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An investigator-initiated, double-blind,vehicle-controlled pilot study: Assessment for

tachyphylaxis to topically occluded halobetasol0.05% ointment in the treatment of psoriasis

Tali Czarnowicki, MD,a Rita V. Linkner, MD,c Mayte Suarez-Fari~nas, PhD,b

Arie Ingber, MD,d and Mark Lebwohl, MDc

New York, New York, and Jerusalem, Israel

Background:Topical corticosteroids are the most common first-line treatment for psoriasis. Tachyphy-laxis, a decreased response to treatment with repetitive application of the drug, is a controversialphenomenon associated with topical corticosteroid treatment.

Objective: We sought to prove or disprove tachyphylaxis to occluded halobetasol 0.05% versus vehicle.

Methods:Patients with plaque psoriasis were recruited to this study. The study involved 3 phases (1, 2A,and 2B) with each phase being separated by a treatment vacation period. In phases 1 and 2A, 2 plaques

were randomized to either halobetasol 0.05% or vehicle ointment application. In phase 2B, halobetasol0.05% was applied to both. Target Lesion Severity Scale was used for clinical assessment.

Results:Twenty patients were enrolled. No difference in time to clearance (P= .88) or time to recurrence(P = .92) of the treated plaques was found between phases 1 and 2A. Percentage of improvement washigher in phase 2A compared with phase 1 (89.4%, P\ .05 vs 71%, P\ .05), as a result of reductionof vehicle effect. In phase 2B, a greater improvement was found for previously corticosteroid-treatedplaques.

Limitations:Limitations are small sample size and 1 corticosteroid tested.

Conclusion: No evidence of tachyphylaxis to the topical corticosteroid halobetasol 0.05% ointmenttreatment in patients with plaque psoriasis was found. ( J Am Acad Dermatol 2014;71:954-9.)

Key words:compliance; corticosteroid; halobetasol 0.05%; psoriasis; tachyphylaxis; vehicle.

Topical corticosteroids are the mostcommonly prescribed therapy for psoria-sis.1-3

The phenomenon where a rapid decrease inresponse to an active agent is exhibitedafter repeatedadministration of the drug is known as tachyphylaxisand is often reported as one of the more troublingfeatures associated with topical corticosteroid use.4

Tachyphylaxis to topical corticosteroids hasbeen previously demonstrated in the experimentalsetting.5,6 For instance, in the hairless mouse model,tachyphylaxis occurred to the vasoconstrictive andDNA-suppressing effects of topically applied

corticosteroids.

7

Elevated histamine levels have been cited asa potential contributor in the pathogenesis of

Laboratory for Investigative Dermatologya and Center for Clinical

and Translational Science,b Rockefeller University, New York;

Department of Dermatology, Icahn School of Medicine at

Mount Sinai, New Yorkc; and Department of Dermatology,

Hadassah University Hospital, Jerusalem.d

Funding sources: None.

Disclosure: Dr Lebwohl was an investigator for Ranbaxy Labora-

tories Ltd during the years 2012 to 2013. Drs Czarnowicki,

Linkner, Suarez-Fari~nas, and Ingber have no conflicts of interest

to declare.

Accepted for publication May 15, 2014.

Reprint requests: Tali Czarnowicki, MD, Laboratory for

Investigative Dermatology, Rockefeller University, Box 178,

1230 York Ave, New York, NY 10065. E-mail: tczarnowic01@

rockefeller.edu.

Published online June 11, 2014.

0190-9622/$36.00

2014 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2014.05.040

954
mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.jaad.2014.05.040http://dx.doi.org/10.1016/j.jaad.2014.05.040mailto:[email protected]:[email protected]


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psoriasis.8 In a comparison of tachyphylaxis (definedhere as histamine-induced wheal suppression) to theaction of occluded 0.05% clobetasol propionatebetween normal-appearing and dermatitic skin, ithas been shown that tachyphylaxis appears earlierin dermatitic skin.9 Another study that measuredhistamine-induced wheal suppression on normal-appearing skin and included10 healthy volunteersconfirmed the occurrence oftachyphylaxis to topical cor-ticosteroids. When the skinwas pricked with histamineacid phosphate solution onalternate days and occludeddaily with fluocinolone ace-tonide cream, 0.1%, maximalwheal suppression by the

topical steroid was observedon day 8. However,by day 14, there wastotal tolerance to topicalcorticosteroid with littlesuppression noted of thehistamine-induced wheal.6

Given histamines potential role in psoriasispathogenesis, along with the diseased psoriaticskin, loss of histamine suppression by repeatedlytopically applied corticosteroids might contribute toaccelerated corticosteroids efficacy reduction in

psoriasis treatment, ie, tachyphylaxis.In a dermatologists survey regarding tachyphy-

laxis, 57% perceived that tachyphylaxis doesoccur. Nevertheless, the same study also included32 patients with plaque psoriasis treated withbetamethasone dipropionate 0.05%over 12 weeksand failed to show tachyphylaxis.10

