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Biologic Therapy for Psoriasis
The New Therapeutic Frontier
Prashant Singri, MD;
Dennis P. West, PhD;
Kenneth B. Gordon, MD
Arch Dermatol. 2002;138:657-663.
ABSTRACT
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Objectives (1) To develop a clinically useful model with which dermatologists can
understand the potential uses of biologic therapy for psoriasis and understand
the potential differences among these novel drugs, (2) to discuss the process
by which recombinant DNA technology is used to develop rationally designed
protein medications along with the potential benefits and difficulties of
therapy with biologic agents, and (3) to provide a short review of the medications
under development for psoriasis.
Data Sources The pertinent literature was reviewed with particular emphasis on published,
randomized, and placebo-controlled trials. Phase 1 and early phase 2 trials
were also included in our review when more stringent studies were not available.
Studies presented as peer-reviewed abstracts at major conferences were also
reviewed.
Conclusions With the development of recombinant DNA techniques, it has become possible
to develop new biologic therapies that can be designed to specifically alter
physiological responses. These new drugs are in use in many different medical
fields and will soon be available for the treatment of dermatological diseases,
primarily psoriasis. Dermatologists should be familiar with the potential
benefits and risks of these therapies to make rational decisions concerning
their use in the treatment of their patients with psoriasis.
INTRODUCTION
AS KNOWLEDGE of the immunopathogenesis of psoriasis has grown over the
past decade, there has been a significant effort to find a more specific therapy
for this disease with fewer adverse outcomes. The standard systemic therapy
for psoriasis has consisted of relatively nonspecific treatment modalities
with adverse effects that involve multiple organ systems. More recently, biotechnology,
using genetic engineering techniques, has created a real possibility for efficacious
and safe psoriasis therapy. Recombinant proteins, the outcome of recent biotechnology
initiatives, function as agents that comprise biologic therapy.
Biologic agents are proteins that possess pharmacologic activity and
can be extracted from animal tissue or, much more commonly, synthesized in
large quantities through recombinant DNA techniques. Outside of dermatology,
biologic therapies have been in use for decades. The most commonly used biologic
therapy has been insulin, a protein first extracted from pigs and now made
as recombinant human insulin. Other areas in which biologic therapy has been
in common use include hematopoietic support (eg, erythropoietin, granulocyte,
and platelet growth factors)1 and in solid
organ transplantation,2 in which monoclonal
antibodies designed to inhibit rejection have been used.3
More recently, immune-mediated diseases analogous to psoriasis, including
Crohn disease and rheumatoid arthritis,4-5
have been treated with biologic agents designed to inhibit immune responses
that are central to their pathological condition. As a consequence of successful
biologic therapy for immune-mediated diseases, psoriasis has become a primary
target for biologic therapy in dermatology.
TYPES OF BIOLOGIC THERAPY
Biologic molecules can be designed to either mimic the actions of normal
human proteins or to interact with circulating proteins or cellular receptors.
There are 3 distinct types of molecules that have been studied for use in
psoriasis: (1) recombinant human cytokines or growth factors, (2) monoclonal
antibodies, and (3) fusion proteins. All of these agents can be manufactured
using recombinant DNA technology. After the molecule is made, complementary
DNA encoding the protein is transfected into a prokaryotic or eukaryotic cell
line that secretes the protein drug.6 The appropriate
protein can then be isolated and purified for use as a therapeutic agent.
Recombinant Human Proteins
Recombinant human proteins are molecules that are either exact replicas
of normal human proteins or fragments thereof that have specific physiological
effects. These drugs function by interacting with normal cellular receptors
to induce their effects.6-8
These effects are often limited to normal physiological function of the protein
as is the case with recombinant insulin and type 1 diabetes mellitus. However,
when these drugs are given in supraphysiological doses, they may have effects
that are not readily predicted.
Monoclonal Antibodies
Monoclonal antibodies are proteins that specifically bind to proteins
on cell surfaces in the circulation or tissue. This interaction alters activity
of the target protein. Most often, the monoclonal antibody inhibits effects
of the protein, thus altering the course of disease. Because the targets of
monoclonal antibody therapy are human proteins, these molecules must originally
be made in other species, usually in mice. Initial monoclonal antibody therapies
were simply these murine antibodies. However, patients given these drugs frequently
developed immune responses to the foreign protein, making them inappropriate
therapy for nonlethal diseases. More recent monoclonal antibody therapies
have been humanized.9 In other words, the specific
binding site from a murine antibody is attached (through recombinant DNA technology)
to the Fc portion of human immunoglobulin.10-12
This process results in a new protein drug similar to a normal human antibody,
significantly reducing immune response to the agent and prolonging both its
half-life and activity.
