MILD-TO-MODERATE

PSORIASIS SECOND EDITION

Edited by

John Y.M. Koo University ofCalifornia Medical Center

San Francisco, California, USA

Chai Sue Lee University ofCalifornia Davis Medical Center

Sacramento, California, USA Sacramento VA Medical Center

Mather, California, USA

Mark G. Lebwohl Mount Sinai School ofAfedicine

New York, New York, USA

informa healthcare

New York london

171 New Developments in Topical Psoriasis Therapy

In a phase III study, the adverse event rate was similar'between clobetasol propionate shampoo and vehicle groups (7). The most common adverse event was skin discomfort which included and burning (10.6% of shampoo subjects vs. 17% of vehicle sUbjects). All adverse events were transient and mild or moderate in intensity. None of these adverse events caused the subjects to discontinue treatment.

In a multicenter, randomized, investigator-blinded study, the application of clobetasol propionate shampoo once daily was compared to the application of caJcipotriene solution (Dovonex®) twice daily for four weeks in the treatment of moderate-to-severe scalp psoriasis (11). Clobetasol propionate shampoo was significantly more effective than calcipotriene solution. Furthermore, clobetasol propionate shampoo was better tolerated than calcipotriene solution. A burning sensation was significantly more common in the calcipotriene solution group.

In another multicenter, randomized, investigator-blinded study, clobeta­sol propionate shampoo once daily was compared to clobetasol propionate gel (Temovate® Scalp Application) once daily for 4 weeks in tlle treatment of moderate-to-severe scalp psoriasis (7). Clobetasol propionate shampoo and 1emo­vate scalp application were shown to have similar efficacy and safety profile.

In summary, clobetasol propionate shampoo offers a convenient, effective, and \~ell-tolerated treatment option for the treatment of moderate-to-severe

scalp psoriasis. Since many patients wash their hair daily already, treatment with clobetasol propionate shampoo can be incorporated into the patient's schedule without taking too much time. This can greatly increase patient compliance and therefore treatment success and patient satisfaction.

CLOBETASOL PROPRIONATE LOTION (CLOBEX® LOTION)

An alcohol-free lotion containing clobetasol propionate has also been recently introduced. This lotion is unique in that it does not contain alcohols and may provide a more patient-friendly application for more widespread body use. In clinical trials, the lotion was as effective as Temovate cream in treating moderate­to-severe psoriasis. Interestingly, at four weeks posttherapy, 50% more patients (p 0.044) who responded to therapy remained in remission from the lotion cohort in comparison to those treated with Temovate cream (7). The clobetasol lotio~as been shown in vitro to deliver twice as much clobetasol to the epidermal compartment (7). Hence the prevailing theory is that psoriatic lesions responsive to thedpy are more thoroughly treated with the lotion versus Temovate cream resulting in a longer duration of response with the lotion.

HYDROGEL PATCH

The successful treatment of psoriasis by occlusion of topical medications has been described in the medical literature for over two decades. The first published account of the effectiveness of occlusion was described by Shore in 1985 in which he

172 Colaco et al.

described the clearance of a psoriasis lesion after a thrl;:~~week period of occlusion with a Band~Aid® bandage (12). This article led to a larger study in which he demonstrated that the use of various waterproof tapes alone, or in combination with a topical steroid, was successful in the clearance of psoriasis lesions (13). These two articles fueled further research in the use of advanced dressing devices, first hydrocolloid dressings and then hydrogel patch, as a method for occluding various topical agents.

