REVIEW

Optimizing Anti-Inflammatoryand Immunomodulatory Effects of Corticosteroidand Vitamin D Analogue Fixed-Dose CombinationTherapy

Siegfried Segaert . Neil H. Shear . Andrea Chiricozzi . Diamant Thaci .

Jose-Manuel Carrascosa . Helen Young . Vincent Descamps

Received: June 30, 2017 / Published online: August 7, 2017� The Author(s) 2017. This article is an open access publication

Abstract: Fixed-dose combination topical ther-apy with corticosteroid and vitamin D analogprovides effective treatment and possiblelong-term management of psoriasis. Theanti-inflammatory and immunomodulatoryeffects of corticosteroids and vitamin D analogsin treating psoriasis are well investigated; theircomplementary effects lead to the disruption ofthe inflammatory feedback loop underlyingpsoriasis pathogenesis. Recent preclinical datashowed that combination therapy is moreeffective than monotherapies of the activeingredients in preventing activation of restingpro-inflammatory cells, inducing

immunomodulation, reducing inflammatoryresponses by regulating T cell production, andnormalizing keratinocytes. The increasedunderstanding of the mechanism of action offixed-dose combination therapy from preclini-cal studies is supported by several clinicalstudies. As the efficacy of topical therapy iscorrelated with the skin penetration of theactive ingredients, new drug delivery systemshave been developed. The fixed-dose combina-tion Cal/BD aerosol foam creates a modifiedsupersaturated formulation when applied to theskin, which is maintained for at least 26 h in thelaboratory setting. Clinical studies havedemonstrated superior efficacy of fixed-dosecombination calcipotriol (Cal) 50 lg/g andbetamethasone dipropionate (BD) 0.5 mg/gaerosol foam compared with monotherapies of

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S. Segaert (&)Dermatology Department, University HospitalLeuven, Leuven, Belgiume-mail: Siegfried.Segaert@med.kuleuven.be

N. H. ShearDivision of Dermatology, Department of Medicine,Sunnybrook Health Sciences Center and Universityof Toronto, Toronto, Canada

A. ChiricozziDermatology Department, University of Pisa, Pisa,Italy

D. ThaciComprehensive Center for Inflammation Medicine,University Hospital Schleswig-Holstein, Universityof Lubeck, Lubeck, Germany

Jose-ManuelCarrascosaDepartment of Dermatology, Hospital UniversitariGermans Trias i Pujol, Universitat Autonoma ofBarcelona, Badalona, Spain

H. YoungDivision of Musculoskeletal and DermatologicalSciences, The Dermatology Research Centre, TheUniversity of Manchester, Manchester AcademicHealth Sciences Centre, Manchester, UK

V. DescampsDepartment of Dermatology, Bichat-Claude BernardHospital, Paris 7 Denis Diderot University, Paris,France

Dermatol Ther (Heidelb) (2017) 7:265–279

DOI 10.1007/s13555-017-0196-z

the active ingredients. Furthermore, Cal/BDaerosol foam has shown significantly improvedefficacy compared with more traditional for-mulations, such as Cal/BD ointment and gel, inother studies. Calcipotriol also mitigates risksassociated with betamethasone dipropionateand vice versa, resulting in the favorable safetyprofile observed with fixed-dose combinationtreatment. Recent data also suggest that fix-ed-dose combination treatment could providelong-term management of psoriasis, althoughfurther clinical investigations are needed.Overall, these data support the value of fix-ed-dose combination therapy of corticosteroidand vitamin D analog and highlight the addedpotential of innovative drug delivery for thetreatment of psoriasis.Funding: LEO Pharma.

Keywords: Anti-inflammatory; Betamethasonedipropionate; Calcipotriol; Fixed-dosecombination; Plaque psoriasis

INTRODUCTION

Plaque psoriasis is a chronic, inflammatory,immune-mediated skin disorder characterizedby recurrent itchy, scaly, erythematous plaques[1]. The burden of psoriasis on a patient’squality of life (QoL) may be considerable; thisburden is not only physical (e.g., painful anddebilitating effects of plaques), but also psy-chologic, with effects including depression,alexithymia, coping with feelings of stigmati-zation, and suicide ideation [2].

Topical treatments containing corticos-teroids and vitamin D analogs, used separately,together, or in a fixed combination, are essen-tial and well-established first-line treatments forpatients with mild-to-moderate psoriasis [3, 4].Although patients with moderate-to-severepsoriasis are commonly treated with pho-totherapy and systemic therapies, includingbiologic agents [5, 6], the combination of thesetherapies with topical treatments can help toindividually optimize disease control andlong-term management [7].

The increased understanding of psoriasispathogenesis has provided further insights into

therapeutic targets, and new treatments forpsoriasis are becoming available [5, 6, 8]. Thatbeing said, critical issues related to topicaltherapies are still unresolved, including thepoor treatment adherence due to perceived lackof efficacy and the cumbersome nature ofavailable treatments [9, 10]. Although there areno new compounds available, considerableresearch has been undertaken for topical treat-ments to: (1) improve efficacy by enhancing thedrug delivery and bioavailability of activeingredients, without compromising safety[11, 12], (2) enhance the convenience of appli-cation, and (3) increase the variety of availableformulations [11]. New topical formulationswith greater efficacy and more convenientapplication could lead to better adherence andprovide subsequent long-term maintenance of adisease-free state.

This review will examine the anti-inflam-matory and immunomodulatory mechanismsof action of fixed-dose combination corticos-teroid and vitamin D analog versus monother-apies of the active ingredients, the drug deliverychallenges, and the clinical relevance of thesedata. The article presented here is based onpreviously conducted studies and does notinvolve any new studies of human or animalsubjects performed by any of the authors.

THE CURRENT UNDERSTANDINGOF PSORIASIS PATHOGENESIS

In individuals with a genetic predisposition,environmental factors, such as physical andpsychologic stress, may trigger the initiation ofpsoriasis, beginning with the activation ofdendritic cells. The key steps in psoriasispathogenesis are summarized in Fig. 1, withfurther descriptions below [1, 13].1. Dendritic cell cytokine release The skin inflam-

matory response is elicited by activatedinflammatory dendritic cells, which secretepro-inflammatory cytokines, such as inter-leukin (IL)-23, IL-12, and tumor necrosisfactor (TNF)-a [1, 13, 14].