Abgenix Inc, Fremont, Calif, has developed a transgenic mouse that can
produce fully human antibodies directed against human proteins.13
The mouse was designed by first knocking out the DNA that encodes mouse immunoglobulin.
The human immunoglobulin locus was then substituted for the mouse DNA to create
a mouse that produces only human antibodies. Since these mice are not developmentally
exposed to human proteins, they will produce fully human antibodies when presented
with a foreign, human protein. Because these antibodies have almost no foreign
elements, this process could produce biologic proteins that are more completely
accepted by the patient's immune system.
Fusion Proteins
The final designs used in biologic therapy include fusion proteins.
Fusion proteins are molecules that combine sections of different proteins.
There are 2 distinct types of fusion proteins. The first combines a human
protein with a toxin.14 Human protein binds
to a cell and causes the entire complex to be internalized. Once inside the
cell, toxin is released, thereby killing the cell.15
The other design is similar to humanized monoclonal antibodies. However, instead
of using a mouse antibody binding site to confer specificity, these agents
use human receptors for proteins.11 Receptors
are then bound to the Fc portion of human immunoglobulin in a similar manner
as humanized monoclonal antibodies.
ADVERSE EFFECTS OF BIOLOGIC AGENTS
As with any new therapy, the adverse effect profile of biologic therapy
will be established after years of experience. However, the current prevailing
attitude is that the greatest advantage of biologic therapy may be its potentially
greater safety profile. Because biologic agents are specific to which cell
types they bind, multiorgan adverse effect profiles (as seen with traditional
antipsoriatic drugs, such as retinoids, methotrexate, and macrolides) should
not present as an issue. In the published literature on solid organ transplants,
along with early studies with biologic agents in psoriasis, the liver and
kidneys seem not to be adversely affected.3, 16-17
Likewise, because these agents are metabolized as endogenous proteins and
antibodies, clinically significant drug interactions are unlikely.
There are 2 areas of concern with biologic therapy that should be addressed.
Cytokine release syndrome has been a long-time concern since early immunotherapy
for organ transplants with OKT3, which is a nonhumanized monoclonal antibody
that binds to CD3, the initial signaling step in the T-cell receptor. After
a transient activation by binding CD3, OKT3 nonselectively depletes all T
cells.18 This often causes fever, hypotension,
headache, skin rash, and abdominal symptoms.19
Immunologically, cytokine release syndrome is characterized by the rapid release
of cytokine tumor necrosis factor  (TNF-) and interferon 
(IFN-).20-21 At times,
cytokine release syndrome due to OKT3 may be life threatening. Importantly,
cytokine release syndrome seems to be a specific manifestation of agents that
bind CD3 and should not be a concern for biologic drugs directed against other
proteins.
Immunosuppression is an additional significant concern for any drug
used to treat immune-mediated diseases such as psoriasis. Systemic therapies
for psoriasis including cyclosporine, methotrexate, and psoralen –UV-A,
as well as other drugs commonly used in dermatology (eg, corticosteroids),
are all potent immunosuppressive agents. While there is no doubt that the
efficacy of biologic therapies is related to their ability to inhibit specific
functions within the immune system, early studies have suggested that the
risk of infection with several biologic agents may not be significantly greater
than placebo.16 Current evidence indicates
that the risk of immunosuppression from biologic agents used in psoriasis
is unlikely to be worse than commonly used dermatological drugs and may more
likely be a significant improvement in immunosuppression risk.
