September 2009 - International Psoriasis Council

I NTERNATIONAL P SORIASIS C OUNCIL
IPC PSORIASIS REVIEW
September 2009 Vol. 5, No. 2
IPC presents the most relevant
psoriasis clinical and research articles
Each year, the International Psoriasis Council (IPC) identifies the top papers in the
field of psoriasis. Papers are nominated for inclusion by our Board of Directors and
then circulated to our membership to identify the most important papers. This year’s
selection includes articles that: further our understanding of the genetic basis of
psoriasis in multiple populations; delineate key mediators of psoriatic disease
pathogenesis such as -defensins, interleukin (IL)-20, and IL-22; describe clinical
research on a new class of drugs that target the IL-12 and IL-23 pathways; and
present a longitudinal analysis of comorbid cardiovascular diseases subsequent to
psoriasis diagnosis.
Co-editors Professor Ricardo Romiti, Department of Dermatology, University of São
Paulo, Brazil; and Professor Errol Prens, Department of Dermatology, Erasmus
University Medical Center, Rotterdam, The Netherlands, provided expert
commentary on each article and its value to clinical practice.
ARTICLES REVIEWED IN THIS ISSUE
JANSEN, ET AL. PLOS ONE. 2009 4(3):e4725.
GOTTLIEB, ET AL. LANCET. 2009 FEB;373(9664):633-40.
NAIR, ET AL. NAT GENET. 2009 FEB;41(2):199-204.
NOGRALES, ET AL. BR J DERMATOL. 2008 NOV;159(5):1092-102.
WOLK, ET AL. J MOL MED. 2009 MAY;87(5):523-36.
KRYCZEK, ET AL. J IMMUNOL. 2008 OCT;181(7):4733-41.
DE CID, ET AL. NAT GENET. 2009 FEB;41(2):211-5.
GELFAND, ET AL. J INVEST DERMATOL. 2009 MAY 21; ONLINE PUBLICATION.
ZHANG, ET AL. NAT GENET. 2009 FEB;41(2):205-10.
KAYE, ET AL. BR J DERMATOL. 2008 SEP;159(4):895-902.
Review of articles begins on page 3.
Calendar
Meet the Experts Berlin
The International Psoriasis Council
invites medical professionals to a
case-based learning forum on difficultto-treat
psoriasis cases.
8 October 2009
17:00 – 18:00
18th EADV Congress
Internationales Congress
Centrum Berlin
Berlin, Germany
Chairman
Wolfram Sterry, M.D.
Berlin, Germany
Panelists
Jonathan Barker, M.D.
London, UK
Alan Menter, M.D.
Dallas, USA
Peter van de Kerkhof, M.D., Ph.D.,
Nijmegen, The Netherlands
For more information about events, visit:
www.psoriasiscouncil.org/events
To learn more about IPC,
visit www.psoriasiscouncil.org,
e-mail info@psoriasiscouncil.org,
or call 800.289.0277
INSIDE THIS ISSUE
► A letter from the President 2
► Annual review of top research papers 3
► Meet the Experts: Treating difficult psoriasis cases 8

A letter from the president
Dear Colleagues,
On behalf of the International Psoriasis Council (IPC) and this
issue’s co-editors Profs Ricardo Romiti and Errol Prens, I am
delighted to introduce the September 2009 edition of our IPC
Psoriasis Review. A big thank you to Professors Romiti and
Prens for all their efforts.
Published several times per year, IPC Psoriasis Review
appraises important current clinical and research publications and
provides commentary on those that we believe make the broadest
contribution to our understanding of the disease and its treatment.
It is certainly not an easy task to choose 10 “top papers” from the
wide range of quality papers published in the Scientific, Medical
and Dermatology literature each year. I very much appreciate my
colleagues on the Board of the IPC helping do a thorough review
of the literature and contributing to the choice.
We also present select cases from our June 27, 2009, 2 nd World
Psoriasis & Psoriatic Arthritis Conference IPC Meet the Experts
Program, chaired by Professor Jonathan Barker, and held in
Stockholm.
In 2009, IPC has continued to expand its mission to enhance
research, education and innovation in the diverse areas of
psoriasis. This has included the initiation of an important
Pediatric Registry Program and the conclusion of a rigorous 200-
patient Outcomes Measure Study currently under statistical
review by James Krueger’s department at Rockefeller University
in New York, as well as the introduction of a mentoring program
for four young residents in the USA soon to expand to Europe.
2009 was also time for change within IPC as Liz Horn transitioned
out of her role as Director of Medical and Scientific Affairs to seek
new career opportunities. We wish Liz all the best in her future
endeavors and express our sincere gratitude for her assiduous
efforts in creating and extending the Medical and Scientific
mission of IPC. As a consequence, we also welcome Paul
Tebbey as our interim Vice-President of Medical and Scientific
Affairs. Paul brings broad and valuable experiences, both
academic and industrial, that will be a great asset as we expand
and enhance IPC’s Medical and Scientific purpose. Many of you
already know Paul from his days in dermatology at Centocor
where he played an integral role in the development of
ustekinumab. With a background of both a Ph.D. and a MBA, I
am very confident that you will all enjoy re-engaging with Paul on
his return to the field of Dermatology and particularly Psoriasis.
He certainly brings a wealth of experience, knowledge and
enthusiasm to IPC.
