New Developments in Topical Sequential Therapy for Psoriasis

J. Y. M. Koo, MD
Department of Dermatology, School of Medicine, University of California at San Francisco, San Francisco, CA, USA

ABSTRACT

Topical agents for the treatment of psoriasis are indicated for patients whose affected area is < 10% of their skin. However, for long-term use, their effectiveness can be limited. Topical sequential therapy involves the application of a class I corticosteroid and calcipotriene in three different phases: the clearance phase, the transition phase and the maintenance phase.

It is an accepted and widely practiced technique that provides a balance between maximizing efficacy and minimizing side-effects thus offering patients rapid clearance of their psoriatic lesions and long-term maintenance of remission.

Key Words: topical treatment, psoriasis, sequential therapy, calcipotriene, corticosteroids

Topical therapy is central in the treatment of psoriasis, and is indicated for most patients who have 20% or less of their body surface affected. Topical agents are associated with a lower side-effect burden compared with systemic therapies, which are generally reserved for patients with severe or non-responsive disease. However, individual topical agents have their own limitations. Topical corticosteroids, the most widely prescribed topical agents for psoriasis in the US, are highly effective in short-term use, but are associated with the potential for significant side-effects with long-term use, including atrophy, telangiectases, striae, and tachyphylaxis.

Sequential Therapy

The technique of sequential therapy was developed to maximize the shortterm efficacy of topical agents while minimizing side-effects associated with long-term maintenance therapy. Other topical agents, such as the vitamin D analog calcipotriene, are safer in long-term use, but they are also slower acting than commonly used high-potency topical steroids. Combining agents such as calcipotriene with corticosteroids in the context of sequential therapy is now widely practiced in the treatment of psoriasis. The utility of this approach has also been clearly demonstrated in recent trials.

As developed in clinical trials, sequential therapy involves three phases (Table 1).^1,2 The first phase, called the clearance phase, consists of short-term daily therapy with two topical agents. For example, a class I corticosteroid might be applied once or twice daily, followed by application of calcipotriene. Patients whose lesions respond to this daily combination therapy then enter the second or transition phase. During this phase, the use of the topical steroid is reduced from daily application to use only on weekends, while calcipotriene is applied

Clearance Phase	Transition Phase	Maintenance Phase
2 weeks-1 month	1-6 months (or longer)	Prevention of recurrence
Class I corticosteroid (e.g., halobetasol, clobetasol) q.d. or b.i.d.	Corticosteroid b.i.d., weekends only	Discontinued
Calcipotriene b.i.d.	Calcipotriene b.i.d., weekdays only	Calcipotriene b.i.d.
Table 1: Phases of sequential therapy

on weekdays, hence the terms “weekday-weekend” or “pulse” therapy. The length of this phase varies; recent trials describing sequential therapy for psoriasis have reported results extending up to 6 months, but longer duration of treatment may be indicated to prevent recurrence in some patients. Eventually, for the third or maintenance phase, only a non-steroid, namely calcipotriene, is used until the lesions clear completely.

Clinical Trials of Sequential Therapy

The technique of pulse therapy was developed in placebo-controlled trials over a decade ago. Katz and colleagues, for example, evaluated the use of betamethasone for extended maintenance therapy.³ Following short-term, twice-daily treatment for 2- 3 weeks, 38 of 59 enrolled subjects achieved 85% improvement from baseline and were rolled into the second phase of the study. Thereafter, subjects were randomized to weekend use of either betamethasone or placebo. Seventy-four percent of the betamethasone group and 21% of the placebo group maintained clinical remission for 12 weeks, suggesting that pulse dosing was safe and efficacious for long-term treatment.

Combination Therapy: Calcipotriene With Corticosteroids

Some years later, following the introduction of calcipotriene, investigators focused on the addition of this vitamin D analog to sequential therapy with corticosteroids. Lebwohl and colleagues evaluated the daily use of both calcipotriene and halobetasol for the sequential treatment of mild-to-moderate psoriasis.⁴ After 2 weeks of daily combination therapy (i.e., clearing phase), 40 of 44 subjects demonstrated 50% or greater improvement, and were randomized to one of two groups: weekend halobetasol therapy with either weekday calcipotriene or weekday placebo. Through 6 months of treatment, 76% of subjects in the calcipotriene group maintained remission, compared with 40% of those in the placebo group (p=0.045). The results of this trial clearly demonstrated that calcipotriene in combination with a class I corticosteroid was tolerable to patients, and that this combination improved remission rates in the second phase of sequential therapy.