2. Activation of the adaptive immune responseCytokines produced by dendritic cells alsopromote the differentiation and activation

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of naıve, or resting, T-cells to effector,helper (Th1/17), and cytotoxic (Tc1/17)T-cells. Evidence also suggests that thealtered balance between helper T-cells(Th1 and Th2) contributes to psoriasispathogenesis by further promoting autoim-mune reactions [1, 15–18].

3. Type 1 T-cell cytokine release The activatedTh1 and Tc1 cells within the skin releaseTNF-a and interferon (IFN)-c, which furthersupport the activation and maturation ofdendritic cells and also promote ker-atinocyte activation [1, 13, 15, 16, 19].

4. Type 17 T-cell cytokine release Similarly,activated Th17 and Tc17 cells within theskin release IL-17 and IL-22, which promotekeratinocyte activation [13, 15, 16, 19, 20].

5. Keratinocyte activation The activation of ker-atinocytes promotes their hyperproliferationand atypical differentiation, causing psoriaticplaque formation on the skin [16, 21–23].

6. Activation of the innate immune responseInnate immune cells, such as neutrophils,may respond quickly to IL-17 [21].

7. Keratinocyte pro-inflammatory mediator releaseThis in turn leads to the production ofadditional inflammatory mediators, includ-ing IL-6, IL-8, IL-17C, IL-20, TNF-a, IFN-c,and antimicrobial peptides (AMPs), whichrecruit and activate cells of the innate andadaptive immune system [16, 21, 24–26].Interactions between the keratinocytes andextracellular matrix (ECM) also promotetissue reorganization and the deposition ofthe ECM [1, 13, 17, 26, 27].

A pro-inflammatory feedback loop is thenestablished among keratinocytes, immune cells,and components of the extracellular matrix(e.g., collagen), leading to sustained, active skininflammation and subsequent reorganization ofthe ECM [1, 15, 16].

Fig. 1 Key components in the pathogenesis of psoriasis. AMPs antimicrobial peptides, DC dendritic cell, IL interleukin,IFN interferon, Tc cytotoxic T-cell, Th T-helper cell, TNF tumor necrosis factor

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CORTICOSTEROID AND VITAMIN DANALOG COMBINATION THERAPYRESULTS IN INCREASEDEFFECTIVENESS VERSUSMONOTHERAPYIN THE TREATMENT OF PSORIASIS

Corticosteroids and vitamin D analogs comple-ment one another in treating the key patho-genic factors of plaque psoriasis [16, 28–30].Corticosteroids have been used for more than50 years for the treatment of psoriasis [31, 32],and their immunosuppressive effects are criticalfor inhibiting the pro-inflammatory environ-ment and T-cell activation [15]. Vitamin Danalogs exert normalizing effects on thehyperproliferation and abnormal differentia-tion of keratinocytes and also haveimmunomodulatory effects [15, 28].

The treatment goal is to clear the psoriaticplaques by inhibiting the underlying inflam-mation and normalizing skin homeostasis, ker-atinocyte proliferation, and differentiation andto provide immunomodulation. Combinationtherapy, unlike monotherapies, has been shownto address all these treatment goals as supportedby preclinical data and is further discussedbelow.• Dendritic cell cytokine release Corticosteroids

and vitamin D analogs both inhibit therelease of cytokines, such as IL-23, whichare known to stimulate the innate andadaptive immune systems. Furthermore,studies with combination treatment inin vitro cultured dendritic cells have shownadditive effects, leading to greater inhibitioncompared with monotherapies of the activeingredients (Fig. 2, adapted from Lovatoet al. [27]).

• Th1-cell cytokine release Combination treat-ment inhibits TNF-a secretion from cyto-toxic Th1-cells, preventing further activationand maturation of dendritic cells and acti-vation of keratinocytes (Fig. 3, adapted fromBailey et al. [33]) [17, 27].

• Th17-cell cytokine release Data have shownthat pro-inflammatory cytokines (e.g.,IL-17A) were inhibited significantly more

with combination treatment thanmonotherapies of the active ingredients incultured and activated cytotoxic and helperT-cells (Figs. 2, 3) [17, 27]. Reduction of thesepro-inflammatory cytokines can inhibit ker-atinocyte hyperproliferation and abnormaldifferentiation.

• Th2-cell cytokine release Although corticos-teroids, such as betamethasone dipropi-onate, suppress IL-10 secretion, vitamin Danalogs, such as calcipotriol, induce Th2-cellproduction (Fig. 2) [27].

• Keratinocyte pro-inflammatory mediator releaseKeratinocytes in psoriatic plaques releaseinflammatory mediators, such as IL-6, IL-8,IL-17C, IL-20, IFN-c, and AMPs, which leadsto the initiation of the pro-inflammatoryfeedback loop. Combination of corticos-teroids and vitamin D analogs inhibits allof the aforementioned pro-inflammatorycytokines more than monotherapies of theactive ingredients (Fig. 2) [27].In summary, corticosteroid and vitamin D

analog combination therapy inhibits the effectsof Th1 and Th17 cytokines in an additive way

Fig. 2 Combination treatment in vitro is significantlymore effective than monotherapies of the active ingredi-ents in inhibiting cytokine released from key cells involvedin psoriasis pathogenesis [27]. Pro-inflammatory (IL-23,IL-17A, and IL-8) and immunomodulatory (IL-10)cytokine levels released by dendritic cells, T-cells, andkeratinocytes are expressed as percentage of vehicle-treatedcontrol (100%). Treatment was applied before DCactivation, after (IL-17A) and before (IL-10) Th-cell(CD4?) differentiation, and on stimulated keratinocytes.DC cultures were differentiated from CD14? cells. CD4?