Tachyphylaxis is still a controversial phenomenon,and some believe poor patient compliance to topicaltherapy to be the cause.11 To date, a study thateffectively tests the hypothesis of tachyphylaxis totopical corticosteroids in a double-blind, vehicle-

controlled fashion has yet to be conducted. In thecurrent study, we aimed to either prove or disprovethe phenomenon of tachyphylaxis to the class 1superpotentcorticosteroidhalobetasol 0.05%ointmentversus a vehicle ointment under occlusion, on patientswith bilateral symmetric psoriasis plaques. It should benoted that the efficacy and safety of superpotentcorticosteroid occlusion for a 1-week period hasbeen previously tested in patients with psoriasis.12-14

METHODSThis was an investigator-initiated, double-blind,

bilateral comparison study that involved 20

patients with psoriasis. Icahn School of Medicineat Mount Sinai (New York, NY) and HadassahMedical Organization (Jerusalem, Israel) part-icipated in the study between the years 2010 and2012. Investigational review board approvals wereobtained from the Program for the Protectionof Human Subjects of Icahn School of Medicine at

Mount Sinai and the HelsinkiCommittee of HadassahMedical Organization.

Each of the 20 adult sub-jects enrolled in the studywas given a diagnosis ofplaque psoriasis, affecting1% to 10% body surfacearea and had at least 2symmetric lesions suitablefor evaluating response to

test agents. Inclusion andexclusion criteria appear inTable I (available at http://www.jaad.org).

Target Lesion SeverityScale (TLSS),15 a validatedtool for psoriasis severity

assessment, was used to evaluate severity and toassess clinical efficacy. It consists of a sum score of 3clinical severity parameters (scaling, erythema,plaque elevation/induration; each graded on a 5-point severity scale; 0 = clear, 1 = almost clear,

2 = mild, 3 = moderate, and 4 = severe/very severe)with a sum score ranging between 0 and 12 points. Amaximum of 50 g of halobetasol 0.05% ointment wasused per subject over the 20-week study period.

At the baseline visit, both plaques had to begraded as at least moderate in severity (TLSS score$ 6) to qualify for inclusion. Clearance was definedas the time point when no or only mild erythemawithout induration or scaling (TLSS score # 1) wasreached. Photographs were taken.

The study involved 3 phases (1, 2A, and 2B),which were separated by an interim treatment

vacation period, permitting treatment plaques toreturn to baseline TLSS score. At the baselinevisit of phase 1, a class 1 topical corticosteroid,halobetasol 0.05% ointment (Ultravate, RanbaxyLaboratories Ltd, Princeton, NJ), was applied underocclusion to the randomized treatment plaque andvehicle ointment (Aquaphor, Beiersdorf, Wilton, CT)was applied under occlusion to the randomizedvehicle plaque. By having an unblinded investigatorapply and occlude both plaques in a randomizedfashion, the study design controlled for thepossibility of nonadherent patient self-dosing. The

investigator then placed a hydrocolloid dressing

CAPSULE SUMMARY

d Tachyphylaxis to topical corticosteroids

in the treatment of plaque psoriasis is

currently in dispute.

d Application of either halobetasol 0.05%

ointment or vehicle ointment under

occlusion to 2 psoriasis plaques in 20

patients did not demonstrate

tachyphylaxis.

d It is uncertain whether these findings

observed after abbreviated application

periods are representative of outcomes

in clinical practice.

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over each of the 2 lesions and instructed the subjectto leave the dressing in place until the next studyvisit. During each weekly visit, plaque severity wasassessed for both plaques by the TLSS. Physicianclinical investigators performed all clinical assess-ments. Phase 1 was considered completed when 1 ofthe 2 plaques achieved TLSS score of 1 or less.

After both plaques returned to baseline severity,phase 2A commenced. If either of the plaques didnot regain baseline severity, the patient did notcontinue to the next phase. Phase 2A of the studywas designed to assess for tachyphylaxis byexamining whether or not a change in response totopical corticosteroid therapy occurs during arepeated second treatment cycle. Phase 2A, likephase 1, was considered completed when 1 of the2 plaques achieved TLSS score of 1 or less.

Phase 2B was designed to assess for tachyphylaxis

when the comparator lesion, previously treated withvehicle under occlusion, was switched to halobeta-sol under occlusion. An unblinded investigatorapplied and occluded halobetasol ointment to bothplaques, and assessed plaque severity during eachweekly visit. Phase 2B was considered completedwhen 1 of the 2 plaques achieved TLSS score of 1 orless.