Other investigators have also demonstrated that combination therapy with calcipotriene and corticosteroids is more efficacious than monotherapy.⁵ Calcipotriene is moderately effective as a topical agent, and benefits from combination with other agents to maximize efficacy, particularly for initial treatment (i.e., the clearance phase of sequential therapy). The reasons for improved efficacy in combination with steroids are likely multifactorial. Steroids and vitamin D analogs act through different mechanisms of action that may be complementary. Corticosteroids have anti-inflammatory, immunosuppressive, antimitotic, and antipruritic actions, whereas calcipotriene reduces keratinocyte proliferation and acts as an immunomodulator. The side-effects of each agent also can be reduced through combination use. Because calcipotriene is safe for long-term use, it is an ideal agent for weekday use in combination with weekend steroid therapy, thus allowing for improved efficacy and reduced steroid side-effects. Furthermore, the most common side-effect of calcipotriene – irritation – may be reduced through concomitant use of topical steroids. Calcipotriene, therefore, is an ideal candidate for use with steroids in sequential therapy. The recent advent of combination agent capcipotriene + betamethasone (Dovobet®, LEO Pharma) also makes the use of the calcipotriene-corticosteroid combination easier. Dovobet® is approved for use in Canada and LEO Pharma, in conjuction with Warner Chilcott submitted an NDA to the US FDA in March 2005.

However, some authors have suggested that extemporaneous compounding of calcipotriene with other agents, such as steroids, may result in the degradation of the vitamin D analog.⁵ Data from several sources should minimize this concern. One in vitro study showed no enhanced degradation of calcipotriene when used immediately after application of a steroid foam.⁶ The results of recent clinical trials also indicate improved efficacy, rather than degradation, when calcipotriene is combined with topical steroids (see below).⁷

New Steroid Formulations and Sequential Therapy

New formulations of topical steroids have proliferated in recent years. Among these formulations is the introduction of foam vehicles such as the clobetasol propionate foam (Olux™, Connetics). This foam is a thermolabile vehicle that breaks down on contact with human skin and at body temperature, providing for convenient and elegant application. Data from a variety of in vitro studies indicate that this foam formulation is a more efficient vehicle for drug delivery than other topical formulations, including both creams and ointments.^8-11

Furthermore, because clobetasol foam is quickly absorbed and leaves no residue, it is an ideal vehicle for use in combination with other topical agents, such as calcipotriene. This relative lack of concern regarding incompatibility applies only to the foam vehicle agent and not to any other situation where the vehicle does not vanish. The utility of this combination – clobetasol foam and calcipotriene – was evaluated in a recently completed clinical trial of topical sequential therapy. The results of this trial were presented in two abstracts at the 2004 and 2005 meetings of the American Academy of Dermatology (AAD).^7,12 Part 1 of the study evaluated the twice-daily use of clobetasol foam and calcipotriene for the clearance phase of therapy.7 Eighty-six subjects were randomized to three groups: combination therapy, or monotherapy with either clobetasol foam or calcipotriene. Subjects in the combination group were directed to apply calcipotriene immediately after the clobetasol foam was absorbed. After 2 weeks of treatment, reductions in psoriasis severity scores for target lesions were significantly greater in the combination therapy group than in either monotherapy group:

• vs. clobetasol: p=0.0017 for trunk lesions, p < 0.0001 for extremity lesions
• vs. calcipotriene: p < 0.0001 for both trunk and extremity lesions.

As mentioned previously, the results also support in vitro data suggesting that degradation of calcipotriene does not occur when it used immediately following application of a topical steroid.⁶ At the 2005 AAD meeting, the results of the second phase of this trial were reported.12 In this part – the second phase of the sequential treatment approach – subjects who achieved at least 50% improvement in target lesions during part one were randomized to one of two groups: weekday calcipotriene b.i.d. with weekend use of either clobetasol foam (b.i.d.) or placebo. Through 6 months of treatment, the combination therapy group showed a consistent, although not statistically significant trend toward greater maintenance of remission compared with the monotherapy group. Because this trend was similar for all assessments used in the study, the authors suggested that there may be a positive effect associated with the combination of clobetasol foam and calcipotriene in pulse therapy. Given the consistency of these trends, it is possible that the results would have been statistically significant if a greater number of subjects had participated in the study (n=38, intent-to-treat population).

