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Pediatrics

The Chronicle

of

& ALLERGY SKIN SKIN

Pso

All rights reserved. Chronicle Information Resources Ltd. Canada Post Canadian Publications Mail Sales Product Agreement Number 40016917

P rACTICAL T herAPeuTICS and C LInICAL n eWS from the W orLD of D erMAToLoGY

n

O CT./N OV. 2017

Long-term studies of biologics indicate benefits are maintained over time see page 4

Methylisothiazolinone contact allergy prevalence on rise in Western Canada Contact allergy

n Improved monitoring and regulation of compound called necessary

T

by JOHN EVANS,

Associate Editor, The Chronicle

he prevalence of contact allergy to the preservative methylisothiazolinone increased in Western Canada between 2008 and 2015, peaking at 15.29%—a finding researchers say supports ongoing efforts to monitor and regulate the ingredient. “We were well aware of methylisothiazolinone or MI as a problematic allergen, especially after 2013 when it was recognized

as Allergen of the Year by the north American Contact Dermatitis Group,” said Dr. Jessica Guy, lead author of the paper, which was published in the Journal of Cutaneous Medicine and Surgery (May/June 2017; 21(3):207–210). Dr. Guy (née Wilford) is a 5th-year resident in the Department of Dermatology and Skin Science at the university of British Columbia, Vancouver. As the more commonly used preservatives such as the

Blog on science of cosmeceuticals designed to benefit patients Cosmetic medicine

U

n More info for patients key goal of project by EMILY INNES-LEROUX, Managing Editor, The Chronicle

niversity of British Columbia medical residents Drs. Danny Guo (dermatology) and Yi Ariel Liu (pathology) have developed a blog focusing on the science (or lack of science) behind skin care products and cosmeceuticals. Their website, called Think Skin MD (www.thinkskin.ca), is intended to help patients make informed decisions about the purchase of over-thePlease turn to Think Skin page 25à counter skin products.

formaldehyde-releasers and the parabens began to have negative connotation in the minds of the general public, or data from patch testing raised concerns about them, industry looked to find alternative preservatives that could be used instead, said Dr. Dr. Jessica Guy Guy. “That led to the really prevalent use of MCI (methylchloroisothiazolinone) and MI. At the time when [the combination of] Please turn to MI page 18à

n The Chronicle is committed to maintaining leadership in environmentally sustainable policies, and to encouraging the adoption of “green-aware” practices in healthcare. We invite your comments via e-mail, at: health@chronicle.org

Diagnosis of mosaic NF type 1 has implications for patient health n Genetic condition may lead to concerns such as hypertension

A

by LOUISE GAGNON,

Correspondent, The Chronicle

diagnosis of mosaic neurofibromatosis type I has implications for overall health and family planning, and may require health surveillance, according to an associate professor at the university of Toronto who is also a pediatric dermatologist at the hospital for Sick Children in Toronto. Speaking in Toronto at the Atlantic Dermatological Conference, Dr. Irene Lara-Corrales discussed complete neurofibromatosis type I and mosaic neurofibromatosis type I, explaining that diagnosing mosaic neurofibromatosis type I usually begins with a consultation where a dermatologist detects the presence of café au lait macules localized in Dr. Irene just one area of Lara-Corrales the body of a patient. “Seeing one café au lait [macule] in a child will be very frequent,” said Dr. Lara-Corrales, noting up to 25% of school-aged children will have at least one café au lait macule. “As the number increases, the likelihood of the café au lait [macules] not being associated with other findings is rarer.” Defining diagnostic criteria Cases with more than six café au lait macules and no other associations is seen in less than 0.1% of patients, she said. Dr. Lara-Corrales cited a retrospective study of patients seen between 2004 and 2007, which found that the majority of patients with six

Please turn to Mosaic NF type 1 page 12à


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The first and only fully human, selective IL-17A inhibitor indicated in PsO, AS and PsA†

+ Over 50,000 patients treated worldwide2‡ + Over 2,000 patients treated in Canada2‡ Pr

COSENTYX® (secukinumab) is indicated for the treatment of: • Moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy • Adult patients with active ankylosing spondylitis who have responded inadequately to conventional therapy • Adult patients with active psoriatic arthritis when the response to previous disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate. COSENTYX® can be used alone or in combination with methotrexate Consult the Product Monograph at www.novartis.ca/CosentyxMonograph for contraindications, warnings, precautions, adverse reactions, interactions, dosing, and conditions of clinical use. The Product Monograph is also available by calling 1-800-363-8883. AS=ankylosing spondylitis. PsA=psoriatic arthritis. PsO=psoriasis. † Comparative clinical significance unknown. ‡ Clinical significance is unknown. References: 1. COSENTYX® Product Monograph. Novartis Pharmaceuticals Canada Inc. April 20, 2016. 2. Data on file. Novartis Pharmaceuticals Canada Inc.

