

30.74

100.00

0.20 (0.01 to 0.39)

0.43 (0.25 to 0.61)

0.09 (0.13 to 0.31)

0.20 (0.00 to 0.41)

0.13 (0.07 to 0.34)

0.22 (0.02 to 0.43)

0.31 (0.11 to 0.51)

0.01 (0.14 to 0.13)

0.16 (0.05 to 0.26)

0.12 (0.00 to 0.23)

0.60 (0.15 to 1.05)

0.19 (0.11 to 0.27)

8.76

9.12

7.62

8.13

8.10

8.04

8.45

12.11

13.83

13.26

2.59

100.00

0.13 (0.11 to 0.37)

0.13 (0.03 to 0.29)

0.36 (0.16 to 0.57)

0.21 (0.05 to 0.36)

26.51

41.16

32.33

100.00

RD (95 % CI) Weight , %

Figure 4. Vitamin A derivative combination therapies and disease clearance efficacy (risk difference [RD]). Vitamin A derivativepsoralenUV-A (PUVA)combination treatment was more effective in inducing disease clearance than vitamin A derivative or PUVA monotherapies. Vitamin A derivativecorticosteroid

combination therapy was more effective than vitamin A derivative monotherapy, and vitamin A derivativeUV-B combination therapy was more effective than UV-Bmonotherapy. Weights are derived from random-effects analysis. Percentages might not total 100 because of rounding. Symbols are explained in the legend toFigure 2.




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excluding studies of patients with palmoplantar pustu-losis found an effect of blinding status similar to that inthe original analysis. When the study by Macdonald etal32 was excluded and the remaining studies were strati-fied by blinding status, all study heterogeneity was re-moved (I2=0.0%[P=.85] for unblinded studies; I2=0.0%[P=.70] for double-blinded studies).

Compared with vitamin A derivativemonotherapy, vi-

tamin A derivativePUVA combination therapy led to a47% increased likelihood of clearance (95% CI, 25%-69%). Both studies were unblinded. There was no sig-nificantheterogeneity between studies(I2=0.0%[P=.68]).

Vitamin A Derivatives and Corticosteroid

Six trials examined the effects of vitamin A derivativecorticosteroid combination therapy compared with amonotherapy (eTable 2).37-42 Of these 6 studies, 4 hadsufficient data to be used in an analysis of clearance ef-

ficacy compared with vitamin A derivative mono-therapy.37,39,40,42 No studies provided sufficient data to ana-lyze the clearance efficacy compared with corticosteroidmonotherapy. No studies had sufficient data to be usedin an analysis based on the disease severity score reduc-tion. Two of the 4 studies included several combinationarms with topical corticosteroid treatmentof differing po-tency. In the 4 studies, there were a total of 4 arms using

class 2 topical corticosteroids,37,39,40

4 arms using class 3topical corticosteroids,39 2 arms using class 4 topical cor-ticosteroids,40,42 and 1 arm using a class 5 topical corti-costeroid.40 Three of the 4 studies used topical tazaro-tene gel,39,40,42 whereas 1 study used oral etretinatetreatment.37

A total of 653 patients were enrolled in the 4 trials.There were 65 dropouts in the combination arm and 49dropouts in the monotherapy arm. Compared with pa-tients receiving vitamin A derivative monotherapy, pa-tients receiving vitamin A derivativecorticosteroid com-

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Risk Difference

Unblinded






Subtotal: I2=46.7%; P=.11Double-blinded



Tanew et al,36 1991

Subtotal: I2=0.0%; P=.70Overall: I2=59.3%; P=.02

0.45 (0.18 to 0.72)

0.50 (0.18 to 0.82)

0.10 (0.48 to 0.28)

0.50 (0.14 to 0.86)

0.33 (0.06 to 0.61)

0.35 (0.16 to 0.55)

13.13

11.46

9.70

10.31

12.93

57.54

0.12 (0.12 to 0.37)

0.03 (0.30 to 0.23)

0.07 (0.16 to 0.30)

0.06 (0.08 to 0.20)

14.27

13.44

14.74

42.46

0.22 (0.07 to 0.38) 100.00

RD (95 % CI) Wei ght, %

Figure 5. Vitamin A derivativepsoralenUV-A (PUVA) combination therapy vs vitamin A derivative monotherapy clearance efficacy by blinding status. Amongunblinded studies, vitamin A derivativePUVA combination therapy led to a higher likelihood of disease clearance than vitamin A derivative monotherapy. Thiseffect was not statistically significant among double-blinded studies. Weights are derived from random-effects analysis. Percentages might not total 100 becauseof rounding. The vertical dashed line indicates the summary estimate when all the studies in the table are pooled for a single estimate. RD indicates risk difference.Other symbols are explained in the legend to Figure 2.

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Risk Difference

Other types of psoriasis






Tanew et al,36 1991

Subtotal: I2=51.7%; P=.07Palmoplantar pustulosis



Subtotal: I2=0.0%; P>.99

0.45 (0.18 to 0.72)

0.10 (0.48 to 0.28)

0.33 (0.06 to 0.61)

0.12 (0.12 to 0.37)

0.03 (0.30 to 0.23)

0.07 (0.16 to 0.30)

0.15 (0.01 to 0.31)

16.74

11.60

16.42

18.60

17.24

19.40

100.00

0.50 (0.18 to 0.82)

0.50 (0.14 to 0.86)

0.50 (0.26 to 0.74)

55.30

44.70

100.00


Figure 6. Vitamin A derivativepsoralenUV-A (PUVA) combination therapy vs vitamin A derivative monotherapy clearance efficacy by psoriasis type. Whenstratified by type of psoriasis, vitamin A derivativePUVA combination treatment was more effective than vitamin A derivative monotherapy in inducing diseaseclearance among patients with palmoplantar pustulosis but not for patients with other types of psoriasis. Weights are derived from random-effects analysis.RD indicates risk difference. Symbols are explained in the legend to Figure 2.