Conclusions

Topical sequential therapy is an accepted and widely practiced technique for rapid clearance of lesions and long-term maintenance of remission. This approach is a fruitful balance between maximizing efficacy and minimizing side-effects. Current sequential therapy paradigms are rooted in the synergistic effects of topical agents with different mechanisms of action and divergent side-effect profiles, in particular, the use of a class I corticosteroid with calcipotriene. Used together in daily application of the clearance phase, these agents complement one another and promote the rapid induction of remission. Subsequent weekend steroid therapy combined with weekday calcipotriene reduces the potential for steroid-related side-effects while improving the maintenance of remission.

Patients who remain stable may then be switched to the third phase of sequential therapy, consisting of monotherapy with daily calcipotriene. Recent clinical trials support this approach. Newer steroid formulations, namely foam vehicles, further improve the convenience and efficacy of sequential therapy, eliminating concerns regarding dilution and incompatibility through their rapid evaporation.

References

1. 1. Koo J. Systemic sequential therapy of psoriasis: a new paradigm for improved therapeutic results. J Am Acad Dermatol 41(3 Pt 2):S25-8 (1999 Sep).
2. 2. Koo JYM. How and why to employ sequential therapy for psoriasis. Skin and Aging Suppl:16-21 (2000).
3. 3. Katz HI, Hien NT, Prawer SE, Scott JC, Grivna EM. Betamethasone dipropionate in optimized vehicle. Intermittent pulse dosing for extended maintenance treatment of psoriasis. Arch Dermatol 123(1):1308-11 (1987 Oct).
4. 4. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 39(3):447-50 (1998 Sep).
5. 5. Lamba S, Lebwohl M. Combination therapy with vitamin D analogues. Br J Dermatol 144 Suppl 58:27-32 (2001 Apr).
6. 6. Franz T, Lehman P, Spellman M. Calcipotriene stability in the presence of steroid foam. Presented at: 60th Annual Meeting of the American Academy of Dermatology: New Orleans, LA. 2002.
7. 7. Blum R, Stern D, Lebwohl M, Bandow G, Koo J, Cheplo K. A multi-center study of calcipotriene ointment, 0.005% and clobetasol propionate foam, 0.05% in the sequential treatment of localized plaque-type psoriasis. Presented at: Summer Meeting of the American Academy of Dermatology: New York, NY. 2004.
8. 8. Lenn J, Tanojo H, Huang X. Anatomical region variations on the in vitro skin permeation of clobetasol propionate formulations. Presented at: 62nd Annual Meeting of the American Academy of Dermatology: Washington, DC. 2004.
9. 9. Lenn J, Madlambayan L, Huang X, Tanojo H. Comparison of clobetasol propionate skin permeation and drug distribution in vitro from various topical drug delivery vehicles (foam, lotion, and wash-off shampoo). Presented at: Summer Meeting of the American Academy of Dermatology: New York, NY. 2004-2005.
10. 10. Deng H, Tanojo H, Lenn J, Cuesico C, Huang X. Foam as a novel vehicle in topical therapy. Presented at: 62nd Annual Meeting of the American Academy of Dermatology: Washington DC. 2004.
11. 11. Huang X, Tanojo H, Lenn J, Cuesico C, Deng H. Impact of vehicle on clobetasol propionate skin permeation and drug distribution in vitro. Presented at: 62nd Annual Meeting of the American Academy of Dermatology: Washington, DC. 2004.
12. 12. Koo J, Blum R, Lebwohl M, Stern D, Bandow G, Cheplo K. A 2-part, multi-center study of calcipotriene ointment, 0.005% and clobetasol propionate foam, 0.05% in the sequential treatment of localized plaque-type psoriasis: long-term outcomes. Presented at: 63rd Annual Meeting of the American Academy of Dermatology: New Orleans, LA. 2005.

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