I am also saddened to report the loss of a member of our own
IPC community, Dr Seija-Liisa Karvonen of the Department of
Dermatology, University Hospital of Oulu, Finland. She passed
away in August after a long battle with pancreatic cancer. Our
sincerest sympathies are extended to her family, colleagues and
friends. We at IPC all recognize her significant contributions to
the field of Psoriasis.
We hope this newsletter is informative and that the knowledge,
experience and insights of our faculty are valuable to you in
evaluating and treating your psoriasis patients. For additional
copies of IPC Psoriasis Review, or to learn more about IPC,
please visit www.psoriasiscouncil.org.
Sincerely,
Alan Menter, M.D., President
International Psoriasis Council
IPC Board of Directors
Professor Jonathan Barker, United Kingdom
Professor Christopher E.M. Griffiths, Honorary
Secretary, United Kingdom
Robert Holland III, United States
Dr. Craig L. Leonardi, Honorary Treasurer, United States
Ms. Malia Tee Lewin, United States
Dr. Alan Menter, President, United States
Karen Baxter Rodman, United States, CEO & Executive
Director
Professor Wolfram Sterry, Germany
Professor Peter van de Kerkhof, The Netherlands
Ms. Melodie Young, United States
IPC Councilors*
Professor Hervé Bachelez, France
Dr. Ian Bruce, United Kingdom
Dr. Wai-Kwong Cheong, Singapore
Professor Andrew Finlay, United Kingdom
Professor Alberto Giannetti, Italy
Dr. Alice Gottlieb, United States
2 IPC Psoriasis Review
Dr. Gerald G. Krueger, United States
Dr. James G. Krueger, United States
Dr. Gladys Aires Martins, Brazil
Dr. Hidemi Nakagawa, Japan
Professor Jean-Paul Ortonne, France
Dr. Kim Alexander Papp, Canada
Professor Errol Prens, The Netherlands
Professor Jean-Hilaire Saurat, Switzerland
Dr. Fernando Stengel, Argentina
Professor John Sullivan, Australia
Dr. Gail Todd, South Africa
* IPC has chosen to honor these members
with the title of “councilor” to acknowledge
their special contributions to psoriasis.
IPC Members
Dr. Wolf-Henning Boehncke, Germay
Dr. Robert J. G. Chalmers, United Kingdom
Professor Sergio Chimenti, Italy
Professor Edgardo Chouela, Argentina
Professor Kevin D. Cooper, United States
Professor Esteban Dauden, Spain
Professor Charles N. Ellis, United States
Professor Carlos Ferrandiz, Spain
Dr. Kenneth Gordon, United States
Dr. Lars Iversen, Denmark
Dr. Seija-Liisa Karvonen, Finland**
Dr. Alexa B. Kimball, United States
Dr. Richard G. Langley, Canada
Dr. Mark Lebwohl, United States
Dr. Ulrich Mrowietz, Germany
Dr. Frank O. Nestle, United Kingdom
Dr. David M. Pariser, United States
Dr. Carlo Pincelli, Italy
Dr. Mark R. Pittelkow, United States
Professor Jörg Prinz, Germany
Professor Ricardo Romiti, Brazil
Professor Mona Ståhle, Sweden
Dr. Bruce Strober, United States
** In memoriam

Top 10 Clinical Research Papers
PRESENTING SUMMARIES AND COMMENTARY
-Defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches
biologically relevant concentrations in lesional skin
In this article, Jansen et al connect previous genetic associations with the biological activity of beta-defensin-2 (hBD-2) in
psoriasis patients in vivo. By determining that systemic levels of hBD-2 were correlated with beta defensin copy number
and by measuring the systemic protein levels of hBD-2 in psoriatics, the authors were able to contribute a potentially
reliable serum biomarker unique to psoriasis disease activity and notably absent in other inflammation-based disease
states such as rheumatoid arthritis (RA). Other beta-defensins such as hBD-1 and hBD-3 were equally up regulated in
RA and atopic dermatitis.
Jansen PA, Rodijk-Olthuis D, Hollox EJ, Kamsteeg M, Tjabringa GS, de Jongh GJ, van Vlijmen-Willems IM, Bergboer JG, van Rossum MM,
de Jong EM, den Heijer M, Evers AW, Bergers M, Armour JA, Zeeuwen PL, Schalkwijk J. Beta-defensin-2 protein is a serum biomarker for
disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin. PLoS ONE. 2009;4(3):e4725.
COMMENTARY
Evidence is permitting a clearer focus on the genetic and pathophysiological underpinnings of psoriasis. Consequently, hBD-2,
contained within the beta defensin cluster on chromosome 8, is a strong candidate gene for psoriasis. This analysis correlated
both copy number and specific gene expression levels to disease severity, suggesting that psoriasis has multiple underlying
factors, both genetic and regulatory in nature, that potentially contribute to the phenotype of the disease. It is of relevance to us in
dermatology that hBD-2 protein is not up regulated in another important inflammatory condition, i.e. atopic dermatitis.