A hydrocolloid dressing is typically composed of a hydrocolloid layer on a flexible, gas and water impermeable backing that adheres to the skin. The hydro~ colloid layer itself consists of a water~soluble polymer, water, a water-retaining agent, and adhesives. Because hydrocolloid dressings are designed primarily as wound care devices, they generally have a very low water content, which allows for "absorption of wound exudate over the course of up to one week. There are at least 11 studies with a combined total of 512 patients that examined the treat~ ment of psoriasis by topical steroids under occlusive hydrocolloid dressing. These studies demonstrated conclusively that occlusion with a hydrocolloid dressing en­hances the efficacy of topical steroids in the treatment of psoriasis (14-24). One study also demonstrated that the use of hydrocolloid dressings as monotherapy without topical steroids is more effective than fluocinolone alone and as effec­tiveJas daily DVB phototherapy (24). Side effects described in these studies in~ clude irritation (14,1 ,23), folliculitis (13,15,17,21), and Koebner phenomenon (20,23,24).

Despite their clinical benefits, hydrocolloid dressings are not routinely used in the treatment of psoriasis because of their high retail costs. As a result, patients and clinicians often resort to the use ofplastic films such as Saran Wrap® as a more economic alternative for occlusion. Plastic wraps, however, lack intrinsic adhesive properties and are thus difficult to apply and uncomfortable to wear. These wraps often have to be secured with tape to keep them in place, which can be irritating to skin and can even cause mechanical trauma in the process of tape application and removaL Other disadvantages of previously used wraps include excessive sweating that tends to occur at areas occluded by plastic and the unsightliness that is inherent in such a wrap. A dressing composed of a hydrogel layer on a thin, flexible, skin-colored, gas and water impermeable urethane backing was designed to address these limitations (Fig. 1.) The hydrogel dressing is considerably more aesthetically pleasing compared to other wraps and requires no secondary method

ffor adhesion. The hydrogel layer differs from the typical hydrocolloid layer in that i1jcontains significantly more water (composed of approximately 50% water).

An open-label, bilaterally controlled study was done at the DCSF Psoriasis Center and Skin Treatment Center in San Francisco, California, to assess the safety and efficacy of the novel occlusive hydrogel dressing used alone and in conjunction with topieal medications in the treatment of plaque psoriasis.

In the study, male and female patients aged 18 years and older with two stable, plaque~type psoriatic lesions, symmetrical in anatomic location and similar

173 New Developments in Topical Psoriasis Therapy

Figure 1 Hydrogel patch application.

in terms of erythema, induration, and scaling, were eligible to enroll. Lesions located on the scalp, face, genitals, hands, or feet were excluded. Patients with evidence"of a skin disorder other than plaque-type psoriasis, clinically infected psoriasis, and/or skin atrophy in the area of the lesions were ineligible. Cessation of intralesional or topical therapies (other than emollients) to target lesions for two weeks and investigational drugs or systemic psoriasis therapies for four weeks was required prior to starting study procedures. The use of lithium, tricyclic antidepressants, j3-blockers, and oral antihistamines was permitted during the study only if the patient was receiving a stable dose at baseline.

Patients were sequentially assigned to one of the six treatment groups based on the severity of target lesions (Fig. 2). Severity was defined by a modified Pso­riasis Area and Severity Index (PASI) score (mild, 1.5 to moderate, >4 to ;27; severe, >7 to ;212). The modified PASI score (ranging from 0 to 12) was calculated as the sum of individual scores for erythema, induration, and scaling (each ranging from 0-4 and representing the spectrum of none to very severe). Each patient had bilaterally symmetric right- and left-sided body lesions chosen for comparison, one lesion to be treated with hydrogel and the other without hy­drog,rl. Target lesions of mild severity were separated into group 1 or 2. For group 1, nd study medications were applied and the hydrogel dressing was applied to one of the fwo target lesions twice daily. while the corresponding bilaterally symmetric lesion was untreated. Group 2 was treated twice daily with hydrocortisone cream 1.0% to a single target lesion and hydrocortisone cream 1.0% plus hydrogel to the bilaterally symmetric target lesion. Lesions of moderate severity were separated into groups 3,4, and 5. Group 3 was treated twice daily with tacrolimus ointment

174 Colam et al.

No therapy HC 1% cream VS. VS.