cells were differentiated into Th1 and Th17 cells and wereprocessed for ribonucleic acid extraction and quantitativereal-time polymerase chain reaction. KC cells wereobtained from primary human epidermal KCs. *Combi-nation treatment also led to TNF-a inhibition (bothP\0.001). �Similar results were found for the inhibitionof IL-22, IL-8, and TNF-a (all P\0.001). �Similar resultswere observed for IL-6, IL-17C, and IL-20 (all P\0.001).BD betamethasone dipropionate, Cal calcipotriol, DCdendritic cells, IL interleukin, KCs keratinocytes, ns notsignificant Adapted from Lovato et al. [27]

c

268 Dermatol Ther (Heidelb) (2017) 7:265–279

(Fig. 3). Corticosteroids can also suppressimmunomodulatory Th2-cells and IL-10 secre-tion when used alone [17, 18, 27]; additionally,altering the Th1/Th2 balance has been sug-gested to further promote autoimmune reac-tions [17, 18]. The vitamin D analog calcipotriolcomplements the effects of corticosteroids byinducing Th2- and T-reg cell production (Fig. 3)

[17, 27]. Equilibrating the Th1 and Th2 ratiocould therefore provide immunomodulationand may prevent rebound [18], while T-reg cellsare central to actively attenuating inflammatoryresponses via inhibition of effector T-cells(Fig. 3) [1]. The effect of combination therapyon cellular targets in the pathophysiology ofpsoriasis is summarized in Fig. 4a–d.

Dermatol Ther (Heidelb) (2017) 7:265–279 269

Corticosteroid and Vitamin D AnalogCombination Topical Treatment May BeAble to Provide Long-Term Managementof Psoriasis

Upon clearance of psoriatic plaques and nor-malization of skin homeostasis, the therapeuticobjective shifts to the maintenance of a relap-se-free state. Psoriatic inflammation tends torecur in the previously affected skin locations,which may be caused by the expression andreactivation of inflammatory cytokines presentin the apparently normalized, plaque-free skinafter treatment [34, 35]. New data indicate thatcombination treatment is able to induce T-regcells as well as counteract the activation anddifferentiation of cytotoxic T-cells more effec-tively than corticosteroids alone [27]. Furtherclinical studies are required to explore the

possibility of combination treatment for thelong-term management of psoriasis (see Fig. 4e).

Fig. 3 Summary of the effects of corticosteroids andvitamin D analogs on T-cell subsets involved in psoriasispathogenesis [33]. Th17-cells are more involved inpsoriasis pathogenesis than Th1 cells. The upward anddownward arrows indicate induction and downregulationof T-cells, respectively, by calcipotriol and steroid. DC

dendritic cells, FOXP3 Forkhead box P3, IFN interferon,IL interleukin, MHC major histocompatibility complex,TCR T-cell receptor, Th T-helper cell, T-reg regulatoryT-cell Adapted from Bailey et al. [33]

Summary: Combination Therapyhas Complementary Effectson the Underlying Pathophysiologyof Psoriasis, Resulting in IncreasedTherapeutic Response

1. As well as their normalizing effect onkeratinocytes, vitamin D analogs, such ascalcipotriol, exert immunomodulatoryeffects on Th1, Th2, Th17, and T-reg cells.

2. Corticosteroids, such as betamethasonedipropionate, combined with vitamin Danalogs, additively inhibit Th1 and Th17pro-inflammatory effects.

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Corticosteroid and Vitamin D AnalogCombination Therapy Attenuates SideEffects Associated with their IndividualMonotherapies

Corticosteroid and vitamin D analogmonotherapy is associated with increased risksof skin atrophy and perilesional skin irritation,

respectively [4, 16, 36]. As the frequency ofapplication of corticosteroids and vitamin Danalogs used in combination therapy is lowerthan in monotherapy [4], the risk of adverseevents associated with monotherapy is reduced[16, 37, 38].

Long-term continuous use of topical corti-costeroid treatment alone can lead to skinatrophy. As a result, the thickness of the skin isreduced and transepidermal water loss increa-ses, causing loss of skin barrier function [37, 39].Recent studies in cultured skin cells havedemonstrated that the addition of calcipotriolreduces the early signs of betamethasone andclobetasol-induced skin atrophy by modulatingkey ECM components [39]. The effects of corti-costeroid, vitamin D analog, and combinationtreatment during skin atrophy are summarizedin Table 1.

3. Calcipotriol induces an immunomodula-tory Th2/T-reg cellular response, whereascorticosteroids suppress this effect, andcombination treatment yields mildinduction.

4. The preclinical results support the supe-rior antipsoriatic effect of corticosteroidand vitamin D analog combination treat-ment compared with monotherapies.

Fig. 4 Summary of the complementary and additiveactions of corticosteroid and vitamin D analog combina-tion treatment on cellular targets in the pathophysiology ofpsoriasis. a–d Therapeutic targets for inhibiting thepro-inflammatory environment. e Possible key targets for

long-term maintenance therapy. Asterisk: Resting and naıvedendritic cells and T-cells; plus and minus signs: indicateinduction and inhibition, respectively. DC dendritic cell,IL interleukin, Tc cytotoxic T-cell, Th T-helper cell, TNFtumor necrosis factor, T-reg regulatory T-cell

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Calcipotriol as monotherapy (50 lg/g twicedaily doses) may cause perilesional skin irrita-tion [16, 36]; however, the addition of a corti-costeroid has shown a beneficial effect: a52-week study demonstrated that daily treat-ment with Cal/BD ointment (Cal 50 lg/g andBD 0.5 mg/g) significantly reduced the overallnumber of adverse events—particularly burn-ing, itching, or erythema of the skin—comparedwith vitamin D analog monotherapy (Cal oint-ment, 50 lg/g) [40].

Authors’ clinical opinion The improvedsafety profile of fixed-dose topical combina-tion treatment, together with the once-dailytreatment use, offers improved convenienceand better acceptance compared withmonotherapies [42, 43]. These factors areessential in the therapeutic armamentariumfor psoriasis and are likely to facilitate adher-ence to treatment, which may subsequently

lead to faster and greater improvements inpatient QoL.