2. Clinical evidence of a role for IL-12 and IL-23 in psoriatic arthritis
In this paper, Gottlieb et al tested the notion that the interleukins 12 and 23 were involved in the pathogenesis of the joint
disease, psoriatic arthritis. By utilizing the human monoclonal antibody, ustekinumab, which inhibits receptor binding of
these two cytokines, the authors were able to quantify the impact on both clinical symptoms and pathological joint
changes. In the phase II trial that involved 146 patients from sites in North America and Europe, the authors tested two
doses of ustekinumab (90 mg and 63 mg) administered every week for 4 weeks prior to the primary endpoint at week 12.
The results were presented in an intent-to-treat format, and showed statistically superior responses in the ACR 20 scores
of patients that received ustekinumab (combined doses, 42%) versus placebo (14%). Adverse events were similar in both
groups with 61% in the drug treated groups reporting an AE versus 63% in placebo. At the week 12 primary endpoint,
three serious adverse events were reported in the placebo group, with none being reported in patients that received
ustekinumab. Thus, the authors concluded that ustekinumab was well tolerated and significantly reduced signs and
symptoms of psoriatic arthritis compared with placebo.
Gottlieb A, Menter A, Mendelsohn A, Shen YK, Li S, Guzzo C, Fretzin S, Kunynetz R, Kavanaugh A. Ustekinumab, a human interleukin 12/23
monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009 Feb 21;373(9664):633-40.
COMMENTARY
This is the first report of a positive clinical impact by an agent that targets IL-12 and IL-23 in joint disease. The data therefore build
upon the impressive results that ustekinumab has demonstrated in the treatment of psoriasis. New treatment options are needed
for patients with both skin and joint disease but who do not respond to standard available agents, such as the anti-TNF class of
therapies. Particular aspects of the trial are interesting; first, the drug achieved impressive ACR 20 scores in patients that can be
considered less severe than those included in previous Psoriatic Arthritis trials; and second, the longevity of the symptomatic
response to ustekinumab was remarkably persistent, even out to 36 weeks after only four doses that ended at week 3.
Biologically, these data also validate a role for IL-12/ 23 in the pathogenesis of psoriatic arthritis, if not overall joint disease, which
had been controversial. Evolving knowledge of IL-23 and its stimulation of IL-17 reveals a possible answer, since it has been
suggested that IL-17 plays a part in bone destruction mechanisms of arthritis. Yet to be elucidated is whether IL-12/23 impacts
psoriatic diseases via a different pathogenic pathway than the more broadly studied TNF-.
September 2009 3

Top 10 Clinical & Research Papers
3 Novel Psoriasis Susceptibility Loci
To further the case for establishing genetic polymorphism as a contributor to psoriasis, Nair et al worked with the Genetic
Association Information Network (GAIN) to compare over 1,400 psoriasis patients with over 1,400 matched controls. In
total, over 438,000 single nucleotide polymorphisms (SNPs) were analyzed to select for those genetic differences that
were more frequently associated with psoriasis. Twenty-one of the genetic variants that displayed association with
psoriasis were subsequently tested in a cohort of over 5,000 psoriasis patients and more than 5,000 controls. The results
highlight the role of several key pathways in disease susceptibility and validate the association of psoriasis with genetic
mutations in HLA-C, part of the human immune system’s major histocompatability complex that controls identification of
self from non-self, as well as mutations in the genes for subunit A of the cytokine IL-23 and the IL-23 receptor. Moreover,
the analysis has identified several new loci potentially associated with psoriasis including two genes that act downstream
of TNF- and regulate NF-B signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune
responses (IL-4, IL-13). The authors further demonstrated differences in the protein expression of these genes by
comparing biopsies from psoriasis-involved and uninvolved skin. The results contribute to the knowledge regarding a
genetic basis for psoriasis.
Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M,
Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB,
Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR; Collaborative Association Study of Psoriasis. Genome-wide scan reveals
association of psoriasis with IL-23 and NF-kappa B pathways. Nat Genet. 2009 Feb;41(2):199-204.
COMMENTARY
Genetic analyses are a powerful mechanism to identify potential therapeutic targets for psoriasis. Of interest in this analysis is that at least five of the targets
point to mutations in the signaling pathways for TNF and IL-23. Indeed, clinical trial study of biologic therapies with specificity to the cytokines, TNF and
IL-23 have proven to be very effective in ameliorating the effects of psoriasis. However, these genetic data extend the repertoire of potential targets that
might impair normal cell signaling thus leading to the inflammatory condition, and that should prove valuable in the development of new clinical approaches.
But the authors are also clear to point out that the strength of the association of these genetic loci with psoriasis does not explain the observed incidence of
psoriasis in siblings. Similarly, a lack in association signal strength for psoriasis and psoriatic arthritis was also noted. Taken together, these observations
suggest that while we have defined some very important genetic underpinnings of psoriasis, there is much more work to be done.
4. Evaluating differential roles of Th17-derived cytokines
Th17 cells have received much attention in terms of their relevance in psoriasis pathogenesis. Now, Nograles et al
investigated the cytokines produced by skin-resident T cells in normal skin, and further identified the receptors for these
cytokines. The authors also examined how cytokines alter gene expression profiles of the cells bearing cognate
receptors. By using a variety of intracellular techniques to localize cytokines and immunohistochemistry to map cellular
phenotypes in the skin, they were able to demonstrate that the Th17-derived cytokines IL-17 and IL-22 mediate distinct
downstream pathways. IL-17 is suggested to be more proinflammatory, while IL-22 retards keratinocyte differentiation
thus fueling hyperproliferation.
Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suárez-Fariñas M, Cardinale I, Khatcherian A, Gonzalez J, Pierson KC, White
TR, Pensabene C, Coats I, Novitskaya I, Lowes MA, Krueger JG. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory
and keratinocyte-response pathways. Br J Dermatol. 2008 Nov;159(5):1092-102.
COMMENTARY
Networks of cytokines have been theorized to be central to the proinflammatory condition that results in psoriasis, but dissecting the individual roles for each
component has proven to be very difficult. By using a unique technique of cytokine staining and flow cytometry to evaluate T cell cytokine production and
immunohistochemistry and double-label immunofluorescence to localize cytokine receptors in skin, the authors were able to co-localize different cytokines to
specific cells thus providing an explanation for their roles. Similar to the results presented by Wolk et al (page 5) these authors also found that IL-22
regulated the expression of keratinocyte mobility and terminal differentiation. Moreover, IL-17 induced neutrophilic granulocyte-attracting chemokines and
CCL20 and demonstrated enhanced expression of these mediators in lesional skin compared to nonlesional skin from psoriasis patients. This paper
confirms the view that a number of genes up regulated in psoriasis lesions can be attributable to IFN-, further showing that other cytokines (IL-17 and IL-22)
can regulate other sets of psoriasis-related genes. It is the collective impact of both IL-17 and IL-22 that might explain the pathogenic effect during
inflammation, contributing to the combined influx of neutrophils, memory T cells and DCs, and delaying keratinocyte differentiation, respectively. Thus, a
new model for differential cytokine involvement in psoriasis is born that is based upon the activation of multiple independent pathways.
4 IPC Psoriasis Review

Top 10 Clinical & Research Papers
5. IL-22 and IL-20 are key mediators in the distal stage of psoriasis pathogenesis that
involves psoriatic epidermis alterations
By over-expressing IL-22 in transgenic mice, Wolk et al have defined a potential role for IL-20 and IL-22 in the epidermal
alterations leading to psoriasis, but seemingly have precluded an impact by either IL-17 or IFN-. This is because the IL-
22 overexpression was sufficient to cause psoriasis-like skin alterations as well as neonatal mortality. Furthermore, the
IL-22 gene upregulation was specific to keratinocytes, as similar effects were not seen in other cell types; skin fibroblasts,
endothelial cells, melanocytes, or adipocytes. The IL-22 effect on differentiation-regulating genes was also found to be
STAT3-dependent. In addition to IL-22, IL-20 demonstrated similar effects but of lower comparative potency, and TNF
was found to amplify some of the effects of IL-22 when present in combination. However, while IFN- and IL-17 strongly
induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively, they did not result in psoriasis-like
morphological changes. This study suggests that while different cytokines may be players in psoriasis pathogenesis, it is
IL-22 and IL-20 that are key to the characteristic epidermal alteration.
Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, Vom Baur E, Witte K, Warszawska K, Philipp S, Johnson-Leger C, Volk HD, Sterry W, Sabat
R. IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not. J Mol Med. 2009 May;87(5):523-36.
COMMENTARY
This paper contributes to the rapidly evolving knowledge of the key cytokines involved in the pathogenesis of psoriasis, and thereby
identifies potential new therapeutic targets that can more selectively regulate the disease. In this case the authors propose to target
IL-22R1 as a mechanism to prevent the action of both IL-22 and IL-20, both members of the IL-10 family of cytokines and which
therefore bind to shared receptors. Moreover, keratinocytes appear to be the only cells that express IL-22R1 in the skin, providing
some unique selectivity to potential therapeutic agents. Especially when compared to pluripotent TNFα, the blockade of IL-22R1 may
induce fewer systemic side-effects, although the repercussion of this specific blockage on skin homeostasis remains unknown.
6. Orchestrating psoriasis: elucidating the complex roles for different cytokines and cell
subsets that populate the psoriatic lesion
In this report, Kryczek et al explore the phenotype and function of IL-17-secreting T cells in psoriatic skin, and investigate
the factors supporting their trafficking to and subsequent induction that leads to the manifestation of the psoriatic lesion.
Specifically, the data show that IFN- may promote trafficking, induction, and function of IL-17+ T cells in people with
psoriasis, a view that challenges previous theories wherein Th1 cells were thought to suppress Th17 cell development.
Increased numbers of CD4+ IL-17+ and CD8+ IL-17+ T cells were measured in skin lesions of psoriasis patients. Using
T-cell culture systems, myeloid antigen-presenting cells (APC) were found to respond to the Th1 cytokine, IFN-, thus
triggering the induction of IL-1 and IL-23 resulting in the stimulation of IL-17+ T cells. To define the mechanism by which
these activated T cells trafficked to the skin, the investigators took advantage of a transwell migration system. In this
assay, activated CD4+ IL-17+ and CD8+ IL-17+ T cells were found to traffic toward CCL20, the ligand for the CCR6
chemokine receptor found on the surface of the IL-17+ T cells. Moreover, it was discovered that such trafficking was IFN-
-dependent, thus placing this Th1 cytokine as the conductor of the resultant psoriatic lesion.
Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L, Szeliga W, Wang Y, Liu Y, Welling TH, Elder JT, Zou W. Induction of IL-17+
T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J Immunol. 2008 Oct 1;181(7):4733-41.