Hydrogel alone Hydrogel + HC 1%

Tacrolimus 0,1 %

vs. Calcipotriene

VS.

Halobetasol + Calcipotriene vs.

Hydrogel + Halobetasol + Calcipotriene

Hydrogel + Tacrolimus 0.1 % , Hydrogel + Calcipotriene . !

Triamcinolone 0,1%

Hydrogel Triamcir)olol1e 0.1 %

Figure 2 Assignment of patients to treatment groups.

0.1 % to one target lesion and tacrolimus ointment 0.1 % plus hydrogel to the bilat­erally symmetric target lesion. Group 4 was treated twice daily with triamcinolone cream 0.1 % to a single target lesion and triamcinolone cream 0.1 % plus hydrogel to the bilaterally symmetric target lesion. Similarly, group 5 was treated twice daily with calcipotriene cream 0.005% to a single target lesion and calcipotriene cream 0.005% plus hydrogel to the bilaterally symmetric target lesion. Corresponding bilaterally symmetric severe lesions were treated twice daily with a combination of halobetasol propionate cream 0.05% and calcipotriene cream 0.005% or the com­bination halobetasol propionate cream OJ)5% and calcipotriene cream 0.005% plus hydrogel (group 6). Application of study medications and hydrogel dressings was done twice daily for eight weeks regardless of disease improvement. For psoria­sis othfJ than target lesions, patients were allowed to continue topical regimens institutedaPrior to study participation.

Patients were evaluated at screening, baseline (day 0), and during treatment at weeks 2,4,6, and 8. At each visit, target lesions were photographed and assigned a modified PAS! score by an unblinded investigator for each ofthe two target lesions. Patient satisfaction was determined via a brief voluntary questionnaire completed during the final visit. Safety was assessed based on the incidence of observed or elicited adverse events.

The primary endpoint was a modified PAS! score as described above for each target lesion at baseline (day 0), and weeks 2, 4, 6, and 8. Secondary

New Developments in Topical Psoriasis Therapy 175

endpoints were individual scores for erythema, induration, and scaling using a 5-point scale (0-4). A series of t-tests were performed within the six different treatment groups, comparing outcome variables with and without occlusive dress­ing. Statistical significance was based on resulting two-sided p-values of 0.05 or less. Last observation carried forward was used to impute missing data. Analyses were conducted on an intent-to-treat population (all subjects enrolled and receiving the occlusive dressing). Analyses on the per-protocol (PP) population were con­sidered supportive of the ITT analyses. Subject data was included in PP analyses if they completed the eight-week evaluation without any noteworthy study protocol violations.

A total of 131 patients were enrolled in the study and received at least one dose of study medication. Twenty-seven patients discontinued prematurely from the study. The most common reasons for early discontinuation were subject request (n 12),losttofollow-up(n = ll}, and adverse events (n 4).Thedemographic and baseline characteristics between all treatment groups were statistically similar with to gender, race, and age. Baseline disease characteristics were statis­tically similar within mild, moderate, and severe treatment groups with respect to study outcomes.

For all six treatment groups, the total modified PASI scores were significantly improved in the occluded arm when compared to the non occluded arm at the end of the treatment (Fig. 3). A statistically superior benefit was observed as early as week 2 (the first visit after baseline) and this benefit was maintained through the end of the treatment. Of the individual PASI components, induration and scaling, but not erythema, demonstrated statistically significant differences in favor of the occluded arm for all treatment groups. The ITT and PP populations led to similar conclusions concerning efficacy of the occluded arm compared to the non occluded arm 4).

The most common adverse events related to use of the hydrogel dressing were application site irritation, purpura, and pruritus (3.0%, and 1.5%. re­spectively). Application site irritation warranted discontinuation from the study in three cases (one subject in the triamcinolone group and two in the calcipotriene group). The final subject who was discontinued from the study following an ad­verse event was involved in a bicycle accident, judged to be unrelated to the study medication, in which the subject sustained a fractured humerus preventing dressing application. The single serious adverse event was a lacerated determined by the investigator to be unrelated to the study medication.