IMMUNOLOGICAL BASIS OF PSORIASIS
It is currently understood that psoriasis is driven by activated memory
T cells.22-23 There are 2 populations
of these T cells: dermal cells (which are primarily CD4+ cells)
and epidermal T cells (which are predominantly CD8+ cells). CD4+ T cells as well as many CD8+ cells migrate preferentially
to the skin from the circulation via cutaneous lymphocyte antigen. Some CD8+ cells in the epidermis may be resident to the skin. For these T cells
to induce psoriatic plaques, they must be activated by antigen-presenting
cells (APCs). This process of activation requires 2 signals between the T
cell and the APC (Figure 1). Signal
1 requires recognition of a specific antigen processed and presented by the
APC and recognized by the T-cell receptor of the interacting T cell. At present,
however, no specific antigens have been recognized in psoriasis. If this recognition
is accomplished, the T cell must receive a second, costimulatory signal from
the APC. There are a number of interactions that participate in this costimulatory
apparatus, some of which are listed in Table 1. This activation process has been a target for many biologic
drugs.
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Figure 1. Antigen-presenting cell (APC)–T-cell
interactions needed for T-cell activation. Interactions for antigen-specific
recognition are shown in green (signal 1), while interactions needed for costimulation
are shown in blue (signal 2). ICAM-1 indicates intracellular adhesion molecule-1;
LFA, lymphocyte function–associated antigen; MHC, major histocompatibility
complex; and TCR, T-cell receptor.
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Potential Targets for Biologic Agents Using Strategy 2*
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T cells in psoriatic plaques are mainly effector T cells that have been
previously activated, which is demonstrated by their expression of the memory
T-cell marker CD45RO. The effector function of many of the T cells is the
secretion of cytokines. The specific cytokine pattern produced in psoriasis
is the T1 type,24 primarily with interleukin
(IL) 2 and IFN-.25
CD4+ cells may activate or
provide help to the epidermal T cells through their cytokine secretion and
are necessary for the development and maintenance of psoriasis. Likewise,
the epidermal changes in psoriasis are likely a function of the cytokines
produced by epidermal T cells or cell-cell interactions that have not been
fully elucidated. These factors produce keratinocyte and vascular changes,
including increased proliferation and decreased cellular maturation that is
clinically recognized as psoriasis. Keratinocytes and other local cells including
dendritic cells and monocytes produce other cytokines that magnify these effects,
including TNF-26-27 and
IL-8.28-29 Many therapies have
sought to alter these cytokine responses to treat psoriatic plaques.
STRATEGIES FOR IMMUNOMODULATION: A MODEL FOR BIOLOGIC THERAPY FOR PSORIASIS
The immunopathological features of psoriasis provide the basis for a
conceptual model that incorporates the mechanism of action and target for
rationally designed biologic therapy. There are 4 strategies within this model
that clarify the mechanism of action for the various biologic agents (Figure 2). These strategies include (1) reduction
of the pathogenic T cells, (2) inhibition of T-cell activation, (3) immune
deviation, and (4) blocking the activity of inflammatory cytokines. Some biologic
agents may have multiple mechanisms of action.
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Figure 2. Sites of action of the different
strategies for biologic therapy in the immunological cascade of psoriasis:
strategy 1, elimination of the effector T cell; strategy 2, blockade of T-cell
stimulation by inhibiting signal 1 or signal 2; strategy 3, immune deviation
inhibiting TH1 cytokine secretion; and strategy 4, binding and
blocking action of postsecretory cytokines. APC indicates antigen-presenting
cell.
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Strategy 1: Reduction in the Number of Pathogenic T Cells
An obvious approach to treating psoriasis would be to reduce the numbers
of T cells that are inducing the disease. Ideally, this strategy would work
best when the cells most responsible for psoriasis (CD45RO+ T cells30 in the skin producing TH1 cytokines) could
be targeted without altering other immunological processes. This strategy
would have the potential advantage of inducing longer lasting remissions because
it is likely that some of the T cells, particularly the epidermal cells, may
take time to repopulate the skin. This mechanism may explain why psoralen–UV-A
therapy induces relatively long remissions by inducing apoptosis in epidermal
T cells.31
Strategy 2: Inhibition of T-Cell Activation and Migration
Because pathogenic cells in psoriasis are activated T cells, it is reasonable
to believe that if T cells are not able to become activated, they cannot induce
psoriasis. T-cell activation requires interactions between an APC and T cell.22 These are currently referred to as signal 1 and signal
2. Signal 1 is the well-known interaction in which the APC presents a specific
antigen to the T cell in the context of the major histocompatibility complex
and an association with CD4 or CD8 on the T cell. The T cell recognizes this
antigen through the T-cell receptor and signals through CD3. Signal 2 is termed costimulation and is accomplished through the multiple
APC–T-cell interactions listed in Table 1.32-33 Biologic
agents are therefore designed to interact with either signal 1 or signal 2
and may block the ability of the T cell to become activated and, thus, propagate
psoriasis. Activation and migration are coupled in this model because many
of the cell-cell interactions are mediated via the same receptors.
