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
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.
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.
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
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
Calcipotriene b.i.d., weekdays only
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
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
Combination Therapy: Calcipotriene With
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
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).
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
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.
- 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. Koo JYM. How and why to employ sequential therapy for psoriasis. Skin and Aging Suppl:16-21 (2000).
- 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. 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. Lamba S, Lebwohl M. Combination therapy with vitamin D analogues. Br J Dermatol 144 Suppl 58:27-32 (2001 Apr).
- 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. 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. 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. 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. 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. 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. 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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