1 Although the therapeutic mechanism of occlusion is not completely under­stood, it has been shown to restore defective barrier function and to normalize the

~ epidermal calcium gradient in psoriatic plaques (25). Studies have demonstrated that occlusion also decreases epidermal mitotic activity in psoriatic plaques (26,27) and increases hydration ofthe stratum corneum thereby facilitating desquamation, preventing parakeratosis (28,29), and restoring the granular cell layer (26). Clin­ical studies have demonstrated the effectiveness of occlusion in the treatment of psoriasis however, almost all of these studies have focused on the

Group 1 total PASI score (N:: 22) 12

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Group 2 total PASI score (N =20) 12

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Day 0 Week 2 Week 4 Week 6 WeekS

Visit

Group 3 lotal PASI score (N:: 22)

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Day 0 Week 2 Week 4 Week 6 WeekS

Visit

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Group 4 total PASI score (N :: 23)

"'" ~

Week 2 Week 4 Week 6

Visit

Group 5 tolal PASI score (N:: 23)

Weok2 Week 4 WeekS

Visit

Group 6 total PASI score (N:: 21)

Week 2 Week 4 WeekS

Visit

Week 8

Week 8

~ s;-WeekS

11>-Figure 3 Groups 1 to 6 total PAS! scores (intent-tll-treat *p-Values calculated from a paired [-test with between occluded mean :­

and nonoceluded mean visit. Last observation earried forward was used to imDute missing scores.

8

III

177 New Developments in Topical Psoriasis Therapy

Pretreatment

Posttreatment

With occlusion Without occlusion (A)

Hydrogel + protopic 01 % ointment

Post-tx

PosHx

Hydrogel + protopic 0.1% ointment Protopic 0.1 % ointment alone

(8) , ~

Figure 4 Clinical treatment response. (A) Calcipotriene and halobetasol propionate with and without occlusion, both pre- and posttreatment. (B) HydrogeJltacrolimus 0.1 % ointment VS. lacrolimus 0.1 <10 ointment alone.

178 Co/aco et al.

hydrocolloid dressing as an occlusion device. In clinical practice, adhesive tapes and plastic wraps are cumbersome to use while hydrocolloid dressings are limited by their high retail cost. An inexpensive, easy-to-use hydrogel dressing specifi­cally designed for occlusion was developed to address these shortcomings. The results of this study demonstrate that this occlusive hydrogel dressing significantly enhances the efficacy of topical agents in plaque psoriasis.

When interpreting these results, the reader should be aware oftwo limitations to this study. Most notably, this is an open-label study in which neither the patient nor the investigators were blinded to the use of occlusive hydrogel dressing. Visible skin changes cannot be masked by removing the dressing prior to study visits and a "placebo" dressing would have confounded study results. As a result, the PASI score assessment was performed in a nonblinded fashion. Furthermore, this study did not evaluate the relapse rate or the possible rebound of psoriasis at the end of eight weeks. However, there is some evidence in the existing literature to suggest that the relapse rate is similar, if not less common, with occlusion. In two studies examining the occlusion of topical clobetasollotion with hydrocolloid dressings, one demonstrated a reduction in the relapse rate of psoriasis if the treatment was carried out to Jcomplete clinical and histologic remission (17), while the other study showed similar relapse rate (14). Most importantly, neither study showed any rebound of psoriasis.