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bination therapy had a 19% increased likelihood ofclearance (95% CI, 11%-27%) (Figure 4). The estimatewas robust to the removal of individual studies and wassimilar when the trials were not analyzed with separate

treatment arms based on the type of corticosteroid used(23%; 95% CI, 14%-31%). There was significant hetero-geneity (I2=53.9%[P=.02]); the numberof patient drop-outs, baseline disease severity, blinding status, and in-tention-to-treat status were significant sources ofheterogeneity when evaluated individually. However,there was not sufficient trial size to analyze the indepen-dent effect of each factor.

Vitamin A Derivatives and UV-B

Four trials examined the effects of vitamin A derivativeUV-B combination therapy compared with UV-B mono-therapy (eTable 2).43-46 Three trials had sufficient data to

be included in the analysis of clearance efficacy,43,44,46

andonly 1 trial had sufficient data to be included in efficacyanalysis based on reduction in disease severity score.45

Two of the 3 studies used oral vitamin A derivative treat-ments, etretinate43 or acitretin.46 The third study used atopical tazarotene therapy.44

One-hundred sixty-two patients enrolled in these 3trials. There was 1 dropout fromthe combination therapygroup and 3 dropouts from the UV-B monotherapy groupamong the parallel group studies and 14 dropouts fromthe left-right study by Koo et al.44 Compared with UV-B

monotherapy, patients using vitamin A derivativeUV-B combination therapy had a 21% increased likeli-hood of clearance (95% CI, 5%-36%) (Figure 4). This es-timate was somewhat unstable because the effect lost

statistical significance when the study by Ruzicka et al46

was removed. There was no significant heterogeneity(I2=42.9% [P=.17]).

UV-B COMBINATIONS

UV-B and Balneotherapy

Five randomized controlled trials examined the efficacyof UV-Bbalneotherapy combinations (eTable 3).47-51 Allexcept 1 trial compared UV-Bbalneotherapy combina-tion therapy with UV-B monotherapy. Leaute-Labrze etal51 used UV-B and balneotherapy monotherapy arms.Four studies had sufficient data reported to be used in

an analysis of clearance efficacy,47-49,51

and 2 studies hadsufficient data to analyze efficacy by the disease severityscore reduction.49,50

A total of 465 patients enrolled in these 5 trials. Therewere 27 dropouts from thecombination arms and55 drop-outs from the monotherapy arms. Compared with pa-tients using UV-B monotherapy, patients using UV-Bbalneotherapy combination therapywere not more likelyto achieve disease clearance (14%; 95% CI, 3% to 31%)(Figure 7). There was significant heterogeneity in thisestimate, with I2=84.9% (P .001). Several differences

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Risk Difference

UV-B + balneotherapy vs UV-B

Brockow et al,47 (high-concentrated saline bath)

Brockow et al,48 2007 (low-concentrated saline bath)

Dawe et al,49 2005

Laut-Labrze et al,51 2001

Overall: I2=84.9%; P


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between studies (ie, study duration, baseline disease se-verity, type of randomization, blinding status, and useof intention to treat) were significant sources of hetero-geneity when analyzed independently. These differ-ences all correlated with differences between the 2 stud-ies conducted by Brockow et al47,48 and the 2 studies byother investigators.49,51 There was instability in the esti-mate when individual studies were removed. Examin-ing the effect on reduction of the disease severity score,

there was not a significant effect of UV-Bbalneo-therapy combined therapy compared with UV-B mono-therapy (0.68; 95% CI, 1.87 to 0.51).

UV-B and Biologicals

Two trials examined the efficacy of UV-Balefacept com-bination therapy compared with alefacept mono-therapy, and 1 trial examined the efficacy of UV-Balefacept combination therapy compared with UV-Bmonotherapy (eTable 3).52-55 The 2 trials examining UV-Balefacept combination therapy compared with alef-acept monotherapy each provided sufficient evidence toanalyze the clearance efficacy but did not provide suffi-

cient data to evaluate the efficacy of the treatment basedon reduction in the disease severity score.A total of 74 patients were included in these 2 trials.

There were 4 dropouts from the alefaceptUV-B combi-nation treatment arm and 5 dropouts from the alefaceptmonotherapy arm. Patients using UV-Balefacept com-bination therapy had a 68% increased likelihood of clear-ance than did patients receiving alefacept monotherapy(95% CI, 51%-85%) (Figure 7). There was no signifi-cant heterogeneity (I2=39.9% [P=.19]).

UV-B and Immunomodulator

TwotrialsexaminedtheefficacyofUV-Bmethotrexateso-

diumcombinationtherapycomparedwithUVBmonotherapy(eTable 3).56,57 They each provided sufficient evidence toanalyze the efficacy at disease clearance, and only 1 studyprovided sufficientdatato evaluatethe efficacy of the treat-ment based on a reduction in the disease severity score.56

A total of 64 patients were included in these 2 trials.There were2 dropoutsfrom the methotrexateUV-Btreat-ment arm and 5 dropouts from the UV-B monotherapytreatment arm. Patients using UV-Bmethotrexate com-bination therapy had a 36% increased likelihood of dis-ease clearance than did patients receiving UV-B mono-therapy (95% CI, 10%-63%) (Figure 7). There was nosignificant heterogeneity (I2=48.8% [P=.16]).

UV-B and Psoralen

Two trials examined the efficacy of UV-Bpsoralen com-bination therapy compared with UV-B monotherapy(eTable 3).58,59 They each provided sufficient data to ana-lyze the disease clearance efficacy and to evaluate effi-cacy by the degree of disease severity score reduction.