Table 1 Summary of the effects of corticosteroids and vitamin D analogs in skin atrophy [37, 39, 41]

Mechanism Effect ofcorticosteroids

Effect of vitaminD analogs

Overall clinical effect of combination treatment

Lipid synthesis � æ Prevents skin barrier and water loss impairment caused by

corticosteroidsAMPs, e.g., LL-37 � æ

KC proliferation* � = Attenuates epidermal thinning by corticosteroid-induced

reduction of epidermal cells

Change in tissue

modeling and

structure:

–Hyaluronic acid

–Matrix

metalloproteinases

� æ Limits epidermal thinning from corticosteroid-induced

loss of cellular volume

Collagen synthesis and

turnover

� æ Reduces dermal thinning caused by corticosteroid induced

decrease in matrix network

Glycosamine synthesis � æ Increases water-binding capacity of the skin, decreasing

corticosteroid-induced dermal thinning

Elastic fiber synthesis � æ Attenuates reduced skin flexibility/elasticity observed in

topical steroidal monotherapy

Downward arrow indicates downregulation; upward arrow indicates upregulation; equal sign indicates no effect; AMPsantimicrobial peptides; KC keratinocytes* KC proliferation is psoriasis activity-dependent. The data presented here are based on non-inflamed skin

Summary: Combination TreatmentMinimizes Skin Atrophy and DecreasesOther Monotherapy-Related Risks

1. Long-term continuous use of corticos-teroids leads to skin atrophy. Vitamin Danalogs can reduce corticosteroid-in-duced skin atrophy by modulating keyECM components.

2. Combination treatment reduces the fre-quency of application of corticosteroidand vitamin D analogs used to treatpsoriasis compared with monotherapy.This leads to a significant reduction ofadverse events associated with monother-apies of both active ingredients.

272 Dermatol Ther (Heidelb) (2017) 7:265–279

CHALLENGES OF DRUG DELIVERYIN TOPICAL FORMULATIONS

Poor penetration of active ingredients into theskin can result in low, or lack of, clinical effi-cacy; therefore, considerable research has beenundertaken to improve drug delivery in topicalformulations. The ability for an active ingredi-ent to penetrate the skin depends primarily on(1) the condition of the skin barrier, (2) thephysicochemical properties of the combineddrug and vehicle, and (3) the concentration ofactive ingredients dissolved into the vehicle.1. Condition of the skin barrier Skin permeability

depends on hydration levels on the outersurface [44, 45]. Occlusion of the skin byplastic wraps, impermeable dressings, orvehicles containing fats or polymer oils—such as oils, gels, and ointments—are well--known methods to increase skin hydrationlevels and thus influence the permeability ofactive ingredients of topical treatments [44].

2. Physicochemical properties of combined drugand vehicle Physicochemical properties, suchas the shape, lipophilicity, viscosity, occlu-sive properties, charge, and size, of bothactive ingredients, as well as excipients,influence the partitioning of the activeingredients between the vehicle and skinand their subsequent ability to penetratethe skin [11, 45].

3. Concentration of active ingredients dissolvedinto the vehicle The rate of skin penetration isproportional to the concentration of activeingredient dissolved in the vehicle becauseof the resulting increase in thermodynamicactivity [12, 46, 47]. This is a rate-limitingstep for most topical treatments, whoseactive ingredients have limited solubilitiesin their vehicles. One potential method toenhance the rate of skin penetration is toincrease the concentration of active ingre-dients dissolved in the applied productbeyond the normal solubility limit—i.e., tocreate a supersaturated solution. A recentstudy demonstrated that a supersaturatedenvironment was created and maintainedwith Cal/BD when applied as an aerosolfoam; this state was created after rapid

evaporation of the propellants during appli-cation [11]. A supersaturated solution isonly clinically relevant if it is stable, ascrystallization of ingredients will decreasepenetrative properties of the treatment [46].Results from the same study showed thatthe supersaturated solution of Cal/BD aero-sol foam was maintained in the laboratorysetting, post-application, for clinically rele-vant time periods (at least 26 h in thelaboratory setting) [11], which may explainthe observed increase in bioavailability ofCal/BD aerosol foam versus Cal/BD oint-ment [11].

CLINICAL BENEFITSOF CORTICOSTEROIDAND VITAMIN D ANALOGFIXED-DOSE COMBINATIONTREATMENT

Corticosteroids and vitamin D analogs aredirected at different targets in the pathogenesisof psoriasis. Their complementary and additiveeffects observed in preclinical data have beentranslated into effective fixed-dose combinationtherapies. The corticosteroid component largelyallows for fast and efficacious anti-inflamma-tory effects, whereas the vitamin D analogensures durability of the treatment and possible

Summary: Challenges in Drug Delivery

1. Enhancing the penetration of activeingredients into the skin is one of themain challenges in topical drug delivery.

2. The success of drug delivery depends onskin hydration levels, physicochemicalproperties of the combined drug andvehicle, and the concentration of activeingredients dissolved into the vehicle.

3. A modified, stable supersaturated solu-tion—such as the one observed with Cal/BD aerosol foam—may contribute to thesuperior efficacy observed when com-pared with more traditional vehicles,e.g., ointment and gel.

Dermatol Ther (Heidelb) (2017) 7:265–279 273

maintenance of a relapse-free state. The currentclinical evidence for corticosteroid and vitaminD analog combination treatment, and what thismeans for the treating physician, are discussedbelow.

Corticosteroid and Vitamin D AnalogFixed-Dose Combination Treatment isMore Efficacious than Monotherapiesin Treating the Underlying Psoriasis

The superior efficacy of corticosteroid and vita-min D analog combination treatment comparedwith monotherapy is supported by randomized,double-blind controlled clinical studies [48, 49].A three-arm, multicenter study demonstratedthat fixed-dose combination Cal/BD aerosolfoam was significantly more efficacious inimproving the mean modified Psoriasis Areaand Severity Index score (mPASI; excluding thehead, which was not treated) than the individ-ual active ingredients after 4 weeks (P\0.001versus both Cal foam and BD foam) [48]. Thesedata were supported in a plaque test studywhere the total clinical score, which measuresthe changes in erythema, scaling, and plaquethickness, was significantly improved with Cal/BD foam compared with BD foam after 4 weeksof treatment (P = 0.005) [49].

