PSORIASIS AND BIOLOGICS
Mar
2010
Vol. 29. No. 1
Introduction
Twenty years ago I trained in dermatology at the University
of Miami. At that time, Miami had an important voice
in psoriasis research, with faculty members such as Gerald
Weinstein, Phillip Frost, Vincent Ziboh, Kenneth Halprin,
and J. Richard Taylor leading the charge to develop new
insights and new therapies for the disease.
As dermatology residents, we were taught that psoriasis
was a primary keratinocyte disorder. We learned that the
keratinocytes had escaped normal control of the cell cycle
and frequently used a cancer model to describe the disease to
each other and to the patients. We used antimetabolites such
as methotrexate to disrupt the cell cycle and, on the basis of
detailed DNA synthesis studies, used a split dosing strategy
(every 12 hours for a total of 3 doses each week) to optimize
exposure of keratinocyte DNA synthesis to the drug. At that
time, cyclic adenosine monophosphate was thought to play a
critical role in keratinocyte regulation and generation of psoriasis.
As for therapy, the pharmaceutical industry generated a
spectacular and largely redundant array of topical steroids.
As clinicians, we learned to use specific strengths for different
areas of the body. Topical vitamin A and vitamin D analogues
were in development and seemed to show some benefit. Our
patients rarely escaped the dermatology clinic without receiving
at least 4 different prescriptions for treating their
psoriasis, most of which were topical and applied twice daily.
Only the most dedicated patients could adhere to the regimen.
When patients experienced a flare or were hopelessly beyond
topical therapy, they were admitted to the hospital for
inpatient phototherapy using either PUVA (ie, psoralen and
long-wave ultraviolet radiation) or modified Goekermann
therapy. During my first year, the dermatology inpatient census
commonly ranged from 10 to 25 patients. When phototherapy
failed to provide long-term benefit or was impractical,
we used methotrexate, hydroxyurea, or 6-thioguanine.
Sometimes we changed these therapies in an attempt to minimize
patient exposure to specific side-effects of each treatment
(rotational therapy).
In 1988, etretinate was approved by the US Food and Drug
Administration (FDA) for treating psoriasis. This drug was
long-awaited because it had a unique mechanism of action
and had shown benefit for palmar-planter pustular psoriasis.
Shortly after approval, we learned to combine etretinate with
UVB or PUVA to achieve clinical goals in some of our patients.
On a few occasions, a resident would raise the issue of the
role of the immune system in generating the disease. They
were usually sent to the library to relearn the old lessons.
Nonetheless, a body of evidence was accumulating that implicated
the role of immunity in psoriasis. One of the earliest
papers of interest was a report by Ellis, who documented the
impressive response of psoriasis to cyclosporine in a doubleblind
study.1 This report was followed by another of cyclosporine
use, this time in psoriatic arthritis.2
In 1990, Jowitt and Yin published an important finding in
an “experiment of nature.”3 They documented the resolution
of psoriasis in a patient receiving an allogeneic bone marrow
transplant from an uninvolved patient. Other similar reports
followed, including one of a patient without psoriasis who
received an allogeneic bone marrow transplant from an affected
patient and subsequently developed psoriasis de novo
(David Fivenson, MD, personal communication). Further
studies followed shortly demonstrating the lack of effect of
cyclosporine in keratinocytes.4 At the same time, experiments
in which researchers used animal models showed that
injection of lymphocytes was sufficient to induce a psoriasis
phenotype.5
The biological era in psoriasis formally started in 1995
when dermatology investigators at Rockefeller University infused
10 psoriasis patients with DAB389IL-2, a receptor fusion
protein consisting of interleukin-2 and diphtheria toxin.6
This engineered protein selectively bound to and destroyed
activated T cells while having no effect on keratinocytes.
Eight of the 10 patients receiving treatment had significant
clinical improvement, a reduction in keratin-16 expression
in the epidermis and a reduction of CD4 and CD8 lymphocytes
in the involved skin, thereby providing an important
proof of concept.