COMMENTARY
Recent biology concerning psoriasis pathogenesis has focused on the role of the Th17 cell and upstream cytokines, such as IL-23, and
downstream cytokines that lead to keratinocyte proliferation, such as IL-20, IL-21 and IL-22. This has been at the expense of the CD4+Th1
cell and Th1 cytokines, including IFN-. In this report, Ilona Kryczek and colleagues have delivered mechanistic insight into the coordinated
roles for multiple cell types and cytokines in an effort to explain the inflammatory underpinnings of psoriasis. Using a combination of
intracellular staining, cytokine inhibition, and immune cell culture systems, the data indicate a novel mechanistic interaction between Th1 and
Th17 cells that implies collaboration and synergism rather than the antagonism that was previously theorized. Kryczek et al for example show
that IFN- stimulates APC to produce CCL20, which supports the migration of IL-17+ T cells, and synergizes with IL-17 in the production of
human beta-defensin 2. The painting of a clearer picture of the abnormal immune interactions that lead to psoriasis facilitates better
opportunities for the specific design of targeted therapies.
September 2009 5

Top 10 Clinical & Research Papers
7. Identification of specific genes as susceptibility factors for psoriasis
The analysis of the copy number of genes in samples from psoriasis patients compared to controls can lead to the
localization of areas in the genome where susceptibility genes lie. In this case, de Cid et al performed a genome-wide
search for copy number variants (CNV) using a sample pooling approach and an array comparative genomic hybridization
(aCGH) method. In so doing, the authors identified a deletion comprising LCE3B and LCE3C, members of the late
cornified envelope (LCE) gene cluster. Moreover, statistical analysis demonstrated that the deletion was significantly
associated with the risk of psoriasis in over 2,800 samples from Spain, The Netherlands, Italy and the United States.
These LCE genes are over-expressed in psoriatic lesions and have a role in the proper regulation of the epidermis. They
can be induced by skin barrier disruption suggesting that compromised skin barrier function has a role in psoriasis
susceptibility leading to unregulated keratinocyte proliferation.
de Cid R, Riveira-Munoz E, Zeeuwen PL, Robarge J, Liao W, Dannhauser EN, Giardina E, Stuart PE, Nair R, Helms C, Escaramís G, Ballana
E, Martín-Ezquerra G, den Heijer M, Kamsteeg M, Joosten I, Eichler EE, Lázaro C, Pujol RM, Armengol L, Abecasis G, Elder JT, Novelli G,
Armour JA, Kwok PY, Bowcock A, Schalkwijk J, Estivill X. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility
factor for psoriasis. Nat Genet. 2009 Feb;41(2):211-5.
COMMENTARY
One has to be in awe of the genetic techniques that can today be employed to search for genes that are associated with specific diseases. Using
pooled samples to minimize individual variations the copy number of genetic regions for the whole genome can be compared in samples from
psoriasis patients and nonpsoriatic controls. The effort first led to a region on chromosome 1q21 that harbored two genes (LCE3C and LCE3B) that
were found to be deleted in a significant proportion of psoriatics. Then the focus can get more detailed via identification of the association of single
nucleotides polymorphisms (SNPs) associated with these deleted regions and which ones support a role for the genes in question. It is
acknowledged that resequencing and fine mapping of the region is still necessary to define the association and any potential contribution of other
genes. Nevertheless, that LCE3C expression is induced upon epidermal activation, as found in psoriatic skin lesions, is good support for the gene’s
involvement. Thus, are we now getting closer to potential causative explanations for psoriasis? As suggested by de Cid et al, mutation in LCE3C may
lead to epidermal dysfunction and consequently the penetration of exogenous agents (allergens and/or microorganisms), which against a positive
HLA-Cw6 background could stimulate persistent inflammation. The LCE3C - LCE3B deletion showed epistatic effects with HLA-Cw6 on psoriasis
development only in the Dutch samples and multiplicative effects in the other samples, and thus needs further validation in other samples.
8. Psoriasis as a major risk factor for stroke
The major common risk factors for stroke include diabetes, hypertension, and smoking. In this retrospective cohort
analysis of the General Practice Research Database in the United Kingdom, Gelfand et al have calculated the risk of
stroke in psoriasis patients. Patients diagnosed with psoriasis within the research database were separated into “mild”
and “severe” categories based upon a treatment history of systemic agents. Risk factors were adjusted for age and sex
and calculated based upon comparison to control patients with no history of psoriasis. Of interest is that the adjusted data
show an increased risk of stroke in psoriasis patients with both mild (hazard ratio [HR] = 1.06; confidence interval [CI] =
1.0 - 1.1) and severe disease [HR = 1.43, 95% CI = 1.1–1.9]. Thus, both mild and severe psoriasis are independent risk
factors for stroke. Moreover, this association cannot be explained by the major stroke risk factors identified in routine
medical care, thus supporting the notion that the psoriatic inflammatory disease is a contributing factor.
Gelfand, J.M., Dommasch, E.D., Shin, D.B. Azfar, R.S., Kurd,S.K., Wang,X., Troxel, A.B. The Risk of Stroke in Patients with Psoriasis.