As well as providing efficient anti-inflam-matory effects, the use of vitamin D analogsmay also lead to long-term management ofpsoriasis by inducing immunomodulatoryresponses. Combination therapy with cal-cipotriol and betamethasone butyrate propi-onate ointment was associated with a decreasein T-cell production of the pro-inflammatorycytokines IL-17 and IFN-c, which correlatedwith a significant improvement in mean PASIscore in patients with moderate-to-severe pso-riasis [50].

Authors’ clinical opinion Targeting specificmolecules involved in the pathophysiology ofpsoriasis, as observed in fixed-dose combinationtreatment, results in an early and rapidresponse. This helps build patient confidence inthe treatment and positively impacts QoL andadherence to therapy. These aspects could, inturn, help in developing a mutually trusting

and successful patient-dermatologist partner-ship. Additionally, patients can personallyadapt fixed-dose combination treatment duringlong-term management. For example, in casesof flares, patients can increase the frequency ofapplication and reduce it accordingly once theflare has been controlled.

An Innovative Drug Delivery FormulationResults in Improved Efficacy

A number of studies have demonstrated thesuperior efficacy of Cal/BD aerosol foam for-mulation compared with traditional formula-tions, such as ointments, gels, and lotions(Table 2) [49, 51–53]. For example, in two 4--week Phase II studies, Cal/BD aerosol foamdemonstrated significant improvements inmPASI (P = 0.005) [51] and plaque symptomseverity (P = 0.038) [49] compared with Cal/BDointment. In a Phase III study designed tocompare Cal/BD aerosol foam and Cal/BD gelbased on the recommended US/Europeantreatment periods (4 weeks for Cal/BD aerosolfoam, and 8 for Cal/BD gel), significantly morepatients treated with aerosol foam than gel hadclear/almost clear skin at weeks 4 and 8,respectively (P\0.001; defined as C2 gradeimprovement according to the Physician’sGlobal Assessment of disease severity) [53].Results from health-related QoL questionnaires,such as Dermatology Life-Quality Index (DLQI),were also significantly improved with Cal/BDaerosol foam than with Cal/BD gel [52]. Nota-bly, significantly more patients treated withCal/BD aerosol foam reported that psoriasis nolonger impacted their daily lives (i.e., achievedDLQI scores of 0/1) at week 4 compared withpatients treated with Cal/BD gel (45.7% vs.32.4%; P = 0.013) [52]. One aspect of psoriasisthat has a strong negative impact on patientQoL is itch [54]. Improvements in DLQI scoresafter 4 weeks of Cal/BD aerosol foam treatmentwere significantly correlated with improve-ments in itch VAS scores [55]. Cal/BD aerosolfoam also provided fast and significantly greateritch relief than placebo (P = 0.013 at day 3) [56].Furthermore, the superior efficacy of Cal/BDaerosol foam is associated with a similar safety

274 Dermatol Ther (Heidelb) (2017) 7:265–279

profile, as demonstrated in a pooled safetyanalysis of three clinical studies comparingfixed combination Cal/BD aerosol foam withBD foam, Cal foam, Cal/BD ointment, andvehicles (foam and ointment) [57].

Authors’ clinical opinion Cal/BD aerosol foamtreatment can significantly reduce the burden

of the disease, as demonstrated by the superiorefficacy and ability to provide significant andmeasurable improvement in QoL comparedwith conventional Cal/BD formulations, such asgel and ointment. The rapid itch relief associ-ated with Cal/BD aerosol foam is crucial fortreatment success as patients perceive itch to be

Table 2 Summary of studies comparing Cal/BD aerosol foam with Cal/BD gel or ointment

References Studyidentifier

Design Duration(weeks)

N Comparator(s) Outcomes

Queille-Roussel

[49]

NCT01347255 Phase IIa,

exploratory,

single-center,

intra-individual

comparison

4 24 Cal/BD foam vs.

Cal/BD ointment

vs. BD foam vs.

foam vehicle (all

n = 24)

TCS decrease: -6.00

vs. -5.25 (Cal/BD

ointment;

P = 0.038), vs.

-4.96 (BD foam;

P = 0.005)

Koo et al. [51] NCT01536886 Phase II,

randomized,

multicenter

4 376 Cal/BD foam

(n = 141) vs. Cal/

BD ointment

(n = 135) vs.

foam (n = 49)

and ointment

(n = 51) vehicle

Treatment success

rates: 54.6% vs.

43.0% (Cal/BD

ointment;

P = 0.025); mPASI

mean difference:

-0.6 vs. Cal/BD

ointment

(P = 0.005)

Paul et al. [52] NCT02132936 Phase III,

randomized,

parallel-group

(PSO-ABLE)

12 463 Cal/BD foam

(n = 185) vs. Cal/

BD gel (n = 188)

vs. foam (n = 47)

and gel (n = 43)

vehicle

Treatment success

rates: 38% vs. 22%

(Cal/BD gel;

P\0.001); mPASI

mean difference:

-0.6 vs. Cal/BD gel

(P = 0.028)

Paul et al. [53] NCT02132936 Phase III,

randomized,

parallel-group

(PSO-ABLE

secondary,

HRQoL

analysis)

12 463 Cal/BD foam

(n = 185) vs. Cal/

BD gel (n = 188)

DLQI scores of 0/1:

61% vs. 44% (Cal/

BD gel; P = 0.003);

EQ-5D utility index:

0.09 vs. 0.03 (Cal/

BD gel; P\0.001)

All studies were investigator-blindedBD bethamethasone dipropionate 0.5 mg/g, Cal calcipotriol 50 lg/g, DLQI Dermatology Life Quality Index, EQ-5DEuroQoL-5D-5L-PSO, HRQoL health-related quality of life, mPASI modified Psoriasis Area and Severity Index (excludingthe head, which was not measured), TCS total clinical score (sum of erythema, scaling and plaque thickness)

Dermatol Ther (Heidelb) (2017) 7:265–279 275

one of the most bothersome symptoms of pso-riasis. Due to its improved efficacy and positiveimpact on QoL, with no additional concernsabout tolerability, Cal/BD aerosol foam is notjust an improvement on previous formulations,but could also be considered a new stand-alonetreatment.