Thirty-one patients were included in these 2 trials.There were 5 dropoutsfrom these left-right trials (eTable3). Patients using UV-Bpsoralen combination therapywerenot more likely to experience disease clearance than

patients using UV-B monotherapy (13%; 95% CI, 7%to 34%) (Figure 7). There was no significant heteroge-neity (I2=0.0% [P=.74]). When we examined the stan-dardized mean difference in the clinical severity score,there was a significant effect of UV-Bpsoralen combi-nation therapy comparedwithUV-Bmonotherapy (1.68;95% CI, 2.37 to 0.99).

UV-B and Tar

Two trials examined the efficacy of UV-Btar combina-tion therapy compared with UV-B monotherapy (eTable3).60,61 They each provided sufficient evidence to ana-lyze clearance efficacy. Only 1 study had sufficient datato evaluate the efficacy of treatment on the basis of a re-duction in the disease severity score.60

Sixty-onepatientswere includedin these 2 trials. Therewere 5 dropouts from the combination and mono-therapy arms, all from the study by Menkes et al.61 Pa-tientsusing UV-Btarcombination therapy were notmorelikely to experience disease clearance than patients usingUV-B monotherapy (5%; 95% CI, 27% to 17%)(Figure 7). There was no significant heterogeneity

(I2

=0.0% [P=.44]).CORTICOSTEROID COMBINATIONS

Corticosteroid and Hydrocolloid Dressing

Three trials examined the efficacy of corticosteroidhydrocolloid dressing combination therapy comparedwith monotherapy (eTable 4).62-64 All 3 trials providedsufficient datato analyze clearanceefficacycomparedwithcorticosteroidmonotherapy.Onetrial also comparedcom-bination therapy with hydrocolloid occlusion dressingmonotherapy.62 No studies provided sufficient data to ana-lyze efficacy on the basis of a reduction in the disease se-

verity score. Two studies used class 3 topical corticoste-roid regimens,62,63 and 1 study used a class 1 topicalcorticosteroid regimen.64

A total of 116 patients were included in these 3 trials,with 5 dropouts from the combination arms and 9 drop-outs from the monotherapy arms. Compared with cor-ticosteroid monotherapy, patients using corticosteroidhydrocolloid occlusiondressing combination therapy hada 44% increased likelihood of disease clearance (95% CI,23%-64%) (Figure 8). The estimate was stable when in-dividual studies were removed from the analysis. Therewas no significant heterogeneity (I2=56.7% [P=.10]).

Corticosteroid and Salicylic Acid

Two trials examined the efficacy of corticosteroidsalicylic acid combination therapy compared withmono-therapy (eTable 4).65,66 Both trials evaluated combina-tiontherapy compared with corticosteroidmonotherapy.Both studies used mometasone furoate ointment, 0.1%(a class 3 topical corticosteroid), in combination with sali-cylic acid ointment, 5%, twice daily. Both provided suf-ficient data to analyze disease clearance efficacy but didnot provide sufficient data to evaluate the efficacy by dis-ease severity score reduction.




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Seven hundred seventy-six patients were included in

these 2 trials. There were 33 dropouts from the cortico-steroidsalicylic acid treatmentarmand37 dropouts fromthe corticosteroid monotherapy treatment arm. Patientsusing corticosteroidsalicylic acid combination therapywerenot more likely to experience disease clearance thanpatients using corticosteroid monotherapy (3%; 95% CI,0%-7%) (Figure 8). There was no significant heteroge-neity (I2=0.0% [P=.78]).

Corticosteroid and UV-B

Two studies evaluated the efficacy of corticosteroidUV-B combination therapy compared with UV-B mono-therapy on the basis of clearance efficacy (eTable 4).67,68

Neither study provided sufficient data to analyze the ef-ficacy by disease severity score reduction. One study useda class 1 topical corticosteroid regimen,68 and 1 study useda class 2 topical corticosteroid regimen.67

One hundred forty-three patients enrolled in these 2trials. In the trial by Larko et al,68 there were 10 dropoutsfrom thecombination groupand7 dropoutsfrom themono-therapy group. No dropouts were reported in the trial byDover et al.67 Patients using corticosteroidUV-B combi-nation treatmentwere notmore likely to experience clear-ance than patients using UV-B treatmentalone (6%; 95%CI, 24% to 12%) (Figure 8). There was no significantheterogeneity in this estimate (I2=0.0% [P=.91]).

VITAMINS A AND D DERIVATIVECOMBINATIONS

Four randomized controlled trials examined the effi-cacy of vitamin A derivativevitamin D derivative com-bination therapy (eTable 6).69-72 Each trial compared com-bination therapy withvitamin A derivative monotherapy.Three of the 4 studies had sufficient data reported to beused in an analysis of clearance efficacy,70-72 and 2 of these4 studies had sufficient data to analyze the efficacy bydisease severity score reduction.69,70

A total of 301 subjects underwent analysis in these 4

trials, with 26 dropouts from the combination arm and31 dropouts from the monotherapy arms. Compared withvitamin A derivative monotherapy, vitamin A derivativevitamin D derivative combination therapy led to a 33%increased likelihoodof clearance (95%CI, 22%-44%). Thiseffect was robust to the removal of individual studies.There was no significant heterogeneity (I2 =28.3%[P=.25]). When we examined the effect on the reduc-tion of the disease severity score, thecombination therapydid nothave a statistically significanteffectcompared withvitamin A derivative monotherapy (12.0; 95% CI, 31.6to 7.49).