Strategy 3: Immune Deviation
As mentioned above, the activated T cells in psoriatic plaques produce
cytokines of the TH1 phenotype. These cytokines include IL-2 and
IFN- and are vital to the expression of psoriasis. It is well known
that cytokines produced by TH2 T cells, including IL-4, IL-10,
and IL-11,34 tend to reduce the activity of
TH1 cells.35-36 Immune
deviation is induced by the "deviation" of a TH1 immune response
toward a greater TH2-type response through the involvement of these
TH2-type cytokines.37 Therefore,
it may be possible to decrease the activity of psoriasis by the administration
of TH2 cytokines in an effort to inhibit the appropriate TH1 cytokine production.
Strategy 4: Blocking the Activity of Inflammatory Cytokines
Many of the phenotypic and pathological changes in psoriasis are related
to the effects of cytokines secreted by T cells, dendritic cells and monocytes,
and local keratinocytes. These cytokines likely induce keratinocyte changes,
induce angiogenesis, and increase the already active immune response. This
strategy relies on the ability of biologic agents to bind to secreted cytokines
and block their ability to contribute to psoriasis.38
Therefore, a biologic medication that can bind to TNF- or IL-839 might be able to decrease the severity of psoriasis
by eliminating the activity of these cytokines and all of their effects on
the various cell types involved in psoriasis.
POTENTIAL BIOLOGIC AGENTS FOR PSORIASIS
Some of the biologic agents being considered for the treatment of psoriasis
are listed in the following tabulation (drugs are listed in the order of the
phase of development).
*Drug was approved by the Food and Drug Association (FDA) for an indication
other than psoriasis.
Considerably more biologic molecules will likely be developed for use
in psoriasis as biotechnology progresses. Selected biologic agents, classified
by the strategy they represent and in the context of available published data,
are described to illustrate the concepts of biologic therapy for psoriasis.
All of the agents discussed in these strategic mechanisms are in various stages
of clinical development as potential agents in the treatment of psoriasis.
Strategy 1
Alefacept
Alefacept (LFA-3TIP) (Amevive; Biogen Pharmaceuticals, Cambridge, Mass)
is a fusion protein combining the binding site of lymphocyte function–associated
antigen-3 (LFA-3) with the Fc portion of human IgG. This medication binds
specifically to T cells expressing CD2, the natural ligand of LFA-3. CD2 is
expressed maximally in T cells that have been activated and express CD45RO,
a sign of a memory T-cell phenotype. These are the specific group of cells
that are most important in the propagation of psoriasis. When this drug is
given therapeutically, the number of these cells circulating in the blood
is reduced.30
Published results with this medication have shown efficacy with an excellent
safety profile. Results of phase 2 trials showed a statistically significant
reduction in psoriasis from baseline measured by the Psoriasis Activity and
Severity Index (PASI).40 Of the patients, 60%
showed more than 50% improvement, and in one dose range, one third of the
patients had at least 75% improvement. It was also noted that of the patients
who "cleared," the mean duration of the remission was 8 months. This likely
reflects slow repopulation of the skin with native T cells. There was also
no increased incidence of infection and no incidence of cytokine release syndrome.
In a retreatment study, the response was similar, with one half of the patients
achieving more than 50% improvement, and one fifth improving by at least 75%.41
Denileukin Diftitox
Denileukin diftitox (DAB386IL2) (Ontak; Ligand Pharmaceuticals,
San Diego, Calif) is one of the first biologic agents used for the treatment
of psoriasis.14 This medication is a fusion
protein that combines IL-2 with a subunit of diphtheria toxin. Because IL-2
is internalized exclusively in activated T cells, the toxin will only eliminate
cells that are active when the drug is given. Thus, denileukin diftitox should
selectively eliminate activated T cells and reduce the activity of psoriasis.15 This drug is approved by the FDA for the treatment
of cutaneous T-cell lymphoma.42-44
Published trials with denileukin diftitox for psoriasis are limited.