CONCLUSIONS

Fixed-dose combination of corticosteroids andvitamin D analog has demonstrated superiorefficacy over monotherapies with topical ster-oids in both preclinical and clinical studies, aswell as in daily practice. Updated knowledge onthe mechanism of action of the active ingredi-ents demonstrates how combination treatmentsuccessfully and significantly inhibits activeinflammation and supports the maintenance ofa relapse-free state. The rationale for fixed-dosecombination treatment is further supported bythe fact that adverse events associated withcorticosteroid and vitamin D analogmonotherapy, such as skin atrophy and perile-sional skin irritation, respectively, can be effec-tively minimized by combining the two activeingredients. Improved delivery of the activeingredients via innovative formulations, such asan aerosol foam, has shown improved clinicalresponse and QoL, while providing patientswith more therapeutic options suited to theirlifestyle. Additional research is still required tounderstand how long-term maintenance of adisease-free state can be achieved in the clinicalsetting. For this reason, a randomized clinicaltrial with Cal/BD aerosol foam has recently beeninitiated to examine the long-term manage-ment of plaque psoriasis (PSO-LONG;NCT02899962).

ACKNOWLEDGEMENTS

This study was sponsored by LEO Pharma.Article-processing charges were funded by LEOPharma. Medical writing support was providedby Mai Kurihara, PhD, from Mudskipper Busi-ness Limited, funded by LEO Pharma. Allnamed authors meet the International

Committee of Medical Journal Editors (ICMJE)criteria for authorship for this manuscript, takeresponsibility for the integrity of the work andthe interpretation of the data from the reviewedpublications, and have given final approval tothe version to be published.

Disclosures. Siegfried Segaert has been aspeaker/consultant for Abbott, Amgen, Biogen,Boehringer-Ingelheim, Celgene, Galderma,Janssen, LEO Pharma, Lilly, Merck Serono,MSD, Novartis, Pierre Fabre, Pfizer, Roche, SunPharma, and UCB. Neil H. Shear has receivedhonoraria related to consultations or servicesprovided by LEO Pharma and support from theCanadian Dermatology Foundation (of whichhe is President) and LEO Pharma. AndreaChiricozzi has been a scientific consultant forLEO Pharma, Novartis, Biogen, Eli-Lilly, andAbbVie. Diamant Thaci has been an advisor,received speaker’s honoraria and grant support,and participated in clinical trials for AbbVie,Almiral, Amgen, Biogen-Idec, Boehringer-In-gelheim, Celgene, Dignitiy, Dr. Reddy, Elli-Lilly,Forward-Pharma, GlaxoSmithKline, LEOPharma, Janssen-Cilag, Maruho, MSD, Mundi-pharma, Novartis, Pfizer, Regeneron, Roche,Sanofi, Sandoz, and Xenoport. Jose-ManuelCarrascosa has been an advisor, receivedspeaker’s honoraria and grant support, andparticipated in clinical trials for AbbVie, Almi-rall, Biogen, Celgene, Eli-Lilly, Janssen, LEOPharma, Novartis, and Pfizer. Helen Young hasreceived grant support and acted as scientificconsultant for AbbVie, Amgen, Jansen, LEOPharma, Lilly, MEDA, Novartis, Stiefel, and UCBPharma. Vincent Descamps is a scientific con-sultant for Elli-Lilly and has been advisor/re-ceived speaker’s honoraria/participated inclinical trials for AbbVie, Celgene, Janssen,Novartis, and Pfizer.

Compliance with Ethics Guidelines. Thearticle presented here is based on previouslyconducted studies and does not involve anynew studies of human or animal subjects per-formed by any of the authors.

Open Access. This article is distributedunder the terms of the Creative Commons

276 Dermatol Ther (Heidelb) (2017) 7:265–279

Attribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

REFERENCES

1. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl JMed. 2009;361:496–509.

2. Hrehorow E, Salomon J, Matusiak L, Reich A,Szepietowski JC. Patients with psoriasis feel stig-matized. Acta Derm Venereol. 2012;92:67–72.

3. Laws PM, Young HS. Topical treatment of psoriasis.Expert Opin Pharmacother. 2010;11:1999–2009.

4. Menter A, Korman NJ, Elmets CA, Feldman SR,Gelfand JM, Gordon KB, et al. Guidelines of care forthe management of psoriasis and psoriatic arthritis.Section 3. Guidelines of care for the managementand treatment of psoriasis with topical therapies.J Am Acad Dermatol. 2009;60:643–59.

5. Higgins E, Markham T. Current treatment optionsin the management of psoriasis. Prescriber.2010;21:31–44.

6. Salgo R, Thaci D. Treatment of moderate-to-severeplaque psoriasis. G Ital Dermatol Venereol.2009;144:701–11.

7. Lebwohl M, Menter A, Koo J, Feldman SR. Combi-nation therapy to treat moderate to severe psoriasis.J Am Acad Dermatol. 2004;50:416–30.

8. Gordon KM. Update on new and emerging thera-pies in the management of psoriasis. Semin CutanMed Surg. 2015;34:S34–6.

9. Feldman SR, Horn EJ, Balkrishnan R, Basra MK,Finlay AY, McCoy D, et al. Psoriasis: improvingadherence to topical therapy. J Am Acad Dermatol.2008;59:1009–16.

10. Thorneloe RJ, Bundy C, Griffiths CE, Ashcroft DM,Cordingley L. Adherence to medication in patientswith psoriasis: a systematic literature review. Br JDermatol. 2013;168:20–31.