COSENTYX is a registered trademark. Product Monograph available on request. Printed in Canada PRO/COSps/0069E © Novartis Pharmaceuticals Canada Inc. 2017


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Vol. 23, No. 7

TOP of the MONTH

Long-term studies of biologics show maintenance of benefit over time Biologics that target the IL-17 pathway are offering extraordinary efficacy as well as robust safety profiles, but other pathways continue to be explored . . . . . . . . . . . . . . . . 4

Surveying the current dermatologic literature: SIBO the most relevant contributing factor in papulopustular rosacea results from a prospective case control study examining the etiopathogenesis of rosacea suggest that small intestine bacterial overgrowth (SIBo) is the most relevant factor, with treatment of SIBo being crucial to improvement of rosacea and maintenance of clinical remission . . . . . 14

NEW FEATURE: Chronicle Patient Primer This new graphic feature is designed as a tool for patient counselling and adherence, providing clear and simple information. The feature can be downloaded and printed at no cost from www.derm.city. This instalment provides information on AD . . . . . 19

Chronicle Postgraduate Educational Supplement In this issue, Dr. Jörg Christoph Prinz of Munich investigates the autoimmune aspects of psoriasis. Chronic immune-mediated disorders such as psoriasis constitute a major health crisis, and identifying risk genes and autoimmune targets is integral to the development of potential new therapies . . . . . . 21

Research

University of Ottawa researcher Jennifer Keir (r) and colleagues have discovered that firefighters absorb many mutagenic chemicals through their skin.

Smoke mutagens absorbed by skin From the News Resources of The Chronicle

Canadian researchers have found evidence that firefighters are absorbing significant quantities of mutagenic and other hazardous chemicals from smoke through their skin in the course of their duties. Published in Environmental Science & Technology (oct. 18, 2017, online ahead of print), the research was conducted by a team from the university of ottawa, in collaboration with health Canada, the university of Toronto, and the Institut national de santé publique du Québec. In the study, urine and skin wipe samples were collected from firefighters both before their shift and after responding to a fire in order to measure exposure to polycyclic aromatic hydrocarbons (PAhs), known to cause mutations, as well as other chemicals in smoke. “Firefighters had from three to more than five times the amount of metabolites, or by-products of PAhs, in their urine after a fire compared to

before the fire,” Jennifer Keir, the university of ottawa researcher and the study’s senior author, said in a press release from the university of ottawa. “Mutagenic potency of the urine, which reveals the potential for genetic mutations, also increased on average more than four times after a fire.” A surprise to the researchers was a significant link observed between PAh metabolites in urine and levels of PAhs on the skin—a finding that suggested firefighters were mainly exposed to these chemicals through skin absorption than through inhalation. “our study shows that the best way to reduce a firefighter’s exposure to harmful combustion products is to reduce chemical exposure to the skin,” said Jules Blais, professor of environmental toxicology at the university of ottawa and research team leader. “our research shows how firefighters are exposed to harmful chemicals, which helps us find ways to reduce those exposures—and hopefully reduce the onset of disease.”

Subscriptions: $85.60 per year in Canada, $129.95 per year in all other countries. Single copies: $10.00 per issue (plus 13% HST).

Oct./Nov. 2017 • Vol. 23 No. 7

Published eight times per year by the proprietor, Chronicle Information Resources Ltd., with offices at 555 Burnhamthorpe Road, Ste 306, Toronto, Ont. M9C 2Y3 Canada. Telephone: (416) 9162476; Facs. (416) 352-6199. E-mail: health@chronicle.org ISSN No. 1209-0581

Contents © Chronicle Information Resources Ltd., 2017 except where noted. All rights

oct./nov. 2017 · 3

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The ChronICLe of S K I N & A L L E R G Y

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A Message from the Medical Editor

A

utumn in newfoundland and Labrador is certainly a very pleasant time to enjoy the sights and colours. The other wonderful thing about autumn is that The ChronICLe publishes its annual fall psoriasis update highlighting the many treatment advances that we and our patients can look forward to (see page 4). In this issue, Drs. Gooderham, Lynde and Adam update us on therapies including the new anti IL-17 inhibitor expected to be introduced to the Canadian market in the near future, and provide some new understandings of the anti IL-23 landscape. The article also reviews the positive impact of the anti IL-23s on psoriatic arthritis. even though we do have many new treatment options, Dr. Zip reminds us that phototherapy is still an excellent one for many of our patients. Another article of interest is the new Think Skin Blog created by Drs. Guo and Liu (see page 1). These creative innovations will help drag all of us dinosaurs kicking and screaming into the new technology age. I wanted to let readers know that in upcoming issues, we will be presenting articles based on presentations related to the Canadian Dermatology Association’s new Investigator’s Program. It is important for all of us to take time to acknowledge the contribuPlease turn to Message page 25à