SYSTEMIC IMMUNOMODULATOR

COMBINATIONS

Five randomized controlled trials evaluated the efficacyof an immunomodulator treatment in combination withanother therapy.73-77 These studies examined the effi-cacy of tacrolimus in combination with salicylic acid,73

cyclosporine in combination with a low-calorie diet,74 si-rolimus in combination with cyclosporine,75 methotrex-ate in combination with folic acid,76 and methotrexatein combination with etanercept.77 The characteristics andkey findings of these studies are described in eTable 7.

COMMENT

Many of the examined combination therapies were moreeffectivethanmonotherapy regimens(eTable8). Ouranaly-sis provides an important summary of the current evi-dence formanycommonlyusedpsoriasiscombinationtreat-ments and is the first study, to our knowledge, to analyzestatistically the evidence for topical and systemic combi-nation therapies for all severities of psoriasis.

Some treatment combinations in our study have beenexaminedin previousmeta-analyses.6,8,78 There were somedifferences in the studies included in our analysis and

2.00 0 2.00

Risk Difference

Corticosteroid + hydrocolloid dressing vs corticosteroid

Agius et al,62 1999

Kragballe and Larsen,63 1991

Volden et al,64 2001

Overall: I2=56.7%; P=.10Corticosteroid + salicylic acid vs corticosteroid

Koo et al,65 1998

Tiplica and Salavastru,66 2009

Overall: I2=0.0%; P=.78Corticosteroid + UV-B vs UV-B

Dover et al,67 1989

Lark et al,68 1984

Overall: I2=0.0%; P=.91

0.61 (0.35 to 0.87)

0.47 (0.20 to 0.75)

0.28 (0.10 to 0.46)

0.44 (0.23 to 0.64)

30.49

28.94

40.57

100.00

0.04 (0.31 to 0.22)

0.07 (0.31 to 0.18)

0.06 (0.24 to 0.12)

45.16

54.84

100.00

0.03 (0.01 to 0.07)

0.05 (0.05 to 0.14)

0.03 (0.00 to 0.07)

87.36

12.64

100.00


Figure 8. Combination corticosteroid derivative therapies and disease clearance efficacy (risk difference [RD]). Combination corticosteroidhydrocolloid dressingtherapy led to a higher likelihood of disease clearance than corticosteroid monotherapy. Combination corticosteroidsalicylic acid therapy was not more effectivethan corticosteroid monotherapy, and combination corticosteroidUV-B therapy was not more effective than UV-B monotherapy. Weights are derived fromrandom-effects analysis. Symbols are explained in the legend to Figure 2.




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those in previous systematic reviews, likely owing to vari-ability in search criteria, addition of more recent stud-ies, and differences in criteria for study inclusion. Theresults found in our study were consistent with previ-ously reported results.6,8,78

VitaminD derivativecorticosteroid combination therapywas more effective than vitamin D derivative mono-therapy in our study, based on clearance efficacy and dis-ease severity score reduction. These results are consistent

with results from a previous meta-analysis that also re-ported the standardized meandifference in severityscore.6

In our study, vitamin A derivativePUVA and vitamin Aderivativecorticosteroidcombination therapies were eachmoreeffectivethan vitaminA derivative monotherapybasedon likelihood of disease clearance. Vitamin A derivativePUVA combination therapy was also more effective thanPUVA monotherapy based on clearance efficacy, and vi-tamin A derivativeUV-B combination therapy was moreeffective than UV-B monotherapy based on clearanceefficacy. A previous meta-analysis demonstrated similarresults based on the likelihood of clearance but did notana-lyze an overall effect estimate for vitamin A derivativecorticosteroid or vitamin A derivativeUV-B combination

therapy trials.8

A previous meta-analysis examining treat-ments for chronic palmoplantar pustulosis found similarresults fortheefficacyof vitamin A derivativePUVA com-bination therapycompared with eithermonotherapybasedon disease clearance.78

We also showed that corticosteroidhydrocolloid oc-clusion dressing therapy was more effective than corti-costeroid monotherapy, based on likelihood of clear-ance. This result is similar to the result from a single trialof patients with palmoplantar pustulosis described in ameta-analysis by Marsland et al.78

Based on the results from the vitamin A derivativePUVA combination therapy subset, we also showed thatblinding can significantly affect results. When stratified

by blinding status, studies thatuseda double-blinded de-sign did not show a significant increase in disease clear-ance with vitamin A derivativePUVA combinationtherapy compared with PUVA monotherapy, whereas un-blindedstudies demonstrated a significant effect. This ef-fect was not explored in the previousmeta-analyses.8 Thesignificant effect of study blinding may be due to differ-ences in the evaluation or treatment of patients in un-blinded studies compared with double-blinded studies.

In some combination subsets, such as the UV-Bpsoralen combination therapy and vitamin A derivativevitamin D derivative combination therapy, the analysesusing the 2 different outcome measures (clearance effi-cacy and disease severity score reduction) led to different

conclusions about efficacy. For the vitamin A derivativevitamin D derivative combination subset, there is limitedinterpretability of the clinical value of one outcome mea-sure compared with another because each set of analysesused a different set of trials. However, the analysis of UV-Bpsoralen combination therapy used the same 2 studiesfor both trials. Combination therapy was not more effec-tive than UV-B monotherapy based on thelikelihoodof dis-ease clearance but was more effective based on change indisease severity score. These findings highlight that sometreatments that effectively reducedisease severity maynot

lead to complete disease clearance. An analysis based ondisease clearancecouldmiss theefficacy of this type of treat-ment in reducing disease severity.

Because we analyzed the results of trialswith many dif-ferencesin design characteristics(ie, length of study, treat-mentdosing,andpatientcharacteristics),these studiescouldnot be pooled on a patient level and required pooling on astudy level using random-effects analysis to take into ac-count differences in design and quality between studies.