Journal of Investigative Dermatology. 2009 May; 129: 2411-2418
COMMENTARY
Evidence is consistently accumulating to define the association of psoriasis with various cardiovascular co-morbidities such as diabetes mellitus and
atherosclerosis. By defining stroke as an additional potential sequela for psoriasis, this paper contributes an important message to all physicians who
care for psoriasis patients – that is to thoroughly assess and treat, according to relevant guidelines, for the collective cardiovascular risk factors,
including stroke. In this case the authors have defined a highly significant 43% increase in the risk of stroke in severe psoriasis patients versus the
control cohort. Even for mild patients the risk was statistically significant, which stimulates discussion on whether patients with mild disease should be
treated with consideration for the inflammatory basis of their disease and the concomitant risk of inflammatory based co-morbidities rather than merely
by the degree of psoriatic lesions on their skin. It would be interesting to know the risk factor for other subtypes of psoriasis. In any case, these
observations stress the importance of a holistic approach when treating patients with any kind of psoriasis.
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Top 10 Clinical & Research Papers
9. Psoriasis susceptibility loci in the Chinese population
Zhang et al report the first large genome-wide association study (GWAS) in a Chinese population to identify susceptibility
variants for psoriasis. This study was a two-stage case-control design that first isolated genetic associations in 1,139
cases and 1,132 controls of Chinese Han ancestry and then subsequently analyzed the resultant SNPs in larger samples
(> 5,500 patients) of both Chinese Han and Chinese Uygur ancestry. Similar to the Nair study reported above, these
authors also validated involvement of the known susceptibility loci for HLA-C and IL12B in psoriasis and demonstrate that
these are pervasive across both western and Chinese populations. But potentially of more interest is that they also
identified a new susceptibility locus within the Late Cornified Envelope (LCE) gene cluster.
Zhang XJ, Huang W, Yang S, Sun LD, Zhang FY, Zhu QX, Zhang FR, Zhang C, Du WH, Pu XM, Li H, Xiao FL, Wang ZX, Cui Y, Hao
F, Zheng J, Yang XQ, Cheng H, He CD, Liu XM, Xu LM, Zheng HF, Zhang SM, Zhang JZ, Wang HY, Cheng YL, Ji BH, Fang QY, Li
YZ, Zhou FS, Han JW, Quan C, Chen B, Liu JL, Lin D, Fan L, Zhang AP, Liu SX, Yang CJ, Wang PG, Zhou WM, Lin GS, Wu WD, Fan
X, Gao M, Yang BQ, Lu WS, Zhang Z, Zhu KJ, Shen SK, Li M, Zhang XY, Cao TT, Ren W, Zhang X, He J, Tang XF, Lu S, Yang JQ,
Zhang L, Wang DN, Yuan F, Yin XY, Huang HJ, Wang HF, Lin XY, Liu JJ. Psoriasis genome-wide association study identifies
susceptibility variants within LCE gene cluster at 1q21. Nat Genet. 2009 Feb;41(2):205-10.
COMMENTARY
A better understanding of the genetic basis of for the pathogenesis of psoriasis and the genetic differences underpinning the disease are
essential to customizing appropriate treatment regimens for individual patients. Zhang et al have delivered important genetic information in
patients of Chinese ancestry that confirm the genetic basis for psoriasis that has been seen in populations of western origin. Moreover, the
authors have identified potential novel genes involved in psoriasis, at least in the Chinese population. These genes are highly conserved
genes encoding stratum-corneum proteins and are thought to be involved in subtle attributes of skin function, which potentially impact the
proper regulation of the epidermis facilitating its hyperactivity and hyperproliferation. It will be interesting to observe if the LCE locus is unique
to the patients of Chinese descent, or is an important core genetic contributor to the psoriasis disease state. As well, it will be interesting to
determine of the genes within this LCE locus are regulated by IL-22.
10. Elevated incidence of cardiovascular co-morbid conditions subsequent to a diagnosis
of psoriasis
Evidence is accumulating for the association of psoriasis with various co-morbidities and such data generally derive from
cross-sectional analyses of patient databases to define associated conditions. But central to better management of
psoriasis is to determine whether the psoriatic condition is a consequence of, or a predicate to, the development of these
associated conditions. In this study, Kaye et al utilized the UK General Practice Research Database to conduct a cohort
study of 44,164 patients with a first-time diagnosis of psoriasis and 219,784 non-psoriasis comparison subjects psoriasismatched
on age, sex, and index date. But interestingly, they tracked the incident diagnosis of various cardiovascular
conditions known to be associated with psoriasis, subsequent to the initial development of psoriasis. In this way, the
authors were able to track the hazard ratios (HRs) for these cardiovascular conditions in patients with psoriasis. The data
demonstrated that the HRs were statistically increased in patients with psoriasis vs. the comparison cohort for incident
diabetes, hypertension, and hyperlipidaemia. Similarly, psoriatics had higher risks of incident myocardial infarction,
angina, atherosclerosis, peripheral vascular disease and stroke.
Kaye JA, Li L, Jick SS. Incidence of risk factors for myocardial infarction and other vascular diseases in patients with psoriasis. Br J
Dermatol. 2008 Sep;159(4):895-902.
COMMENTARY
This report complements and extends the accumulating body of evidence that describes the association of psoriasis with a wide range of comorbid
conditions. Indeed, in last year’s review of the top research papers, IPC highlighted the research of Gelfand et al, which described the
association of severe psoriasis with an increased risk of mortality [Gelfand JM, Troxel AB, Lewis JD, Kurd SK, Shin DB, Wang X, Margolis DJ,
Strom BL. The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol. 2007 Dec;143(12):14939].
