ARTICLE
Auteur(s) : Jean-Paul ORTONNE1, Jörg C.
PRINZ2
1 Department of Dermatology, Hôpital L'Archet II, 15
rue de Saint Antoine de Ginestiere, BP 079, Nice, France
2 Department of Dermatology, Ludwig-Maximilians University,
Munich, Germany
Article accepted 07/10/2003
Psoriasis is a chronic inflammatory skin disease that follows a
waxing and waning course, but generally continues to affect
patients throughout their lives. It affects up to 3% of the world's
population and is associated with medical costs of nearly
$650 million each year in the United States alone [1, 2]. In
the United Kingdom, the annual total treatment cost of plaque
psoriasis, the most common form of the disease, has been estimated
at 54,413,812 (approximately 82,013,694.57 EUR), assuming a 2%
prevalence rate [3]. This excludes the significant economic burden
associated with hospital admissions, ambulatory and primary care,
as well as indirect costs (e.g. time off work).
Characteristic symptoms of plaque psoriasis include dry, red,
scaly, raised lesions that may be localized or appear over
widespread areas of the body. Patients often suffer from related
problems such as chronic skin pain, itching, cracking, infection,
and even disabling arthritis. In addition, psoriasis often has a
negative effect on patient quality of life, a fact that may be
underappreciated by many clinicians [4, 5]. Patients with psoriasis
report decreases in quality of life comparable to those caused by
cancer, arthritis, heart disease, diabetes, and major depression
[6]. It is not surprising, then, that up to 10% of patients with
psoriasis experience disease-related quality-of-life compromises
grave enough to consider suicide [4]. Studies have also found a
positive correlation between alcohol intake and psoriasis [7].
Therefore, it is extremely important that clinicians consider both
the psychosocial and physical aspects of psoriasis when selecting
therapy.
Treatments available for psoriasis include topical agents, light
therapy (UVA and UVB), and systemic drug treatment. Unfortunately,
most of these therapies are associated with substantial drawbacks,
such as lack of long-lasting disease remission, safety concerns,
and treatment inconvenience [8-14]. In addition, many patients fail
existing treatments or reach the maximum recommended lifetime
exposure. Novel biologic agents are being developed with the goal
of prolonging the duration of remission of psoriasis symptoms,
improving tolerability, and enhancing treatment convenience. The
objective of this article is to briefly highlight the clinical
profile of the recombinant human fusion protein, alefacept
(Amevive®, Biogen, Inc., Cambridge, MA, USA), and to
describe several case studies based on the authors' personal
experience with this drug. Phase 3 clinical trials have been
recently completed with alefacept [15, 16] and, in the United
States, it has been approved for the treatment of adult patients
with moderate to severe chronic plaque psoriasis who are candidates
for systemic therapy or phototherapy.
Alefacept – mechanism of action
Psoriasis is now recognized as an immune-mediated disease, and
activated memory T cells play a pivotal role in its pathogenesis
[17]. These T cells infiltrate the skin where they secrete the
T1-type cytokines that drive the underlying inflammatory process
causing keratinocytes to proliferate rapidly. Alefacept, which
consists of the first extracellular domain of LFA-3 fused to the
hinge, CH2, and CH3 domains of human IgG1, interferes with two key
events in the immunological cascade leading to psoriasis. The LFA-3
domain of alefacept binds CD2 on T cells to inhibit T cell
activation and proliferation, and the IgG1 domain of alefacept
binds FcγRIII on accessory cells to induce apoptosis of T cells
(Fig. 1) [18,
19]. Because CD2 is up-regulated on memory T cells [20, 21],
alefacept has selective effects on this T cell subset while
leaving other T cell populations relatively intact [22].