Time to clearance and time to recurrence wereevaluated and compared between study phases.Time to clearance was defined as time needed forthe halobetasol-treated plaque to achieve TLSS score

of 1 or less. Time to recurrence was defined as thetime needed for the halobetasol-treated plaque toreturn to its baseline severity. Tachyphylaxis of thehalobetasol ointment plaque was defined as either ofthe following: (1) a longer number of days toclearance in phase 2A versus phase 1 or (2) shorternumber of days to recurrence in phase 2B versusphase 2A.

RESULTSDemographics

In all, 20 patients with moderate to severe

psoriasis were enrolled. There were 9 female and11 male subjects. Ages ranged between 19 and65 years (mean 41 years). Patients had psoriasison average 19.7 years (range 4-60 years). Fig 1demonstrates the study design including treatmentand vacation-interval durations, number of patients,and study plaques dynamics.

Time to clearance and time to recurrenceTo compare the time to clearance and time to

recurrence between phases, we used Kaplan Meierand Cox proportional models stratified by patients,

which depict the estimates of the survival function

for time to clearance for phases 1 and 2A and fortime to recurrence after these phases for thecorticosteroid-treated plaques. No differences werefound between phases 1 and 2A in terms of time toclearance (P= .88) or time to recurrence (P= .92) forthe robust score (log rank) test and Wald test. Theresults show that the definition of tachyphylaxis wasinvalidated, or more basically, halobetasol-treatedplaques took the same amount of time to clear andthe same amount of time to recur. Baseline TLSSscoring did not affect the time to clearance. Inaddition, the TLSS degree of improvement in theprevious phase did not have any effect on the time torecurrence. An additional Spearman correlation wasdone to verify the correlation between time to clearand time to recur on the different phases. The resultsshowed no correlation between time to clearanceand time to recurrence (data not shown).

Table IIsummarizes the change and the percentimprovement differences in TLSS scoring, which arefound in Fig 2. The treatment effect seems to begreater in phase 2A than in phase 1 (89.4%,P\.05 vs71%, P\ .05) because of reduction of the vehicleeffect. The final scores for the halobetasol-treatedplaques did not change from phase 1 to 2A, but therewas a reduction on the vehicle effect. Tachyphylaxisis defined here as less improvement in thehalobetasol plaque in phase 2A versus phase 1.Given this definition, the halobetasol plaque didnot exhibit tachyphylaxis; however, the vehicle-

occluded plaque did (P= .0084).

Overall response to treatmentIn phase 2B both plaques had halobetasol

applied. Those plaques that were previously treatedwith halobetasol in phase 2A (and phase 1) showed alarger percent improvement in TLSS scoring versusthose previously vehicle-treated plaques in phase2A (and phase 1). This implies that thoseplaques previously treated with halobetasol notonly continued to sustain but also amplified theimprovement when additional corticosteroid was

applied. The results are extremely similar if responseby week is measured (Fig 3). Although thedifferences did not reach significance, tachyphylaxisto the topical corticosteroid was not evident.

DISCUSSIONOur study results show no evidence of tachyphy-

laxis to the occluded topical superpotent corticoste-roid halobetasol 0.05% ointment in 20 patients withplaque psoriasis.

Occlusion itself transiently improves psoria-sis.16-18 In our study, occlusion may account for

some of the clinical improvement achieved in the

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vehicle plaques. In addition, we chose the regimenof weekly-occluded application of the corticoste-roid, as it is superior to twice-a-day nonoccludedapplication19 and to control for self-dosing andnonadherence.

Psoriasis is a chronic disorder and patients oftenexpress steroid phobia, which can limit adequatetreatment.20 In 2004, Zaghloul and Goodfield21

evaluated compliance with topical and oral therapiesin patients with psoriasis using either pill counts ortube weights to objectively measure medicationadherence. They showed that the mean medicationadherence for oral, topical, and combined treatmentswas 46%, 72%, and 74%, respectively. In light of thesefacts, poor patient compliance to topical therapy isoften cited as a better explanation for tachyphylaxisthan loss of corticosteroid receptor function.22 In ourstudy, the treatment was investigator applied, elim-inating patient self-compliance, which may explainwhy tachyphylaxis was not found.

Fig 1. Plaque psoriasis. Study design. The flow chart exemplifies the 3 study phases (1, 2A, and2B), time duration for each phase, duration of interim vacation between phases, andhalobetasol versus vehicle dynamics during the study. TLSS, Target Lesion Severity Scale.