This type of analysis is helpful for providing more robusttreatment efficacy results using existing study data, par-ticularlyforlooking ata numberof differenttherapieswhenmorehomogeneouspoolingdataare notavailable. Onelimi-tation of this study is that there may be therapies for whichwe did not find a statistically significant difference in effi-cacy butfor which clinicallymeaningful benefitsmight nothave been captured owing to insufficient sample size or thelimitations of the outcome measures available for thisstudy.79 However, we attempted to present the data avail-able as completelyandobjectively as possible to guide clini-cal practice, as is appropriate given the limitations, and todirect further research.

In summary, the current literature on combination

therapy in psoriasis has focused on the comparison be-tween a combination regimen with a monotherapy. It ap-pears that combination topical therapies are generallymore effective than topical monotherapy.Overall, the ad-dition of phototherapy to a topical regimen results in sig-nificant clearance of psoriasis compared with a topicalregimen alone. However, compared with phototherapyalone, the addition of a topical treatment to photo-therapy does not appear to significantly decrease dis-ease severity. The literature is lacking in combination sys-temic therapies. Future research in combination therapyis necessary to devise new therapeutic strategies to maxi-mize efficacy while minimizing adverse effects.

Accepted for Publication: September 25, 2011.Published Online: December 19, 2011. doi:10.1001/archdermatol.2011.1916Correspondence: April W. Armstrong, MD, MPH, De-partment of Dermatology, University of California, Da-vis, School of Medicine, 3301 C St, Ste 1400, Sacra-mento, CA 95816 ([email protected]).Author Contributions: All authors had full access to allthe data in the study and take responsibility for the in-tegrity of the data and the accuracy of the data analysis.Study concept and design: Bailey, Alikhan, and Arm-strong.Acquisition of data: Bailey, Ference, Alikhan, Hes-sion, and Armstrong. Analysis and interpretation of data:Bailey, Ference, and Hession. Drafting of the manuscript:

Bailey, Ference, Alikhan, Hession, and Armstrong. Criti-cal revision of the manuscript for important intellectual con-tent: Bailey, Alikhan, and Armstrong. Statistical analy-sis: Bailey and Ference. Administrative, technical, andmaterial support: Armstrong. Study supervision: Arm-strong.Financial Disclosure: Dr Armstrongis an investigatorandconsultant forAmgen, Abbott, andJanssen Biotech andhasreceived honoraria and grants from these companies.Online-Only Material: The eAppendixes, eReferences, andeTables are available at http://www.archdermatol.com.




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Additional Contributions: Caitlin Harskamp, BA, pro-vided input for revision of this manuscript.

REFERENCES

1. Augustin M, KrugerK, RadtkeMA, SchwipplI, ReichK. Disease severity,quality

of lifeand health carein plaque-typepsoriasis:a multicentercross-sectionalstudy

in Germany. Dermatology. 2008;216(4):366-372.

2. Kimball AB, Jacobson C, Weiss S, Vreeland MG, Wu Y. The psychosocial bur-

den of psoriasis. Am J Clin Dermatol. 2005;6(6):383-392.

3. Lebwohl MG, Corvari L. Compatibility of topical therapies for psoriasis: chal-lenges and innovations. Cutis. 2007;79(1)(suppl 2):5-10.

4. Jensen P, Skov L, Zachariae C. Systemic combination treatment for psoriasis: a

review. Acta Derm Venereol. 2010;90(4):341-349.

5. Koo JY. Using topical multimodal strategies for patients with psoriasis. Cutis.

2007;79(1)(suppl 2):11-17.

6. Mason AR,MasonJ, CorkM, DooleyG, EdwardsG. Topicaltreatmentsfor chronic

plaque psoriasis. Cochrane Database Syst Rev. 2009;(2):CD005028.

7. Jacob SE,SteeleT. Corticosteroid classes:a quick reference guide including patch

test substances and cross-reactivity. J Am Acad Dermatol. 2006;54(4):723-

727.

8. Griffiths CE, Clark CM, Chalmers RJ, Li Wan Po A, Williams HC. A systematic

review of treatments for severe psoriasis. Health Technol Assess. 2000;4(40):

1-125.

9. Egger M, Smith GD, Altman D, eds. Systematic Reviews in Health Care: Meta-

analysis in Context. 2nd ed. London, England: BMJ Books; 2001.

10. Austad J, Bjerke JR, Gjertsen BT, et al. Clobetasol propionate followed by calci-

potriol is superior to calcipotriol alone in topical treatment of psoriasis. J EurAcad Dermatol Venereol. 1998;11(1):19-24.

11. Katoh N, Kishimoto S. Combination of calcipotriol and clobetasol propionate as

a premixed ointment for the treatment of psoriasis. Eur J Dermatol. 2003;13

(4):382-384.

12. Koo J, Blum RR, Lebwohl M. A randomized, multicenter study of calcipotriene

ointment and clobetasol propionate foam in the sequential treatment of local-

izedplaque-typepsoriasis:short-and long-termoutcomes. J AmAcadDermatol.

2006;55(4):637-641.

13. Kaufmann R, Bibby AJ, Bissonnette R, et al. A new calcipotriol/betamethasone

dipropionate formulation (DaivobetTM) is aneffective once-daily treatment forpso-

riasis vulgaris. Dermatology. 2002;205(4):389-393.

14. KragballeK, BarnesL, Hamberg KJ,et al.Calcipotriolcreamwithor without con-

current topicalcorticosteroid in psoriasis: tolerabilityand efficacy.BrJ Dermatol.

1998;139(4):649-654.