Alefacept – clinical profile
The efficacy and safety of alefacept were evaluated in two
multicenter, randomized, double-blind, placebo-controlled, phase
3 trials including more than 1,000 patients with chronic
plaque psoriasis [15, 16]. Alefacept was administered by
intravenous (IV) bolus or intramuscular (IM) injection to patients
at least 16 years of age suffering from chronic plaque
psoriasis for at least one year. All enrolled patients had normal
CD4+T cell counts at baseline and had not received
systemic agents or light therapy within 4 weeks of beginning
alefacept treatment. Each course of treatment consisted of
alefacept 7.5 mg IV or 15 mg IM administered once weekly
for 12 weeks followed by 12 weeks of observation.
In the IV study, 56% of patients (n = 367) treated with
one course of alefacept 7.5 mg achieved a ≥ 50% decrease
in PASI (PASI 50), and 28% achieved a 75% improvement in
PASI (PASI ≥ 75) during the study period (both P <.001
versus placebo) (Fig. 2) [15]. In the IM
study, 57% of patients (n = 166) treated with a single
course of alefacept 15 mg achieved PASI 50, and 33% achieved a
PASI 75 during the study period (both
P <.001 versus placebo) [16]. Patients
receiving two courses of IV or IM alefacept experienced additional
symptomatic improvement (Fig. 2) [15, 23].
The IV study was designed to evaluate duration of response to
alefacept [15]. In course 1, remission in patients who achieved
a = 75% decrease in PASI persisted for a median of
216 days (> 7 months) without the use of
significant topical therapy, phototherapy, or systemic therapy. The
median duration of response could not be determined among patients
who received two courses of IV alefacept because more than 50% of
patients were still in remission at the time of analysis, and this
appears to be extended beyond that obtained with a single course of
therapy.
Quality of life was assessed in both of the phase 3 trials
using the Dermatology Life Quality Index (DLQI), which was
completed at baseline and at 2 and 12 weeks after the
last alefacept dose [24, 25]. The results of the DLQI demonstrated
that alefacept 7.5 mg IV and 15 mg IM significantly
improved patient quality of life (Fig. 3). A second course of
IV alefacept provided additional improvements. Regardless of the
route of administration of alefacept, patients who achieved a
reduction in PASI between = 50% and < 75% at
2 weeks after the last dose in course 1 experienced a
significant improvement in their quality of life, and this benefit
was maintained 12 weeks after treatment cessation. The
combination of visible clinical amelioration and quality-of-life
benefit achieved when PASI was reduced by at least 50% demonstrates
that PASI 50 is an endpoint that reflects a considerable
improvement for patients. The results obtained using the DLQI were
similar to those achieved using another dermatology-specific
quality-of-life instrument, the Dermatology Quality of Life Scales
(DQOLS).
Alefacept was well tolerated [15, 16]. The most common adverse
effects were headache, accidental injury, pharyngitis, and
pruritus, with incidences similar to that associated with placebo.
Injection site reactions were observed with IM administration and
were typically classified as mild and did not lead to
discontinuation of therapy. Chills were observed with IV alefacept
but were limited to one or two occasions early during
treatment; > 90% of episodes occurred within
24 hours of treatment. No clinically meaningful cases of
sustained T cell suppression have occurred to date, and no
significant increased risk of infection has been linked to
alefacept use. No opportunistic infections, hypersensitivity
reactions, or disease flares after drug discontinuation were noted.
Alefacept has demonstrated minimal potential for
immunogenicity.
Case studies
Our experiences with alefacept result from participating in
three studies evaluating the efficacy of treatment and retreatment
of chronic plaque psoriasis with alefacept. Eleven patients with
PASI ranging from 11.4 to 44 (mean, 24.2) were included in the
first double-blind study receiving either placebo or 10 mg or
15 mg alefacept IM once weekly for 12 weeks with a
12-week follow-up. All patients had a long history
(= 15 years) of psoriasis with frequent disease relapses
and at least one systemic and/or phototherapeutic regimen.