Nonetheless, this study is important for several reasons. First, a dressing containing hydrogel with mueh higher water content than that of traditional hy­drocolloid has rarely been studied for occlusion of topical therapy. It is the high water content that allows hydrogel to be hydrating to the skin and can improve absorption of other topical agents seeondary to this hydrating effect. Seeond, all previous clinical studies with oeclusive use of hydroeolloid dressings have only focused on eorticosteroids as the agent under occlusion. Third, the efficacy of combination therapy with halobetasol and calcipotriene under occlusion has not been extensively studied. This study demonstrates that hydrogel dressing occlu­sion can enhanee the clinical efficaey of a range of topical steroids, tacrolimus, as well as combination halobetasol and ealcipotriene, in the treatment of psoriasis. The impenneable urethane backing of hydrogel gives it a far superior advantage to other trad~tional occlusive wraps that are penneable to the agent they are trying to enhanee. 'Similar to hydrocolloid dressings, the use of the hydrogel dressing was also effecti~e as a monotherapy, without the addition of topical agents. Statistically significant differenees were observed in all groups as early as the second week of treatment and sustained through week 8 of the study.

The incidence of adverse events in this study is similar to the rates cited by other studies involving hydrocolloid dressing. It has been suggested that eorti­eosteroids under occlusion are potentially more atrophogenic than corticosteroids without occlusion (30). In this study, no local adverse events such as skin atrophy, telangiectasias, or striae associated with the use of topical corticosteroids under hydrogel occlusion were observed. Nonetheless, it is very important to monitor patients closely for signs of skin atrophy and other cutaneous side effects when

New Developments in Topical Psoriasis Therapy 179

topical corticosteroids are used under occlusion. Rare localized irritation with the hydrogel dressing was seen most often in conjunction with calcipotriene, a medication that is known to have a higher incidence of irritation than topical cor­ticosteroids (31). Finally, although the Koebner phenomenon has been observed with the use ofhydrocolloid dressings, it was not observed in this study (20,23,24).

The ability of the hydrogel dressing to enhance the efficacy of topical med­ications may have a wide range of applications. Moreover, the dressing may act as a physical barrier to discourage patients from excoriating skin lesions. Other skin conditions such as lichen simplex chronicus or prurigo nodularis are logical candidates. Future possibilities include infusing the hydrogel dressing with topical agents to further simplify therapy and encourage compliance. Recently, hydrogel was approved by the FDA as a device for the treatment of psoriasis alone. Its use to enhance other topical therapies is considered "off label" at this time. Hydrogel is anticipated to be available in one and a half to two years and will be marketed under the name Envela®.

In summary, this study demonstrates that the hydrogel dressing can be safely used as a monotherapy and as an occlusive device to enhance the efficacy of topical medications including calcipotriene in the treatment of psoriasis. Further studies should be undertaken to examine the effect of hydrogel dressing occlusion on the relapse rate of psoriasis and its use in other dermatoses.

CONCLUSIONS

Psoriasis is a chronic disease that requires long-term treatment. However, only 60% of patients are compliant with their therapy (32). There are several reasons why psoriasis patients are not compliant with their treatments. These reasons include treatment not working as well as expected, treatment may be too toxic, inconvenience of use, or association with rapid disease relapse (33). The new topical treatment options discussed in this chapter will hopefully improve patient compliance and patient satisfaction. Lastly, the development of hydrogel patches for use in occlusive enhancement of topical therapies of psoriasis may increase the efficacy of all topical agents.

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2. Jemec GB, Ganslandt C Ortonne JP, et al. A new formulation ofcalcipotriene plus betamethasone compared with its active ingredients and the vehicle in the treatment of scalp psoriasis: A randomized, double-blind, controlled trial. J Am Acad Demlatol 2008; 59(3):455-463.

3. van de Kerkhof PC, de Hoop D. de Korte J, et al. Scalp psoriasis, clinical presentations and therapeutic management. Dermatology 1998; 197:326334.

180 Colaco et a/.

4. Warner Chilcott. Taclonex scalp (calcipotriene 0.005% and betarnethasone dipropionate 0.064%) pamphlet insert. May 2008.

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13. Shore RN. Treatment of psoriasis with prolonged application of tape. J Am Acad Dermatol 1986; 15:540-542.