15. Kragballe K, Noerrelund KL, Lui H, et al. Efficacy of once-daily treatment regi-

mens with calcipotriol/betamethasone dipropionateointment and calcipotrioloint-

ment in psoriasis vulgaris. Br J Dermatol. 2004;150(6):1167-1173.16. Kragballe K, Hoffmann V, Ortonne JP, Tan J, Nordin P, Segaert S. Efficacy and

safety of calcipotriol plus betamethasone dipropionate scalp formulation com-

pared with calcipotriol scalp solution in the treatment of scalp psoriasis: a ran-

domized controlled trial. Br J Dermatol. 2009;161(1):159-166.

17. Ortonne JP, Kaufmann R, Lecha M, Goodfield M. Efficacy of treatment with cal-

cipotriol/betamethasone dipropionate followed by calcipotriol alone compared

with tacalcitol for the treatment of psoriasis vulgaris: a randomised, double-

blind trial. Dermatology. 2004;209(4):308-313.

18. PappKA, GuentherL, BoydenB, et al.Early onsetof actionandefficacyof a com-

bination of calcipotriene and betamethasone dipropionate in the treatment of

psoriasis. J Am Acad Dermatol. 2003;48(1):48-54.

19. Ruzicka T, Lorenz B. Comparison of calcipotriol monotherapy and a combina-

tionof calcipotrioland betamethasone valerate after2 weeks treatment withcal-

cipotriol in the topical therapy of psoriasis vulgaris: a multicentre, double-blind,

randomized study. Br J Dermatol. 1998;138(2):254-258.

20. SalmhoferW, Maier H, Soyer HP,Honigsmann H, Hodl S. Double-blind, placebo-

controlled,randomized, right-leftstudy comparingcalcipotriol monotherapywitha combinedtreatment of calcipotrioland diflucortolone valeratein chronicplaque

psoriasis. Acta Derm Venereol Suppl (Stockh). 2000;(211):5-8.

21. Tzung TY, Chen CY, Yang CY, Lo PY, Chen YH. Calcipotriol used as mono-

therapy or combination therapy with betamethasone dipropionate in the treat-

ment of nail psoriasis. Acta Derm Venereol. 2008;88(3):279-280.

22. Bourke JF, Iqbal SJ, Hutchinson PE. The effects of UVB plus calcipotriol on sys-

temic calcium homeostasis in patients with chronic plaque psoriasis. Clin Exp

Dermatol. 1997;22(6):259-261.

23. Messer G, Degitz K, Plewig G, Rocken M. Pretreatment of psoriasis with the vita-

min D3 derivative tacalcitol increases the responsiveness to 311-nm ultraviolet B:

results of a controlled, right/left study. Br J Dermatol. 2001;144(3):628-629.

24. Molin L; Calcipotriol-UVB Study Group. Topical calcipotriol combined with pho-

totherapy for psoriasis: the results of two randomized trials and a review of the

literature. Dermatology. 1999;198(4):375-381.

25. PrystowskyJH, Knobler EH,Muzio PJ. Oralcalcitriol (1,25-dihydroxyvitamin D3)

doesnot augment UVB phototherapy for plaque psoriasis.J Am Acad Dermatol.

1996;35(2, pt 1):272-274.

26. Ramsay CA, Schwartz BE, Lowson D, Papp K, Bolduc A, Gilbert M; The Cana-

dian Calcipotriol and UVB Study Group. Calcipotriol cream combined with twice

weekly broad-band UVB phototherapy: a safe, effective and UVB-sparing anti-

psoriatric combination treatment. Dermatology. 2000;200(1):17-24.

27. RimJH,ChoeYB, Youn JI.Positive effectof usingcalcipotriol ointmentwithnarrow-

band ultraviolet B phototherapy in psoriatic patients. Photodermatol Photoim-

munol Photomed. 2002;18(3):131-134.

28. Ring J, Kowalzick L, Christophers E, et al. Calcitriol 3 g g1 ointment in com-

bination with ultraviolet B phototherapy for the treatment of plaque psoriasis:

results of a comparative study. Br J Dermatol. 2001;144(3):495-499.

29. Woo WK, McKenna KE. Combination TL01 ultraviolet B phototherapy and topi-

cal calcipotriol for psoriasis:a prospectiverandomizedplacebo-controlledclini-

cal trial. Br J Dermatol. 2003;149(1):146-150.

30. Lauharanta J, Juvakoski T, Lassus A. A clinical evaluation of the effects of an

aromatic retinoid (Tigason),combination of retinoid and PUVA, and PUVAalone

in severe psoriasis. Br J Dermatol. 1981;104(3):325-332.

31. Lawrence CM, Marks J, Parker S, Shuster S. A comparison of PUVA-etretinate

and PUVA-placebo for palmoplantar pustular psoriasis. Br J Dermatol. 1984;

110(2):221-226.

32. Macdonald K, Holti G, Marks J. Is there a place for beta-carotene/canthaxanthin

in photochemotherapy for psoriasis? Dermatologica. 1984;169(1):41-46.

33. Matsunami E, Takashima A, Mizuno N, Jinno T, Ito H. Topical PUVA, etretinate,

and combined PUVA and etretinate for palmoplantar pustulosis: comparison of

therapeutic efficacy and the influences of tonsillar and dental focal infections.

J Dermatol. 1990;17(2):92-96.

34. Parker S, Coburn P, Lawrence C, Marks J, Shuster S. A randomized double-

blindcomparison of PUVA-etretinate andPUVA-placebo in the treatment of chronic

plaque psoriasis. Br J Dermatol. 1984;110(2):215-220.

35. Saurat JH, Geiger JM, Amblard P, et al. Randomized double-blind multicenter

study comparing acitretin-PUVA,etretinate-PUVA andplacebo-PUVA inthe treat-

ment of severe psoriasis. Dermatologica. 1988;177(4):218-224.