11. Lind M, Nielsen KT, Schefe LH, Norremark K,Eriksson AH, Norsgaard H, et al. Supersaturation ofcalcipotriene and betamethasone dipropionate in a

novel aerosol foam formulation for topical treat-ment of psoriasis provides enhanced bioavailabilityof the active ingredients. Dermatol Ther (Heidelb).2016;6:413–25.

12. Surber C, Smith EW. The mystical effects of derma-tological vehicles. Dermatology. 2005;210:157–68.

13. Kim J, Krueger JG. The immunopathogenesis ofpsoriasis. Dermatol Clin. 2015;33:13–23.

14. Lee E, Trepicchio WL, Oestreicher JL, Pittman D,Wang F, Chamian F, et al. Increased expression ofinterleukin 23 p19 and p40 in lesional skin ofpatients with psoriasis vulgaris. J Exp Med.2004;199:125–30.

15. Gottlieb A. Immune modulation with combinedvitamin D analogs and corticosteriods in psoriasis.Psoriasis Forum. 2015;21:35–41.

16. Segaert S, Røpke M. The biological rationale for useof vitamin D analogs in combination with corti-costeroids for the topical treatment of plaque pso-riasis. J Drugs Dermatol. 2013;12:e129–37.

17. Fujiyama T, Ito T, Umayahara T, Ikeya S, Tatsuno K,Funakoshi A, et al. Topical application of a vitaminD3 analogue and corticosteroid to psoriasis plaquesdecreases skin infiltration of TH17 cells and theirex vivo expansion. J Allergy Clin Immunol.2016;138:517–28.

18. Jadali Z, Eslami MB. T cell immune responses inpsoriasis. Iran J Allergy Asthma Immunol.2014;13:220–30.

19. Nograles KE, Zaba LC, Guttman-Yassky E,Fuentes-Duculan J, Suarez-Farinas M, Cardinale I,et al. Th17 cytokines interleukin (IL)-17 and IL-22modulate distinct inflammatory and ker-atinocyte-response pathways. Br J Dermatol.2008;159:1092–102.

20. Harper EG, Guo C, Rizzo H, Lillis JV, Kurtz SE,Skorcheva I, et al. Th17 cytokines stimulate CCL20expression in keratinocytes in vitro and in vivo:implications for psoriasis pathogenesis. J InvestDermatol. 2009;129:2175–83.

21. Reich K, Papp KA, Matheson RT, Tu JH, BissonnetteR, Bourcier M, et al. Evidence that a neu-trophil-keratinocyte crosstalk is an early target ofIL-17A inhibition in psoriasis. Exp Dermatol.2015;24:529–35.

22. Chiricozzi A, Guttman-Yassky E, Suarez-Farinas M,Nograles KE, Tian S, Cardinale I, et al. Integrativeresponses to IL-17 and TNF-alpha in human ker-atinocytes account for key inflammatory patho-genic circuits in psoriasis. J Invest Dermatol.2011;131:677–87.

Dermatol Ther (Heidelb) (2017) 7:265–279 277

23. Chiricozzi A, Nograles KE, Johnson-Huang LM,Fuentes-Duculan J, Cardinale I, Bonifacio KM, et al.IL-17 induces an expanded range of downstreamgenes in reconstituted human epidermis model.PLoS One. 2014;9:e90284.

24. Cai Y, Fleming C, Yan J. New insights of T cells inthe pathogenesis of psoriasis. Cell Mol Immunol.2012;9:302–9.

25. Johansen C, Funding AT, Otkjaer K, Kragballe K,Jensen UB, Madsen M, et al. Protein expression ofTNF-alpha in psoriatic skin is regulated at a post-transcriptional level by MAPK-activated proteinkinase 2. J Immunol. 2006;176:1431–8.

26. Howie SE, Aldridge RD, McVittie E, Forsey RJ, SandsC, Hunter JA. Epidermal keratinocyte production ofinterferon-gamma immunoreactive protein andmRNA is an early event in allergic contact der-matitis. J Invest Dermatol. 1996;106:1218–23.

27. Lovato P, Norsgaard H, Tokura Y, Ropke MA. Cal-cipotriol and betamethasone dipropionate exertadditive inhibitory effects on the cytokine expres-sion of inflammatory dendritic cell-Th17 cell axis inpsoriasis. J Dermatol Sci. 2016;81:153–64.

28. Bikle DD. 1,25(OH)2D3-regulated human ker-atinocyte proliferation and differentiation: basicstudies and their clinical application. J Nutr.1995;125:1709S–14S.

29. Lange K, Kleuser B, Gysler A, Bader M, Maia C,Scheidereit C, et al. Cutaneous inflammation andproliferation in vitro: differential effects and modeof action of topical glucocorticoids. Skin PharmacolAppl Skin Physiol. 2000;13:93–103.

30. Norris DA. Mechanisms of action of topical thera-pies and the rationale for combination therapy.J Am Acad Dermatol. 2005;53:S17–25.

31. Castela E, Archier E, Devaux S, Gallini A, AractingiS, Cribier B, et al. Topical corticosteroids in plaquepsoriasis: a systematic review of risk of adrenal axissuppression and skin atrophy. J Eur Acad DermatolVenereol. 2012;26(Suppl 3):47–51.

32. Uva L, Miguel D, Pinheiro C, Antunes J, Cruz D,Ferreira J, et al. Mechanisms of action of topicalcorticosteroids in psoriasis. Int J Endocrinol.2012;2012:561018.

33. Bailey SR, Nelson MH, Himes RA, Li Z, Mehrotra S,Paulos CM. Th17 cells in cancer: the ultimateidentity crisis. Front Immunol. 2014;5:276.

34. Clark RA. Gone but not forgotten: lesional memoryin psoriatic skin. J Invest Dermatol. 2011;131:283–5.

35. Suarez-Farinas M, Fuentes-Duculan J, Lowes MA,Krueger JG. Resolved psoriasis lesions retainexpression of a subset of disease-related genes. J In-vest Dermatol. 2011;131:391–400.

36. Scott LJ, Dunn CJ, Goa KL. Calcipotriol ointment. Areview of its use in the management of psoriasis.Am J Clin Dermatol. 2001;2:95–120.