Five of seven patients who received active drug improved
significantly, while two showed little improvement. Improvement of
disease tended to occur at about 6 – 8 weeks, and
continued during the follow-up period. Quality of life improved
noticeably in these patients. The trial design allowed patients to
be retreated with alefacept if they had mild or worsening psoriasis
by physician global assessment (PGA) that persisted or reappeared
after the first treatment course. As observed in other trials [15,
22], the effect of alefacept therapy was long-lasting. Retreatment
was initiated 4.5-6.5 months after the last alefacept dose of
the first course in six patients who met the criteria for
retreatment. Onset of remission occurred faster and more
efficiently in the second course compared with the first course.
After the follow-up period of the second course, two of the six
patients had only mild psoriasis and three patients were clear or
almost clear by PGA. One patient did not respond to the first or
the second course of alefacept. Interestingly, another patient who
had a minimal response to the first treatment course became clear
at the end of the second course. Retreatment induced longer
remission from disease than did the first treatment course.
Intramuscular drug administration was easy and well tolerated. No
local side effects were observed. The overall effort that patients
had to put into treatment was low. All patients were highly
compliant and content with the mode of application.
As a specific example, we treated a 51-year-old psychotherapist
who had been suffering from extensive plaque psoriasis since the
age of 24, and the impact on his quality of life was very
significant. He had an unremarkable medical history and did not
take medication that could exacerbate psoriasis. His psoriasis was
severe, involving the forearms, arms, back, and legs. On the face,
the lesions on the sebaceous zones (ie, eyebrows, naso-labial) were
very visible. The scalp was affected as well as the nails of the
hands and feet (ie, subungual onchylosis and hyperkeratosis). The
palms and soles were also affected, but the body folds were
undisturbed. The patient did not complain of itching. He consulted
a dozen dermatologists who proposed local treatments, essentially
composed of corticosteroid ointments and lotions. The results were
very scant, and the constraint of a local, daily treatment was
accepted reluctantly by the patient who became progressively lax
over time. Over these long years, in spite of everything, he
achieved some improvement, but not a total clearing, in the summer
after sunbathing.
In 1985, after 9 years of evolution of the psoriasis, a
dermatologist proposed balneo-PUVA therapy (topical 8-MOP and
ultraviolet light therapy) to the patient. A very significant
improvement occurred after 10 sessions, and complete clearing
was obtained by the 20th session. Ultraviolet light therapy was
stopped. A relapse occurred after 3 months of remission, and
it was as severe as before the treatment. After several
unsuccessful attempts to treat his psoriasis through application of
vitamin D3 analogs, the patient gave up and turned towards
alternative medicine without much success. In 1999, he returned to
traditional medicine by consulting our department. Taking into
account the severity of his outbreak, several systemic treatment
strategies were proposed to him. The patient decided to try
alefacept by intramuscular injection once a week for 12 weeks.
He obtained clearing of disease that was maintained for
4 months. The patient appreciated the convenience of the
treatment compared with the topical and phototherapies he had
previously received. In addition, he tolerated alefacept well, and
he volunteered to renew this treatment for 12 weeks. This
second course of treatment led to approximately 60% improvement
that was maintained for 3.5 months. A third course of
treatment was initiated and resulted in complete clearing that
persisted 8 months after treatment was complete. The patient
expressed satisfaction with alefacept therapy and stressed the ease
of treatment because of the way the drug is administered and how
well it is tolerated. Figure 4 shows change in
PASI, PGA, and CD4+ T cell counts over the three
treatment courses for this patient.
Alefacept therefore appears an effective treatment modality for
many patients. Constraints may result only from three aspects: (1)
Treatment response cannot yet be predicted. Because alefacept is a
remittive therapy and results are apparent later in the treatment
course, sometimes peaking after the end of treatment during the
follow-up period, a full course is necessary to fully distinguish
those patients who may best benefit. (2) Determination of
CD4+ and/or CD8+ T cell counts in
peripheral blood T cells before and during therapy may not be
available in all settings. (3) Although there is a clear value for
the use of biologics in the treatment of psoriasis, the cost of
these products may require a change in the pharmacoeconomical
perception of health care costs. Treatment with alefacept appeared
to be safe. Future observations will have to confirm long-term
safety and exclude an increased risk of malignancies.