While the results of this analysis do not preclude that in some patients psoriasis may develop subsequent to incident cardiovascular risk
factors, they certainly point to at least a subpopulation of patients with psoriasis that has a higher propensity to develop cardiovascular
sequelae, which may ultimately lead to increased mortality. The observations reported in this article may finally deliver the credence
necessary for psoriasis to be managed as a complex systemic condition with far-reaching and highly detrimental complications. It also
emphasizes the need for further studies on the mechanism of action.
September 2009 7

Treating Difficult Psoriasis Cases
Meet the Experts
The most recent IPC Meet the Experts program was held June 27, 2009 in Stockholm, Sweden, under the chairmanship
of Jonathan Barker. Two cases of difficult-to-treat psoriasis patients were presented to our panel of experts, Hervé
Bachelez (France), Mona Ståhle (Sweden), and Melodie Young (USA). Here, we summarize the key issues and
discussion of these two cases.
CASE 1:
34-year-old man with severe plaque psoriasis who wants rapid control and
complete clearance of his symptoms for his wedding.
History and presentation: This patient had a 19-year history of plaque psoriasis and presented with 30% body surface
area (BSA) involvement on his trunk and limbs (Figure 1). Prior therapies included multiple topical corticosteroids, PUVA
with acitretin (discontinued because of hypercholesterolemia), and methotrexate (discontinued because of liver toxicity).
He also had asymmetrical polyarthralgia with evidence of enthesitis (Figure 2).
How do you initiate methotrexate
therapy and monitor patients on
methotrexate therapy? Is there a
requirement for liver biopsies in
psoriasis patients?
Hervé starts with a test dose of 5
mg and moves directly to the 15
to 25 mg efficient range without a
gradual increase in dosage.
Methotrexate is always
supplemented with folic acid.
Methotrexate is initially
administered orally, but switched
to subcutaneous or intramuscular
injections if increased efficacy is
needed.
Mona uses stepwise dose
escalation to achieve the final
optimal dose. Liver biopsies for
screening or monitoring are rarely
performed, as serum tests for liver
function are now available. The
use of injections to administer
methotrexate is increasingly used
to reduce gastrointestinal side
effects.
Melodie notes that the American
guidelines recommend biopsy at a
cumulative dose of 1.5 g*, but in
her practice patients are
frequently switched to another
therapy to prevent the risks
associated with liver biopsies.
Figure 1. Plaque psoriasis on trunk and limbs.
8 IPC Psoriasis Review

Meet the Experts
What is the most appropriate treatment option for this patient?
Mona would have initiated anti-TNF therapy, probably with etanercept because it is associated with slightly less toxicity
than the other drugs in the class.
Melodie thought that her team would also have next considered anti-TNF therapy for reasons of rapid onset and
convenience (self-administration). She would also have initiated a discussion with the patient on his hypertension and
obesity.
An additional point brought up in the discussion with the audience was the issue of treatment options in countries where
TNF antagonists are too expensive or not readily available. In this case, the patient required treatment of both skin and
joint symptoms; both types of symptoms respond to the TNF antagonists, but not necessarily to other traditional therapies.
Treatment options offered in these circumstances included cyclosporine or acitretin for the skin in combination with antiinflammatory
medications for the joints. Methotrexate can be efficacious in the treatment of joint symptoms, but requires
treatment of long duration before an effect is noted. PUVA (oral or bath) and low-dose corticosteroids were also
considered to be viable options.
Clinical Course: Hervé treated the patient with adalimumab (loading dose of 80 mg followed by 40 mg every other
week). Significant improvement in symptoms was noted after three months, including remission of all joint symptoms.
The advantages to this approach included the rapid onset of drug efficacy and convenience of self injections.
*Recent American Academy of Dermatology (AAD) guidance has changed the cumulative dose to 3.5 grams/4 grams
metrotrexate before consideration for first liver biopsy. For subsequent biopsies, AAD recommends 1 gram/1.5 grams.
Menter; JAAD, 2009. 61: 451-485
Figure 2. Asymmetric polyarthralgia with evidence of Achilles enthesitis.
September 2009 9

Meet the Experts
CASE 2:
28-year-old woman with plaque psoriasis and psoriatic arthritis who wants to
become pregnant.
History and presentation: This patient had a 10-year history of plaque psoriasis and three-year history of psoriatic
arthritis. She presented with 10% BSA involvement. She was currently receiving methotrexate, with an estimated
cumulative dose of 1.5 to 1.8 g. She had suffered a flare when methotrexate was discontinued during a previous
pregnancy.
How long do you stop different treatments prior to attempts at conception?
The panel and audience responses ranged from three months for men (sperm maturation time) and one month (or one
menstrual cycle) in women to six months in all patients.
What is the most appropriate treatment option?
Mona noted that avoidance of all medications during the first trimester is preferable; however, in the event of an acute
flare a short course of cyclosporine would be considered.
Hervé agreed with the use of cyclosporine, but also noted that if the severity of the patient’s psoriatic arthritis was an
issue, corticosteroids should be considered.
Suggestions from the audience included the use of narrow-band UVB during and after tapering methotrexate to help with
skin symptoms, and sulfasalazine for the psoriatic arthritis.