One trial of low doses of this medication demonstrated clinical responses
in 8 of 10 patients.14 More importantly, there
was a marked reduction in the inflammatory infiltrate in patients treated
with denileukin diftitox, along with correction of many of the immunohistochemical
changes associated with psoriasis. In an early phase 2 clinical trial, all
6 patients achieved greater than 30% response, and 2 patients improved more
than 50% from baseline PASI.45
Strategy 2
Efalizumab
Efalizumab (anti-CD11a) (Genentech and XOMA; South San Francisco, Calif)
is a humanized monoclonal antibody aimed at binding CD11a on T cells. CD11a
is a component of LFA-1, that, when bound to intracellular adhesion molecule-1
(ICAM-1) on APCs, provides an important costimulatory signal. Moreover, the
LFA-1–ICAM-1 interaction is also vital to T-cell adhesion to endothelial
cells and is necessary for T-cell migration into inflamed tissues, including
skin. Thus, efalizumab may block both T-cell activation and cellular migration,
potential areas of therapeutic benefit in psoriasis.16
Clinical studies with efalizumab have shown efficacy with few adverse
effects. In the optimal dose group in phase 2 trials, 62% of patients showed
at least a 50% decrease in the PASI, while 30% had a 75% improvement.46 Adverse effects consisted of mild headache, fever,
and chills that generally subsided with continued use of the drug. Importantly,
none of these effects was serious enough for a patient to choose to stop using
the medication. In these phase 2 trials, there were no significant infectious
complications that might suggest an immunosuppressive effect.47
IDEC-114
Among the most important interactions for T-cell stimulation is the
costimulatory signal between the APCs CD80 (B7-1) and CD28 on the T cell.
The anti-CD80 molecule (IDEC-114) blocks this interaction through a humanized
monoclonal antibody directed against CD80. Not only should this block T-cell
stimulation, but without binding of CD28 through B7, a T cell may become energized
and not be able to respond to stimuli for some time.48
Clinical data for this drug are just beginning to emerge. In a phase 1 trial
with a single-dose regimen of IDEC-114, there was clinical efficacy with mild
adverse effects such as headache, fever, chills, and upper respiratory tract
infections.49 Of the patients, 40% achieved
at least 50% reduction in PASI after receiving 4 biweekly doses.50
Daclizumab
Daclizumab (anti-CD25) (Zenapax; Protein Design Labs, Fremont, Calif)
is a humanized monoclonal antibody that has been FDA approved for the prevention
of acute renal transplant rejection.51 Daclizumab
binds to the CD25 subunit of the IL-2 receptor on T cells, thus blocking T-cell
proliferation and responses to an important T-cell growth factor, IL-2. Because
CD25 is expressed in high levels in lesions of psoriasis, the inhibition of
IL-2 binding could play a role in suppressing psoriasis. One phase 2 trial
of daclizumab in psoriasis has been published and demonstrates a mean reduction
in PASI of 30% and a 44.8% decrease in IL-2 expression. Improvement was also
noted to continue up to 4 weeks after the last dose.52
Siplizumab
Siplizumab (Medi-507; Medimmune, Gaithersburg, Md) is a humanized monoclonal
antibody directed against CD2 expressed in high concentrations on activated
T cells. It is designed to block costimulation by inhibiting the CD2–LFA-3
interaction. However, similar to alefacept, peripheral lymphocyte counts are
diminished in patients treated in early phase 1/2 studies with siplizumab,
suggesting that this drug may work through strategy 1.53
Though only early phase 1/2 studies have been completed, some patients treated
with siplizumab have achieved significant responses to therapy.53
Strategy 3
Oprelvekin
Instead of trying to block the immunological process, drugs that use
strategy 3 push the immune response in a direction that will help control
the disease pathological course. In psoriasis, immune deviation suggests that
inhibiting TH1-type T cells that drive the disease by the addition
of TH2-type cytokines will improve psoriasis.54
Oprelvekin (rhIL-11) (Neumega; Genetics Institute, Cambridge, Mass), a recombinant
form of human IL-11, is an FDA-approved therapy for the treatment of chemotherapy-induced
thrombocytopenia. It has been determined that IL-11 may also act to induce
immune deviation in TH1-mediated immune diseases such as psoriasis.55 In early trials with subcutaneously injected oprelvekin,
there has been some histological evidence of decreased TH1 gene
expression and cytokine release. At present, clinical efficacy has not been
reported.