Table II. Target Lesion Severity Scale change(difference between halobetasol and vehicle) andpercent improvement in Target Lesion SeverityScale

Change in TLSS Percent improvement

Phase 1 5.90 (0.57) 70.82 (6.33)

Halobetasol vs

vehicle

P= 1.96 3 1013 P= 3.55 3 1014

Phase 2A

7.25 (0.62) 89.4 (9.27)Halobetasol vs

vehicle

P= 9.7 3 1015 P= 6.6 3 1016

Phase 1 vs 2A 1.35 (0.83) 18.57 (9.497)

Halobetasol vs

vehicle

P= .13 P= .057

Phase 1 vs 2A 1.44 (0.60) 18.58 (6.71)

Vehicle P= .02 P= .0084

Phase 1 vs 2A 0.09 (0.6) 0 (8.03)

Halobetasol P= .88

Numbers in parenthesis are SEM.

TLSS, Target Lesion Severity Scale.




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In the current study, the vehicle-treated compar-ator lesions underwent TLSS improvement both inphases 1 and 2A, with less improvement for phase2A, and thereby evidence of slight tachyphylaxis wasshown for the vehicle ointment. Systemic absorptionof the halobetasol was not assessed and mightprovide a possible explanation for the improvementseen in the vehicle plaques, although this isspeculative.

Emollients positive effect on psoriasis23 mayalternatively account for the improvement that wasobserved in the vehicle-treated plaques. Anotherpotential explanation is that the vehicle (or occlusionof the vehicle) is not inert but has biological activity.

One explanation for the failure to show tachyphy-laxis is the length of the interim treatment vacationinterval between phases that was implemented in thestudy design to permit plaques to return to baselineTLSS score. This time frame may have permittedcorticosteroid receptors to recover and thereforetachyphylaxis would be prevented. This observation

has important therapeutic implications as it supportsthe use of regimens using vacation periods whenusing high-potency corticosteroids.24

There were several limitations to this trial. Only 1high-potency-class corticosteroid was tested, andunder occlusion, causing uncertainty regarding othersteroid potency classes and unconcluded applica-tion. Even though not more than a fingertip amountof halobetasol was applied, a topical medicationdose was not measured accurately. In addition, thesmall sample size of this pilot study limited moresophisticated statistical approaches. Finally, it is

uncertain whether our findings observed after

abbreviated application periods are representativeof outcomes in clinical practice.

In light of psoriasis prevalence and the high rate oftopical corticosteroid prescription, an investigationinto tachyphylaxis is of utmost significance for

establishing good clinical practice. In the future,alternative study designs that will divide patientsaccording to different corticosteroid occlusion timeperiods, various corticosteroids classes of potency,and different dermatologic indications for corticoste-roid prescription (eg, psoriasis vs atopic dermatitis)will not only shed more light on the tachyphylaxisphenomenon but will also help to delineate itsmechanisms better. In addition, more long-term ran-domized, double-blind studies with larger cohortscould be further explored to evaluate whether thiscontroversial phenomenon truly occurs.

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Fig 2. Plaque psoriasis. Treatment effect by phase.Percent improvement for halobetasol was similar in

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Fig 3. Plaque psoriasis. Percent improvement of thehalobetasol and vehicle plaques in phase 2B accordingto the treatment in previous phases. Plaques that werepreviously halobetasol treated showed a larger percentimprovement in Target Lesion Severity Scale scoring

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Table I. Inclusion and exclusion criteria

Inclusion criteria

Subjects must be at least 18 y of age and in good general health as confirmed by a medical history

Females of childbearing potential must have a negative urine pregnancy test on baseline/d 0 and must agree to use

adequate birth control methods during the entire study

Stable plaque psoriasis affecting 1% to 10% body surface areaAt least 2 symmetric lesions 1-5 cm in diameter, preferentially on bilateral limbs (or separated by at least 15 cm)

The severity of the disease for each target lesion at baseline/wk 0 must be rated at least 2 (mild) for each of the key

psoriasis characteristics on the Target Lesion Severity Scale

Exclusion criteria

Pregnancy and/or lactation

Known hypersensitivity to any components of the test medication

Nonplaque psoriasis (eg, guttate, erythrodermic)

Psoriasis involves only the scalp, face, groin, axillae, and/or other intertriginous areas

Subjects requiring any other medication (topical or systemic) that may affect the course of the disease during the study

period as determined by the study investigators

Subjects using biologics or any other systemic treatment (eg, immunosuppressants, acitretin) for psoriasis within 12 wk of

entering the study

Subjects using systemic corticosteroids within 28 d of entering the study

Subjects using topical corticosteroids or other topical therapies (other than emollients) at the target area locations within

14 d of entering the study

Overt pre-existing telangiectasia or skin atrophy at intended treatment sites


959.e1 Czarnowicki et al

(rini)an investigator-initiated, double-blind, vehicle-controlled pilot study assessment for...

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