36. Tanew A, Guggenbichler A, Honigsmann H, Geiger JM, Fritsch P. Photochemo-

therapy for severe psoriasis without or in combination with acitretin: a random-

ized, double-blind comparison study. J Am Acad Dermatol. 1991;25(4):682-

684.

37. Christiansen JV, Holm P, Mller R, Reymann F, Schmidt H. Etretinate (Tigason)

and betamethasone valerate (Celeston valerate) in the treatment of psoriasis: a

double-blind, randomized, multicenter trial. Dermatologica. 1982;165(3):204-

207.

38. Gollnick H, Menter A. Combination therapy with tazarotene plus a topical corti-

costeroid for the treatment of plaque psoriasis. Br J Dermatol. 1999;140(suppl54):18-23.

39. GreenL, SadoffW. A clinicalevaluationof tazarotene 0.1% gel, with andwithout

a high-or mid-high-potencycorticosteroid, in patients withstable plaque psoriasis.

J Cutan Med Surg. 2002;6(2):95-102.

40. Lebwohl MG, Breneman DL, Goffe BS, et al. Tazarotene 0.1% gel plus cortico-

steroid cream in the treatment of plaque psoriasis. J Am Acad Dermatol. 1998;

39(4, pt 1):590-596.

41. Lebwohl M, Lombardi K, Tan MH. Duration of improvement in psoriasis after

treatment with tazarotene 0.1% gel plus clobetasol propionate 0.05% ointment:

comparison of maintenance treatments. Int J Dermatol. 2001;40(1):64-66.

42. Poulin YP. Tazarotene0.1% gel in combination withmometasone furoate cream

in plaque psoriasis: a photographic tracking study. Cutis. 1999;63(1):41-48.

43. GreenC, LakshmipathiT, Johnson BE,FergusonJ. A comparison of theefficacy

and relapse rates of narrowband UVB (TL-01) monotherapy vs etretinate (re-

TL-01) vs etretinate-PUVA(re-PUVA)in the treatment of psoriasispatients. Br J

Dermatol. 1992;127(1):5-9.

44. Koo JY, Lowe NJ, Lew-Kaya DA, et al. Tazarotene plus UVB phototherapy in thetreatment of psoriasis. J Am Acad Dermatol. 2000;43(5, pt 1):821-828.

45. Lowe NJ, Prystowsky JH, Bourget T, Edelstein J, Nychay S, Armstrong R. Ac-

itretin plus UVB therapy for psoriasis: comparisons with placebo plus UVB and

acitretin alone. J Am Acad Dermatol. 1991;24(4):591-594.

46. Ruzicka T, Sommerburg C, Braun-Falco O, et al. Efficiency of acitretin in com-

bination with UV-B in the treatment of severe psoriasis. Arch Dermatol. 1990;

126(4):482-486.

47. Brockow T, Schiener R, Franke A, Resch KL, Peter RU. A pragmatic randomized

controlled trialon the effectiveness of highly concentrated saline spa water baths

followed by UVB compared to UVB only in moderate to severe psoriasis. J Al-

tern Complement Med. 2007;13(7):725-732.

48. Brockow T, Schiener R, Franke A, Resch KL, Peter RU. A pragmatic randomized




12/12

controlled trial on the effectiveness of low concentrated saline spa water baths

followed by ultraviolet B (UVB) compared to UVB only in moderate to severe

psoriasis. J Eur Acad Dermatol Venereol. 2007;21(8):1027-1037.

49. Dawe RS, Yule S, Cameron H, Moseley H, Ibbotson SH, Ferguson J. A random-

ized controlled comparison of the efficacy of Dead Sea salt balneophototherapy

vs narrowband ultraviolet B monotherapy for chronic plaque psoriasis. Br J

Dermatol. 2005;153(3):613-619.

50. Gambichler T, Rapp S, Senger E, Altmeyer P, Hoffmann K. Balneophototherapy

of psoriasis: highly concentrated saltwater versus tap water: a randomized, one-

blind, right/leftcomparativestudy.Photodermatol Photoimmunol Photomed. 2001;

17(1):22-25.

51. Leaute-Labrze C, SaillourF, Chene G, et al. Saline spa wateror combined water

and UV-B for psoriasis vs conventional UV-B: lessons from the Salies de Bearnrandomized study. Arch Dermatol. 2001;137(8):1035-1039.

52. Legat FJ, Hofer A, Wackernagel A, et al. Narrowband UV-B phototherapy, alef-

acept, and clearance of psoriasis. Arch Dermatol. 2007;143(8):1016-

1022.

53. Ortonne JP, Khemis A, Koo JY, Choi J. An open-label study of alefacept plus ul-

traviolet B light as combination therapy for chronic plaque psoriasis. J Eur Acad

Dermatol Venereol. 2005;19(5):556-563.

54. Jacobe H, WinterfieldL, KimF, Huet-AdamsB, Cayce R. Theroleof narrowband

UV-Bplusalefaceptcombination therapyin thetreatment of psoriasis [comment].

Arch Dermatol. 2008;144(8):1067-1068.

55. Legat FJ, Hofer A, Wackernagel A, et al. The role of narrowband UV-B plus alef-

acept combination therapy in the treatment of psoriasis [reply]. Arch Dermatol.

2008;144(8):1068-1069.

56. Asawanonda P, Nateetongrungsak Y. Methotrexate plus narrowband UVB pho-

totherapyversusnarrowbandUVB phototherapyalonein thetreatment of plaque-

type psoriasis: a randomized, placebo-controlled study. J Am Acad Dermatol.