Recombinant Human IL-10
Interleukin 10 is an important TH2-type cytokine that is
extremely important in the down-regulation of ongoing TH1 immune
responses.56 Recombinant human IL-10 (Tenovil;
Schering, Berlin, Germany) is a recombinant cytokine that can be given in
subcutaneous injections. Early phase 1/2 trials have shown that subcutaneous
injections of recombinant human IL-10 three times a week decreased the level
of TH1 cytokines and subsequently improved psoriasis. There was
a mean reduction of 55% in the PASI to patients receiving the molecule, with
the immunological changes persisting for several months after the last dose.
In general, the research subjects tolerated the medication with few and nonserious
adverse effects.57-58
Strategy 4
Etanercept and Infliximab
Tumor necrosis factor is central cytokine to both the persistence
of the immune response that drives psoriasis and the aberrant keratinocyte
response.26 The anti–TNF- agents
etanercept (Embrel; Immunex Corporation, Seattle, Wash) and infliximab (Remicade,
Centocor, Malvern, Pa) bind and inhibit the activity of TNF- through
slightly different mechanisms. Etanercept is a fusion protein using the extracellular
domain of the TNF- receptor given twice a week as a subcutaneous injection.59 Infliximab is a monoclonal antibody derived from
mouse directed against human TNF- and is given as an intravenous infusion
at intervals dependent on the state of the disease.60
Both of these molecules are FDA approved for the treatment of rheumatoid arthritis,
while etanercept is approved for psoriatic arthritis and infliximab is approved
for Crohn disease.5 There is very early evidence
that both these agents will have efficacy in psoriasis. In the psoriatic arthritis
trials with etanercept, there was a noticeable response in several patients'
cutaneous psoriasis. Mean improvement in PASI was 46%, with 12 of 30 patients
achieving at least a 50% improvement. Likewise, a number of case reports support
a response of cutaneous psoriasis to infliximab.61
One recent, small, randomized, controlled study demonstrated a greater than
80% response rate (more than a 75% improvement in PASI) with minimal adverse
effects.62
ABX-IL8
ABX-IL8 (Abgenix Inc, Fremont, Calif) is a fully human monoclonal antibody
designed to bind free IL-8 and deactivate it in the skin. A chemokine that
is secreted in large amounts by keratinocytes and immune cells in psoriatic
plaques, IL-8 is important for the attraction of lymphocytes and neutrophils
into the skin and may play a key role in the vascular responses found in psoriasis.28-29 In early trials, there has been some
demonstrated clinical response to this molecule, with a phase 1 dose escalation
approach showing increased benefit with larger doses. In a phase 2 trial,
about 1 in 5 patients in the group receiving 3 mg/kg every 3 weeks had a 75%
improvement in their PASI. Additionally, there were histological responses
suggesting improvement in psoriasis.63 Importantly,
as would be expected from a fully human molecule, the drug has been well tolerated,
and doses may be escalated to demonstrate increased efficacy.13
SMART Anti–IFN-
Because IFN- is central to both the TH1 cytokine profile
in psoriasis and keratinocyte hyperproliferation in this disease, it should
be a prime target for anticytokine therapy. SMART anti–IFN- (Huzaf;
Protein Design Labs, Fremont, Calif), a humanized monoclonal antibody, binds
and inactivates IFN- and could be an excellent targeted molecule for
this strategy. Early phase 1/2 studies are being performed at this time.
CONCLUSIONS
Systemic treatment of psoriasis has been limited by the safety of many
of the drugs that are effective in clearing this disease. Recent advances
in biotechnology have led to a proliferation of new strategies for treating
this disease with agents that can be designed to specifically act on the immune
system, which may prove to be much safer than traditional therapies. These
therapies hold promise for revolutionizing the therapy for psoriasis for those
patients whose quality of life is reduced by this chronic, debilitating disease.
AUTHOR INFORMATION
Accepted for publication December 12, 2001.
Corresponding author and reprints: Kenneth B. Gordon, MD, Department
of Dermatology, Feinberg School of Medicine, 675 N St Clair St, Suite 19-150,
Chicago, IL 60611 (e-mail: kbg704{at}northwestern.edu).
From the Department of Dermatology, Feinberg School of Medicine, Chicago,
Ill.
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