Since that time, a wide variety of engineered antibodies
and fusion proteins, each targeting specific proteins in the
inflammatory cascade, have been tested in psoriasis. In the
eyes of many, psoriasis patients have become an important
model for inflammatory diseases: they are relatively young,
healthy, and the extent of their disease can be easily measured.
Although some development efforts have failed, 6 biologics
have been approved by the FDA for treating psoriasis. Our
first two were the T-cell antagonists alefacept and efalizumab.
Despite having modest efficacy, these drugs captured the
imagination of both the patients and the medical dermatologists
who prescribed them.
The next 3 drugs to be approved were tumor necrosis
factor antagonists (etanercept, infliximab, adalimumab) and
came to dermatology after approvals for treating rheumatoid
arthritis, psoriatic arthritis and, in 2 cases, Crohn’s disease.
With these drugs came increased efficacy and an awareness of
psoriatic arthritis and the role of dermatology in the early
detection of that disease.
Building on the foundation laid by rheumatology, a range
of comorbid diseases have been identified in our patients. It is
now generally accepted that patients with severe psoriasis
have increased rates of hypertension, obesity, insulin resistance,
and dyslipidemia (the metabolic syndrome).7 In addition,
these patients are much more likely to smoke and drink
heavily. As a consequence, it should have been no surprise
that patients with severe psoriasis have an increased risk for
myocardial infarction compared with those with mild forms
of the disease.8
Most recently, a new inflammatory pathway involving interleukins
12 and 23 has been identified and targeted. Two
new drugs (ustekinumab9 and briakinumab10) inhibit this
pathway and both induce profound clearance of psoriasis
which is durable. Ustekinumab has been approved by the US
FDA and briakinumab is deep into a phase 3 program as of
this writing.
The biological revolution in psoriasis care has not been
without safety issues. Infections continue to be the most frequent
serious safety concern, although they are only seen
occasionally. One of the T-cell inhibitors (efalizumab) was
withdrawn from the market after several reports of progressive
multifocal leukoencephalopathy, a rare and usually fatal
infection of the central nervous system.11 The lack of longterm
data used to assess the rate of malignancies remains
problematic; however, several registries exist and are enrolling
patients to address this concern. Recently, the US FDA
issued a warning about cancers in tumor necrosis factor antagonist-
treated children, requesting additional long-term
safety studies in this population.
The development of new and innovative therapies has
been important for our psoriasis patients and the dermatologists
who struggle to treat them. During the last decade, and
as a direct result of these efforts, our expectations have been
raised, not only in terms of safety and efficacy, but especially
in the areas of trial design, statistical analyses, interpretation
of results, and the critical role of surveillance registries. On
the basis of the results obtained with the use of the interleukin-
12/23 antagonists, a new generation of biologics is in
trial, with many more in the planning stage. In short, we’ve
come a long way since my time as a resident.
In this issue of Seminars, you will find a series of articles,
each written by recognized experts in their respective field of
interest and written with the clinical dermatologist in mind. I
would like to thank each of them for their vital contribution
and hope that you find value in their contributions. I would
also like to recognize the staff at Seminars who expertly assembled
the manuscripts and at all times were gracious and
accommodating throughout the editorial process.
Combining Traditional Systemic and Biologic Therapies for Psoriasis
The year 2010 marks 8 years since etanercept obtained approval from the Food and Drug
Administration for the treatment of psoriatic arthritis. There are 6 biologic therapies
approved by the Food and Drug Administration for the treatment of psoriasis and/or
psoriatic arthritis. These biologics are often used in patients who have received, are
receiving, or will receive in the future the traditional systemic antipsoriatics. In this article,
the currently available data on combining these therapies are reviewed.
Semin Cutan Med Surg 29:67-69 © 2010 Elsevier Inc. All rights reserved.