Vol. 29. No. 1


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.

Safety and Efficacy of the Tumor Necrosis Factor Antagonists

A. Nast, MD | F. Bachman, MD | S. Philipp, MD | W. Sterry, MD

Psoriasis is one of the most common systemic inflammatory diseases and affects the quality of
life of the affected persons profoundly. Further knowledge of the pathogenesis and new
biotechnological techniques have made it possible to develop new targeted therapies, such as
antibodies against tumor necrosis factor (TNF)-alpha. Today, 3 TNF inhibitors, infliximab,
adalimumab, and Etanercept, have been approved for the treatment of psoriasis arthritis,
psoriasis, and other indications like Crohn’s disease, depending on the distinct substance by
the European Medicines Agency. Golimumab was approved in September 2009 for the use in
psoriasis arthritis, respectively. These substances have added new effective treatment options
to the therapeutic armamentarium of psoriasis. To use these new treatments for the best of our
patients, it is important to know the correct application, the advantages, as well as contraindications
or possible adverse effects of the substances. This article provides an update on the
TNF-alpha inhibitors with emphasis on practical daily use. Most data are on the basis of
high-quality studies and official guidelines, but if necessary, data from recent publications or
clinical expertise have been added. In summary, with TNF inhibitors we have gained effective
new treatment options showing a favorable safety profile when paying attention to safety
aspects before and during therapy (screening, monitoring).
Semin Cutan Med Surg 29:35-47 © 2010 Elsevier Inc. All rights reserved.


Anti-p40 Antibodies Ustekinumab and Briakinumab: Blockade of Interleukin-12 and Interleukin-23 in the Treatment of Psoriasis

Eihab Alwawi, BS | Kenneth B. Gordon, MD | Mona Gandhi, MD

The choice of therapeutic agents for patients with moderate-to-severe psoriasis has expanded
significantly in the past decade. With new understanding of the immunologic basis
of psoriasis, multiple new potential targets for therapy have been identified. It is likely that
a series of new medications to focus on the newly identified pathways is on the horizon. The
first pathway targeted by new medications focuses on the p40 subunit that is shared by
interleukin (IL)-12 and IL-23. Two human anti-p40 antibodies have been used therapeutically
in psoriasis to date, ustekinumab (CNTO-1275, Stelara, Centocor, Horsham, PA) and
briakinumab (ABT-874, Abbott, Abbott Park, IL). Ustekinumab was recently approved by the
United States Food and Drug Administration, making it the first medication approved in the
United States to work by this pathway while briakinumab is currently in phase III clinical
Semin Cutan Med Surg 29:48-52 © 2010 Elsevier Inc. All rights reserved.


Alefacept for Psoriasis

Craig L. Leonardi, MD | Michael P. Heffernan, MD

Alefacept was the first biological agent approved by the
Food and Drug Administration for the treatment of psoriasis.
Alefacept was initially approved as an intravenous and
intramuscular medication. It is available only as an intramuscular
medication. Alefacept is an immunosuppressive dimeric
fusion protein that consists of the extracellular CD2-binding
portion of the human leukocyte function antigen-3 linked to
the Fc (hinge, CH2, CH3 domains) portion of human immunoglobulin
G.1 Alefacept selectively blocks the leukocyte
function antigen-3:CD2 costimulatory pathway, which is important
in the reactivation of memory effector T cells. Alefacept
also reduces the number of memory effector T cells in
the blood and in the skin.2
Alefacept is indicated for the treatment of adult patients
with moderate-to-severe chronic plaque psoriasis who are
candidates for systemic therapy or phototherapy. The recommended
dose of alefacept is 15 mg given once weekly as an
intramuscular (IM) injection. The approved regimen is a
course of 12 weekly injections. Retreatment with an additional
12-week course may be initiated if CD4 T lymphocyte
counts are within the normal range and a minimum of a
12-week interval has passed since the previous course of
treatment. Alefacept is Pregnancy category B. It should only
be used when clinically indicated in pregnant women and
nursing mothers.


Treatment of Psoriatic Arthritis with Biological Agents

Arnold Ceponis, MD | Arthur Kavanaugh, MD

Psoriatic arthritis (PsA) is an inflammatory arthritis that occurs in individuals with psoriasis.
The primary goals in the treatment of PsA are reduction of pain; improvement in the other
signs and symptoms of disease, including skin and nail involvement; optimization of
functional capacity and quality of life; and inhibition of the progression of joint damage.
These goals should be achieved while minimizing potential toxicities from treatment. The
management of PsA should simultaneously target arthritis, skin disease, and other manifestations
of PsA, including involvement of the axial skeleton, dactylitis, enthesitis, and eye
inflammation. In this respect targeted biological agents, primarily tumor necrosis factor
inhibitors, have emerged as generally well tolerated and highly effective alternatives to
traditional disease modifying antirheumatic drugs. Herein we review the evidence regarding
the treatment of PsA arthritis with biological agents.
Semin Cutan Med Surg 29:56-62 Published by Elsevier Inc.


The Future of Biological Therapies

Christopher E.M. Griffiths, MD, FRCP | Richard B. Warren, PhD, MRCP

The last decade has witnessed a significant advance in the management of refractory
moderate-to-severe psoriasis. This advance is the introduction of biological therapies to
clinical practice. Three classes of biological therapies have been used. Of the first 2
classes to be introduced, the T-cell inhibitors and tumor necrosis factor (TNF)-
inhibitors, there have been differing fates with one of the T-cell inhibitors, efalizumab,
being withdrawn because of a rare, unpredictable association with a usually fatal neurological
condition, progressive multifocal leukoencephalopathy. In contrast, anti-TNF treatments
are now firmly established offering a high level of efficacy and a good safety record
across several indications, including psoriasis. A new approach involves targeting the p40
subunit, common to interleukins 12 and 23. Ustekinumab, the first drug in this class, now
offers a viable alternative to anti-TNFs in the treatment of moderate-to-severe psoriasis. In
this article, we discuss approaches that may be utilized to refine these existing therapies
and examine future therapeutic targets for biological therapies.
Semin Cutan Med Surg 29:63-66 © 2010 Elsevier Inc. All rights reserved.