According to our experience and the data published in treatment
studies, alefacept represents a promising new addition to the
dermatologist's armamentarium for the treatment of psoriasis. The
challenge now is to position this new product in the context of
existing treatments. In the authors' experience, patients who would
make good candidates for alefacept therapy include those who (1)
have a history of moderate to severe chronically relapsing
psoriasis that requires regular visits to a dermatologist; (2)
require a new treatment option because other treatment modalities
have been ineffective; (3) have had tolerability problems with
prior treatments or would be expected to experience problems with
other systemic treatments; (4) have quality of life strongly
influenced by their physical appearance (ie,exposed areas affected,
face, hands) and are impaired by physical appearance and
psychological pressure as well as by time constraints imposed by
other treatment modalities; and (5) are likely to comply with the
treatment regimen. Patients should be 16 years of age and
older, should not be pregnant or breast feeding, and should be
HIV-negative and without a recent history of malignancies.
Conclusions
Alefacept offers a new effective, safe, disease-remittive
treatment option for adult patients with chronic plaque psoriasis.
In clinical studies, more than 55% of patients achieved a decrease
in PASI of ≥ 50% after a single course of alefacept
treatment and approximately 70% achieved a ≥ 50% decrease
in PASI after two courses. Alefacept is unique among current
therapies for psoriasis because of its ability to induce
long-lasting clinical efficacy, its low incidence of adverse
effects, and the convenience of treatment due to the lengthy
periods spent without a need for therapy. The long-term safety of
alefacept will be monitored to confirm that there is no increased
risk of infection or malignancy with treatment. Alefacept also
offers considerable quality-of-life enhancement to patients
suffering the debilitating psychosocial and physical consequences
of psoriasis. Alefacept is the first therapy that can provide
long-lasting, safe clearance of disease with improved quality of
life for patients with psoriasis. n
References
1. Barker JN. Psoriasis as a T cell-mediated autoimmune
disease. Hosp Med 1998; 59: 530-3.
2. Javitz HS, Ward MM, Farber E, Nail L, Vallow SG. The
direct cost of care for psoriasis and psoriatic arthritis in the
United States. J Am Acad Dermatol 2002; 46: 850-60.
3. Piercy J, Mesrobian X, Viala M, Evans C, Prosek B.
Estimating the cost of moderate to severe chronic plaque psoriasis
in the UK. JEAV 2002; 16: 284. [Abstract P27-32].
4. Krueger G, Koo J, Lebwohl M, Menter A, Stern RS,
Rolstad T. The impact of psoriasis on quality of life. Results of a
1998 National Psoriasis Foundation Patient-Membership Survey.
Arch Dermatol 2001; 137: 280-4.
5. Wong C, Kirby B. Managing the patient with psoriasis.
Practitioner 2001; 245: 913-22.
6. Rapp SR, Feldman SR, Exum ML, Fleischer AB, Jr.,
Reboussin DM. Psoriasis causes as much disability as other major
medical diseases. J Am Acad Dermatol 1999; 41: 401-7.
7. Faber FM, Nall L. Psoriasis and alcoholism.
Cutis 1994; 53: 21-7.
8. Messana JM, Johnson KJ, Mihatsch MJ. Renal structure
and function effects after low dose cyclosporine in psoriasis
patients: a preliminary report. Clin Nephrol 1995;
43:150-3.
9. Zachariae H, Kragballe K, Hansen HE, Marcussen N,
Olsen S. Renal biopsy findings in long-term cyclosporin treatment
of psoriasis. Br J Dermatol 1997; 36: 531-5.