14. Volden G, Kragballe K, van De Kerkhof PC, et a1. Remission and relapse of chronic plaque j'isoriasis treated once a week with c1obetasol propionate occluded with a hy drocolloid dressing versus twice daily treatment with clobetasol propionate alone. J DermatologTreat2001; 12:141-144.

15. van de Kerkhof PC, Chang A, van der Walle HB, et aL Weekly treatment of psoriasis with a hydrocolloid dressing in combination with triamcinolone acetonide. A controlled comparative study. Acta dermato-venereologica 1994; 74: 143-146.

16. van Vlijmen-Willems 1M, Chang A, Boezeman JB, et al. The immunohistochemical effect of a hydrocolloid occlusive dressing (DuoDER1vI E) in psoriasis vulgaris. Der­matology (Basel, Switzerland) 1993; 187:257-262.

17. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta dermato-venereologica 1992; 72:69-71.

18. Kragballe K, Larsen FG. A hydrocolloid occlusive dressing plus triamcinolone ace­tonidc cream is superior to clobetasol cream in palmo-plantar pustulosis. Acta dermato­venereologica 1991; 71:540-542.

19. Wilkinson RD, Ohayon M. Therapeutic response to a dermatologic patch and be­tamethasone valerate 0.1 percent cream in the management of chronic plaques in pso­riasis. Cutis 1990; 45:468-470.

20. Gotllieb AB, Staiano-Coico L, Cohen SR, et aL Occlusive hydrocolloid dressings de­creas<t keratinocyte population growth fraction and clinical scale and skin thickness in active psoriatic plaques. J Dermatol Sci 1990; 1:93-96.

21. A trial of the Actiderm dermatological patch and topical corticosteroids in the treatment of psoriasis vulgaris. The Actiderm Multi-Center Study Group. Cutis 1990; 46:84-88.

22. Juhlin L. Treatment of psoriasis and other dermatoses with a single application of a corticosteroid left u~der a hydrocolloid occlusive dressing for one week. Acta dermato­venereologica 1989; 69:355-357.

23. DavidM, Lowe NJ. Psoriasis therapy: Comparative studies with a hydrocolloid dressing, plastic film occlusion, and triamcinolone acetonide cream. JAm Acad Dennatol 1989; 21:511-514.

181 New Developments in Topical Psoriasis Therapy

24. Friedman S1. Management of psoriasis vulgaris with a hydrocolloid occlusive dressing. Arch Dermatol 1987; 123:1046-1052.

25. Hwang SM, Ahn SK, Menon GK, et al. Basis of occlusive therapy in psoriasis: Cor­recting defects in permeability barrier and calcium gradient. Int J Dermatol 2001; 40:223-231.

26. L, Almeyda J, McMinn RM. Effect of plastic occlusive dressings on psoriatic epidermis. Br.T Dermatol 1970; 82:458-462.

27. Fisher LB, Maibach HI. Physical occlusion controlling epidermal mitosis. J Invest Dermatol 1972; 59: 106-108.

28. Rovee DT, Kurowsky CA, Labun J. Local wound environment and epidermal healing. Mitotic response. Arch DermatoI1972; 106:330-334.

29. Van Scott EJ, Yu RI. Hyperkeratinization, corneocyte cohesion, and alpha hydroxy acids. J Am Acad Dermatol 1984; 11:867-879.

30. Prawer SE, Katz HI. Guidelines for using superpotent topical steroids. Am Fam Physi­cian 1990; 41:1531-1538.

31. Bruner CR, Feldman SR, Ventrapragada M, et al. A systematic review of adverse effects associated with topical treatments for psoriasis. Dermatol Online J 2003; 9:2.

32. Zaghloul SS, Good?eld 11. Objective assessment ofcompliance with psoriasis treatment. Arch Dermatol 2004; 140(4):408-414.

33. Krueger G, Koo.T, Lebwohl M, et al. The impact of psoriasis on quality oflife: Results of a 1998 National Psoriasis Foundation patient-membership survey. Arch Dermatol 2001; 137(;):280-284.