2006;54(6):1013-1018.57. MahajanR, KaurI, KanwarAJ. Methotrexate/narrowbandUVB phototherapycom-

bination vs narrowband UVB phototherapy in the treatment of chronic plaque-

type psoriasis:a randomizedsingle-blinded placebo-controlled study. J EurAcad

Dermatol Venereol. 2010;24(5):595-600.

58. Amornpinyokeit N, Asawanonda P. 8-Methoxypsoralen creamplus targeted nar-

rowband ultraviolet B for psoriasis. Photodermatol Photoimmunol Photomed.

2006;22(6):285-289.

59. Seckin D, Usta I, Yazici Z, Senol A. Topical 8-methoxypsoralen increases the ef-

ficacy of narrowband ultraviolet B in psoriasis. Photodermatol Photoimmunol

Photomed. 2009;25(5):237-241.

60. Bagel J. LCD plus NB-UVB reduces time to improvement of psoriasis vs NB-

UVB alone. J Drugs Dermatol. 2009;8(4):351-357.

61. Menkes A, Stern RS, Arndt KA. Psoriasis treatment with suberythemogenic ul-

traviolet B radiation and a coal tar extract. J Am Acad Dermatol. 1985;12(1, pt

1):21-25.

62. Agius A, Borg E, Pace JL. The value of colloid dressings in psoriasis. Adv Exp

Med Biol. 1999;455:377-385.63. Kragballe K, Larsen FG.A hydrocolloid occlusive dressingplustriamcinolone ace-

tonide cream is superior to clobetasol cream in palmo-plantar pustulosis. Acta

Derm Venereol. 1991;71(6):540-542.

64. Volden G, Kragballe K, Van De Kerkhof PC, Aberg K, White RJ. Remission and

relapse of chronic plaque psoriasis treated once a week with clobetasol propio-

nateoccludedwith a hydrocolloiddressingversustwice daily treatment withclo-

betasol propionate alone. J Dermatolog Treat. 2001;12(3):141-144.

65. Koo J, Cuffie CA, Tanner DJ, et al. Mometasone furoate 0.1%salicylic acid 5%

ointment versusmometasonefuroate 0.1%ointment in the treatment of moderate-

to-severe psoriasis: a multicenter study. Clin Ther. 1998;20(2):283-291.

66. Tiplica GS, Salavastru CM. Mometasone furoate 0.1% and salicylic acid 5% vs

mometasone furoate 0.1% as sequential local therapy in psoriasis vulgaris.

J Eur Acad Dermatol Venereol. 2009;23(8):905-912.

67. Dover JS, McEvoy MT, Rosen CF, Arndt KA, Stern RS. Are topical corticoste-

roids useful in phototherapy for psoriasis? J Am Acad Dermatol. 1989;20(5, pt

1):748-754.

68. Larko O, Swanbeck G, Svartholm H. The effect on psoriasis of clobetasol pro-

pionate used alone or in combination with UVB. Acta Derm Venereol. 1984;

64(2):151-154.

69. Ezquerra GM,Regana MS,Millet PU.Combinationof acitretinand oralcalcitriolfor

treatment of plaque-type psoriasis. Acta Derm Venereol. 2007;87(5):449-450.

70. GiannettiA, CoppiniM, Bertazzoni MG,et al.Clinical trialof theefficacyand safety

of oraletretinate withcalcipotriolcream comparedwith etretinatealone in moderate-

severe psoriasis. J Eur Acad Dermatol Venereol. 1999;13(2):91-95.

71. Rim JH, Park JY, Choe YB, Youn JI. The efficacy of calcipotriol acitretin com-

binationtherapyfor psoriasis: comparisonwith acitretinmonotherapy.AmJ Clin

Dermatol. 2003;4(7):507-510.

72. van de Kerkhof PC, Cambazard F, Hutchinson PE, et al. The effect of addition of

calcipotriol ointment (50 g/g) to acitretin therapy in psoriasis. Br J Dermatol.

1998;138(1):84-89.

73. Carroll CL,Clarke J, Camacho F, Balkrishnan R, Feldman SR.Topicaltacrolimus

ointmentcombined with 6% salicylic acidgel for plaquepsoriasistreatment. Arch

Dermatol. 2005;141(1):43-46.74. Gisondi P, Del Giglio M, Di Francesco V, Zamboni M, Girolomoni G. Weight loss

improvesthe responseof obese patientswith moderate-to-severechronic plaque

psoriasis to low-dose cyclosporinetherapy:a randomized,controlled, investigator-

blinded clinical trial. Am J Clin Nutr. 2008;88(5):1242-1247.

75. Reitamo S, Spuls P, Sassolas B, Lahfa M, Claudy A, Griffiths CE; Sirolimus Eu-

ropean Psoriasis Study Group. Efficacy of sirolimus (Rapamycin) administered

concomitantly with a subtherapeutic dose of cyclosporin in the treatment of se-

vere psoriasis: a randomized controlled trial. Br J Dermatol. 2001;145(3):438-

445.

76. Salim A, Tan E, Ilchyshyn A, Berth-Jones J. Folic acid supplementation during

treatment of psoriasis with methotrexate: a randomized, double-blind, placebo-

controlled trial. Br J Dermatol. 2006;154(6):1169-1174.

77. Zachariae C, MrkNJ, ReunalaT, et al.The combinationof etanercept andmetho-

trexate increases the effectiveness of treatment in active psoriasis despite inad-

equate effect of methotrexate therapy. Acta Derm Venereol. 2008;88(5):495-

501.

78. Marsland AM, Chalmers R, Hollis S, Leonardi-Bee J, Griffiths CE. Interventionsfor chronic palmoplantar pustulosis. Cochrane Database Syst Rev. 2006;(1):

CD001433.

79. Pocock SJ, Ware JH. Translating statistical findings into plain English. Lancet.

2009;373(9679):1926-1928.


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