Additional issues raised during the discussion of this case were the frequency of flares with pregnancy and the use of TNF
antagonists during lactation. Approximately 60% of patients with psoriasis see improvement in symptoms with pregnancy,
30% stay the same, and 10% suffer flares; notably, postpartum flares are very frequent. The use of TNF antagonists
during lactation is approved in the US by many specialists, including gynecologists and the La Leche League (an
organization that assists with breastfeeding issues). This class of drugs is administered to patients via injection because
of gastrointestinal metabolism, which may also be true (but has not been studied) in infants and may protect them from
too much exposure to the drug via breastfeeding. Prior to the use of anti-TNF therapies, cyclosporine was used during
lactation.
Clinical course: Melodie treated the patient with etanercept (50 mg per week twice weekly for 12 weeks, then once
weekly thereafter), and methotrexate was discontinued with instructions to avoid pregnancy for three months. The
rationale behind this treatment was
that etanercept has a short half-life
and could quickly be discontinued and
metabolized, and was also postulated
to slow the recurrence of symptoms
after drug discontinuation. Skin and
joint symptoms improved after eight
weeks. The patient became pregnant,
and discontinued etanercept in her
third trimester because of fear of
harming the fetus with the injections.
After 18 months, she presented with a
flare involving 10% BSA including
flexural psoriasis (Figure 3), and a
healthy baby.
10 IPC Psoriasis Review
Figure 3. Flexural psoriasis.

Meet the Experts
IPC
PSORIASIS REVIEW
Co-Editors
Ricardo Romiti, M.D., Ph.D.
Errol Prens, M.D., Ph.D.
Writers
Paul Tebbey, Ph.D., M.B.A.
Julie Gage, Ph.D.
IPC Stockholm Meet the Experts program faculty: From left to right, Prof. Hervé
Bachelez, Prof. Mona Ståhle, Ms. Melodie Young, Prof. Jonathan Barker
ACKNOWLEDGMENTS
IPC gratefully acknowledges the following experts for their participation in the IPC Stockholm
Meet the Experts program: Jonathan Barker, M.D., St. John’s Institute of Dermatology in
London; Hervé Bachelez, M.D., Ph.D., Department of Dermatology of the Saint-Louis
University Hospital in Paris, France; Mona Ståhle, M.D., Ph.D., Dermatology & Venereology
Unit, Department of Medicine at the Karolinska Institute in Stockholm, Sweden, and Melodie
Young, MSN, ANP-c, Modern Dermatology in Dallas, Texas.
IPC gratefully acknowledges co-editors Professor Ricardo Romiti, Department of
Dermatology, University of São Paulo, Brazil; and Professor Errol Prens, Department of
Dermatology, Erasmus University Medical Center, Rotterdam, The Netherlands, for their
participation in and editorial contribution to the September 2009 IPC Psoriasis Review.
FACULTY DISCLOSURES
Professor Bachelez has served as a consultant for Abbott, Merck-Serono, and Wyeth, and received
financial support from Schering-Plough, and Roche laboratories.
Professor Barker has served as a speaker or advisory board member for Schering-Plough, Wyeth,
Abbott, Merck Serono, and Janssen-Cilag.
IPC would like to acknowledge
would like to acknowledge
Abbott, Amgen, Galderma,
Centocor Ortho Biotech, and
Janssen-Cilag for the
educational grants they
provided for the IPC Psoriasis
Review. This activity has
been planned and
implemented in accordance
with IPC’s program planning
policy. IPC is solely
responsible for all content.
Professor Prens serves as a member of the advisory boards for Abbott, Wyeth, and Janssen-Cilag, a
speaker for Wyeth, MerckSerono, and Schering-Plough, and has received research grants from Wyeth
and MerckSerono.
Professor Romiti has served as a speaker for Janssen-Cilag, Wyeth, Abbott, and Mantecorp.
Professor Ståhle has served as a speaker or advisory board member for Wyeth, Abbott, Janssen-Cilag,
and Schering-Plough.
Ms. Young has served as a speaker or an advisory board member for Abbott, Amgen, Astellas,
Centocor, Coria Laboratories, Genentech, and Stiefel Laboratories.
The International Psoriasis Council is a global nonprofit organization dedicated to advancing psoriasis
research and treatment by providing a forum for education, collaboration and innovation among physicians,
researchers and other professionals interested in psoriasis.
September 2009 11

The International Psoriasis Council presents
Meet the Experts
Case-based learning discussion
The International Psoriasis Council
(IPC) invites medical professionals to
a case-based learning forum on
difficult-to-treat psoriasis patients.
CHAIRMAN:
Wolfram Sterry, M.D., Berlin, Germany
PANELISTS:
Jonathan Barker, M.D., London, UK
Alan Menter, M.D., Dallas, USA
Peter van de Kerkhof, M.D., Ph.D.,
Nijmegen, The Netherlands
18th EADV Congress
Internationales Congress
Centrum Berlin
Berlin, Germany
8 October 2009
17:00 – 18:00
Room - Hall 9
Please contact IPC at
info@psoriasiscouncil.org or visit
www.psoriasiscouncil.org/events
for more information.
This interactive program will include time for
discussion. If you have a challenging case,
please email info@psoriasiscouncil.org for
possible inclusion in the program.