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.

New Insights in the Immunologic Basis of Psoriasis

Batya Davidovici, MD | James G. Krueger, MD, PhD | Kristine E. Nograles, MD

Psoriasis vulgaris is a multifactorial heritable disease characterized by severe inflammation
resulting in poorly differentiated, hyperproliferative keratinocytes. Recent advances in
genetic analyses have implicated components regulating the interleukin (IL)-23 and nuclear
factor-B pathways as risk factors for psoriasis. These inflammatory pathways exhibit
increased activity in skin lesions, and promote secretion of various cytokines, such as IL-17
and IL-22. Unrestrained, the activated inflammatory cytokine network in psoriasis may
trigger a vicious cycle of inflammation and cellular proliferation that ultimately results in
lesion formation. These advances in genetic analyses, together with the progress made in
targeted biological therapy, pave the path to tailor treatment on the basis of an individual’s
genetic and immunologic profile.
Semin Cutan Med Surg 29:3-9 © 2010 Elsevier Inc. All rights reserved.


Comorbidities in Psoriasis Patients

A.A. Marghoob, MD | Breck Thrash, MD | Noori Kim, BS

Psoriasis is a chronic inflammatory disorder that affects approximately 2% of the general
population. Numerous studies have evaluated the increased prevalence of comorbid diseases
and risk factors in psoriatic patients, including obesity, metabolic syndrome, cardiovascular
disease, psoriatic arthritis, autoimmune disease, psychiatric illness, liver disease,
smoking, malignancy, chronic obstructive pulmonary disease, sleep apnea, and alcohol
abuse. Insight into the overlapping pathogenesis of these comorbidities of psoriasis
highlights the importance of immune-mediated mechanisms in these disease states. Psoriasis,
with its comorbidities, must be approached in a multidisciplinary manner to effectively
and comprehensively understand, manage, and treat those with this complex
Semin Cutan Med Surg 29:10-15 © 2010 Elsevier Inc. All rights reserved.


Assessing Long-Term Drug Safety: Lessons (Re) Learned from Raptiva

Joel M. Gelfand, MS, MSCE | Nicole M. Seminara, BA

Efalizumab was approved for moderate to severe psoriasis in 2003 based on studies in
approximately 2700 patients, of whom only 218 were exposed to the drug for more than 1
year. In 2009, after more than 46,000 patients were exposed to efalizumab, the drug was
withdrawn from the market after 3 confirmed and 1 suspected case of progressive multifocal
leukoencephalopathy (PML) were spontaneously reported. As PML is very rare, it is
extremely unlikely that the 4 reported cases were due to chance and given that PML occurs
primarily in patients who are immunosuppressed, the association is likely causal. The
identification of PML as a serious, but statistically rare risk of efalizumab demonstrates the
strengths and weaknesses of the current drug approval and pharmacovigilance processes
for fully measuring the safety of a drug. Patients and clinicians need to be aware of the
relative completeness and limitations of existing safety data of a drug when selecting a
Semin Cutan Med Surg 29:16-19 © 2010 Elsevier Inc. All rights reserved.


The Role of Biologics and Other Systemic Agents in the Treatment of Pediatric Psoriasis

Caroline D.S. Piggot, MD | Lawrence F. Eichenfield, MD | Natalie A. Wright, BS

Psoriasis is a chronic inflammatory disease that is not uncommon
in children and adolescents. While exact prevalence
rates of pediatric psoriasis have not been determined,
30% to 40% of adults with psoriasis report onset of their
signs and symptoms before age 16.1-4 Although the diagnosis
of pediatric psoriasis remains predominantly clinical, its presentation
varies in clinical course, distribution, and morphology.
The management of psoriasis in children ranges from
topical medications for mild and moderate disease to the use
of systemic immunomodulatory agents for more severe disease.
None of the systemic medications, including methotrexate,
cyclosporine, and biological agents, such as etanercept,
infliximab, adalimumab, and ustekinumab have
specific indication by the United States Food and Drug Administration
(FDA) for pediatric psoriasis. The pediatric dermatologic
literature has limited studies in which investigators
examine the use of these therapies, unlike the corresponding
adult literature. Subsequently, experts rely on unpublished clinical
experience and studies of these systemic medications for
other pediatric conditions, such as those published in the rheumatologic,
transplant, oncological, and gastroenterologic
literature. In this article, we discuss the systemic treatment
options for pediatric psoriasis, including drug mechanism of
action and associated risks and benefits of treatment, to aid
dermatologists in treating psoriasis in this special population.


The Treatment of Moderate-to-Severe Psoriasis: Prescreening and Monitoring Psoriatic Patients on Biologics

Bruce E. Strober, MD, PhD | Danielle Levine, BA

The development of biologics has dramatically altered the treatment of moderate-to-severe
psoriasis while also introducing new standards of care for therapeutic monitoring. Currently,
the biologics approved by the US Food and Drug Administration are divided into 3
classes: T-cell modulators, tumor necrosis factor- inhibitors, and interleukin-12/23 inhibitors.
Although the US Food and Drug Administration has established recommendations for
pre- and peri-treatment screening evaluations, much of the evidence comes from clinical
trials evaluating the short-term safety and efficacy of each medication, rather than longterm
data, or studies that summarize either the appropriateness or feasibility of screening.
Instead of following a blanket algorithm, providers must understand the evidence as it
relates to each medication to determine which tests are appropriate for any specific patient.
This chapter summarizes the current body of evidence and recommends a practical
approach for monitoring psoriasis patients who are receiving biologic therapies.
Semin Cutan Med Surg 29:28-34 © 2010 Elsevier Inc. All rights reserved.