37. Schoepe S, Schacke H, May E, Asadullah K. Gluco-corticoid therapy-induced skin atrophy. Exp Der-matol. 2006;15:406–20.

38. Augustin M, Mrowietz U, Bonnekoh B, RosenbachT, Thaci D, Reusch M, et al. Topical long-termtherapy of psoriasis with vitamin D(3) analogues,corticosteroids and their two compound formula-tions: position paper on evidence and use in dailypractice. J Dtsch Dermatol Ges. 2014;12:667–82.

39. Norsgaard H, Kurdykowski S, Descargues P, Gonza-lez T, Marstrand T, Dunstl G, et al. Calcipotriolcounteracts betamethasone-induced decrease inextracellular matrix components related to skinatrophy. Arch Dermatol Res. 2014;306:719–29.

40. Kragballe K, Austad J, Barnes L, Bibby A, de la Bras-sinne M, Cambazard F, et al. A 52-week randomizedsafety study of a calcipotriol/betamethasone dipro-pionate two-compound product (Dovobet�/Daivo-bet�/Taclonex�) in the treatment of psoriasisvulgaris. Br J Dermatol. 2006;154:1155–60.

41. Jensen JD, Fujita M, Dellavalle RP. Validation ofpsoriasis clinical severity and outcome measures:searching for a gold standard. Arch Dermatol.2011;147:95–8.

42. Brown KK, Rehmus WE, Kimball AB. Determiningthe relative importance of patient motivations fornonadherence to topical corticosteroid therapy inpsoriasis. J Am Acad Dermatol. 2006;55:607–13.

43. Lambert J, Hol CW, Vink J. Real-life effectiveness ofonce-daily calcipotriol and betamethasone dipropi-onate gel vs. ointment formulations in psoriasis vul-garis: final analysis of the 52-week PRO-long study.J Eur Acad Dermatol Venereol. 2015;29:2349–55.

44. Bjorklund S, Engblom J, Thuresson K, Sparr E. Awater gradient can be used to regulate drug transportacross skin. J Control Release. 2010;143:191–200.

45. Schaefer H, Redelmeier TE. Skin barrier: principlesof percutaneous absorption. New York: Karger;1996.

46. Hadgraft J, Lane ME. Drug crystallization—impli-cations for topical and transdermal delivery. ExpertOpin Drug Deliv. 2016;13:817–30.

278 Dermatol Ther (Heidelb) (2017) 7:265–279

47. Moser K, Kriwet K, Froehlich C, Kalia YN, Guy RH.Supersaturation: enhancement of skin penetrationand permeation of a lipophilic drug. Pharm Res.2001;18:1006–11.

48. Lebwohl M, Tyring S, Bukhalo M, Alonso-Lla-mazares J, Olesen M, Lowson D, et al. Fixed com-bination aerosol foam calcipotriene 0.005% (Cal)plus betamethasone dipropionate 0.064% (BD) ismore efficacious than Cal or BD aerosol foam alonefor psoriasis vulgaris: a randomized, double-blind,multicenter, three-arm, phase II study. J Clin Aes-thet Dermatol. 2016;9:34–41.

49. Queille-Roussel C, Olesen M, Villumsen J, LacourJP. Efficacy of an innovative aerosol foam formula-tion of fixed combination calcipotriol plusbetamethasone dipropionate in patients with pso-riasis vulgaris. Clin Drug Investig. 2015;35:239–45.

50. Hino R, Kabashima R, Kawakami C, Sugita K, Naka-mura M, Tokura Y. Circulating Th17 cell fluctuationin psoriatic patients treated with topical calcipotrioland betamethasone butyrate propionate. J Eur AcadDermatol Venereol. 2011;25:242–4.

51. Koo J, Tyring S, Werschler WP, Bruce S, Olesen M,Villumsen J, et al. Superior efficacy of calcipotrieneand betamethasone dipropionate aerosol foamversus ointment in patients with psoriasis vul-garis—a randomized phase II study. J DermatolTreat. 2016;27:120–7.

52. Paul C, Stein Gold L, Cambazard F, Kalb R, LowsonD, Moller AH et al. More rapid improvement inquality of life with fixed combination calcipotrieneplus betamethasone dipropionate aerosol foamversus topical suspension (PSO-ABLE study in

patients with psoriasis vulgaris). J Am Acad Der-matol. 2016;74:AB260 (abst P3712).

53. Paul C, Stein Gold L, Cambazard F, Kalb RE, LowsonD, Bang B, et al. Calcipotriol plus betamethasonedipropionate aerosol foam provides superior effi-cacy versus gel in patients with psoriasis vulgaris:randomized, controlled PSO-ABLE study. J Eur AcadDermatol Venereol. 2017;31:119–26.

54. World Health Organization. Global report onPSORIASIS. 2016. http://apps.who.int/iris/bitstream/10665/204417/1/9789241565189_eng.pdf. Accessed11 Apr 2017.

55. Leonardi C, Bagel J, Yamauchi P, Pariser D, Xu Z,Moeller A, et al. The aerosol foam formulation ofthe fixed combination calcipotriene plusbetamethasone dipropionate improves thehealth-related quality of life in patients with pso-riasis vulgaris: results from the randomized PSO--FAST study. J Drugs Dermatol. 2016;15:981–7.

56. Leonardi C, Bagel J, Yamauchi P, Pariser D, Xu Z,Olesen M, et al. Efficacy and safety of calcipotrieneplus betamethasone dipropionate aerosol foam inpatients with psoriasis vulgaris—a randomizedphase III study (PSO-FAST). J Drugs Dermatol.2015;14:1468–77.

57. Menter A, Stein GL, Koo J, Villumsen J, Rosen M,Lebwohl M. Fixed combination calcipotriene plusbetamethasone dipropionate aerosol foam is welltolerated in patients with psoriasis vulgaris (pooleddata from three randomized controlled studies).Skinmed. 2017;15:119–24.

Dermatol Ther (Heidelb) (2017) 7:265–279 279