10. Koo J, Lebwohl M. Duration of remission of psoriasis
therapies. J Am Acad Dermatol 1999; 41: 51-9.
11. Lindelöf B, Sigurgeirsson B, Tegner E, Larkö O,
Johannesson A, Berne B, Ljunggren B, Andersson T, Molin L,
Nylander-Lundqvist E, Emtestam L. PUVA and cancer risk: the Swedish
follow-up study. Br J Dermatol 1999; 141: 108-12.
12. Shephard SE, Panizzon RG. Carcinogenic risk of bath
PUVA in comparison to oral PUVA therapy. Dermatology 1999;
199: 106-12.
13. Stern RS, the PUVA Follow-up Study. The risk of
melanoma in association with long-term exposure to PUVA. J Am
Acad Dermatol 2001; 44: 755-61.
14. McClure SL, Valentine J, Gordon KB. Comparative
tolerability of systemic treatments for plaque-type psoriasis.
Drug Safety 2002; 25: 913-27.
15. Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver
WP, Ellis CN, for the Alefacept Clinical Study Group. A randomized,
double-blind, placebo-controlled phase III study evaluating
efficacy and safety of 2 courses of alefacept in patients with
chromic plaque psoriasis. J Am Acad Dermatol 2002; 47:
821-33.
16. Lebwohl M, Christophers E, Langley R, Ortonne J-P,
Roberts J, Griffiths CEM, for the Alefacept Clinical Study Group.
An international, randomized, double-blind, placebo-controlled
phase 3 trial of intramuscular alefacept in patients with
chronic plaque psoriasis. Arch Dermatol 2003; 139:
719-27.
17. Singri P, West DP, Gordon KB. Biologic therapy for
psoriasis. The new therapeutic frontier. Arch Dermatol 2002;
138: 657-63.
18. Miller GT, Hochman PS, Meier W, Tizard R, Bixler SA,
Rosa MD, Wallner BP. Specific interaction of lymphocyte
function-associated antigen 3 with CD2 can inhibit T cell
responses. J Exp Med 1993; 178: 211-22.
19. Majeau GR, Meier W, Jimmo B, Kioussis D, Hochman PS.
Mechanism of lymphocyte function-associated molecule 3-Ig fusion
proteins inhibition of T cell responses. Structure/function
analysis in vitro and in human CD2 transgenic mice. J
Immunol 1994; 152: 2753-67.
20. Sanders ME, Makgoba MW, Sharrow SO, Stephany D,
Springer TA, Young HA, Shaw S. Human memory T lymphocytes express
increased levels of three cell adhesion molecules (LFA-3, CD2, and
LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have
enhanced IFN-g production. J Immunol 1988; 140: 1401-07.
21. Majeau GR, Whitty A, Yim K, Meier W, Hochman PS. Low
affinity binding of an LFA-3/IgG1 fusion protein to CD2+
T cells is independent of cell activation. Cell Adhes Commun
1999; 7: 267-79.
22. Ellis CN, Krueger GG, for the Alefacept Clinical
Study Group. Treatment of chronic plaque psoriasis by selective
targeting of memory effector T lymphocytes. N Engl J Med
2001; 345: 248-55.
23. Ortonne J-P, Prinz JC, Bos JD, Wozel G, Lahfa M,
Dubertret L, O'Gorman J. Efficacy and tolerability of retreatment
with intramuscular alefacept in psoriasis patients. JEAV
2002; 16: 283. [Abstract P27-30].
24. Finlay AY, Salek MS, Haney J, for the Alefacept
Clinical Study Group. Intramuscular alefacept improves
health-related quality of life in patients with chronic plaque
psoriasis. Dermatology 2003; 206: 307-15.
25. Feldman SR, Menter A, Koo JY. Improved health-related
quality of life following alefacept treatment in patients with
chronic plaque psoriasis. Br J Dermatol in press.
|
Printable version
Version PDF