Medical Editor

Wayne Gulliver,

MD, FRCPC

John P. Arlette, MD, FRCPC Benjamin Barankin, MD, FRCPC Marc Bourcier, MD, FRCPC Eric Goldstein, MD, FRCPC Peter Hull, MD, FRCPC Rod Kunynetz, MD, FRCPC Richard Langley, MD, FRCPC Danielle Marcoux, MD, FRCPC

Editor, Cosmetic Dermatology MD, FRCPC

Sheldon V. Pollack,

R.A.W. Miller, MD, FRCPC H. Eileen Murray, MD, FRCPC Kim Papp, MD, FRCPC Yves Poulin, MD, FRCPC Melanie D. Pratt, MD, FRCPC Denis Sasseville, MD, FRCPC Jerry Tan, MD, FRCPC Ronald B. Vender, MD, FRCPC

Founding Editor Colin A. Ramsay, MD, FRCPC (1936-2003)

Publisher Mitchell Shannon Editorial Director R. Allan Ryan Managing Editor Emily Innes-Leroux Associate Editors John Evans Sales & Marketing Peggy Ahearn, Susan Latter,

Christine Witowych

Manager,Operations Cathy Dusome Comptroller Rose Arciero

Contacting The Chronicle

“It is good for Canadian dermatology and our patients to have all these options. These new drugs can offer hope for people who have previously failed biologics.”

Dr. Charles Lynde, director of the Lynde Institute for Dermatology in Markham, Ont., and associate professor, Department of Medicine, University of Toronto. (see page 4)

n READER SERVICE: To change your address, or for questions about your receipt of the journal, send an e-mail to health@chronicle.org with subject line “Circulation,” or call during business hours at 416.916.Chron (2476), or tollfree at 866.63.Chron (24766). n LETTERS: We welcome your correspondence by mail, fax (416.352.6199), or e-mail. Kindly use the co-ordinates listed above. n ADVERTISING: For current rates and data, please contact the publisher. n REPRINTS: The content of this journal is copyrighted. Please contact Mitchell Shannon for reprint information.


Psoriasis

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4 · oct./nov. 2017

Lead article

The ChronICLe of SKIN & A L L E R G Y

Clinical practice

Long-term studies of biologics demonstrate benefits are maintained over time

T

n efficacy of biologics consistent with treat-to-target recommendations developed by Canadian leaders by LOUISE GAGNON,

Correspondent, The Chronicle

he availability of treatments like brodalumab and guselkumab in the u.S. in 2017, and the anticipated commercial availability of these agents in Canada, will broaden the therapeutic choices in the treatment of moderate-tosevere psoriasis.

Various data on the use of IL-17 inhibitors and IL-23 inhibitors were presented this fall in Geneva at the annual meeting of the european Association of Dermatology and Venereology (eADV). Dr. Melinda Gooderham, dermatologist and medical director of the Skin Centre for Dermatology in Peterborough, ont., presented data at the eADV meeting regarding dosing of ixekizumab in patients with moderate-to-severe plaque psoriasis, showing every two-week dosing to be superior to every four-week dosing over 52 weeks. Data on secukinumab, which targets IL-17A, were also presented at the eADV meeting and demonstrated that the biologic provided skin clearance in patients with moderate-tosevere plaque psoriasis at five years. Specifically, the majority of patients

who achieved Psoriasis Area Severity Index (PASI) 90 and 100 maintained their response out to five years. Similar long-term Dr. Melinda data on the effiGooderham cacy and safety of ixekizumab up to two years were presented. These biologics that target the IL-17 pathway are offering great efficacy as well as robust safety, said Dr. Charles Lynde Dr. Charles Lynde, director of the Lynde Institute for Dermatology in Markham, ont., and associate professor, Department of Medicine, university of Toronto.

Enhanced management of psoriasis The remarkable efficacy of those agents is consistent with treat-to-target recommendations for psoriasis and psoriatic arthritis as developed by Canadian leaders in dermatology and rheumatology. Canadian dermatologists and rheumatologists published recommendations earlier this year on the enhanced management of the two chronic conditions in daily practice after conducting a needs assessment among Canadian physicians managing the diseases as well as a

literature review on outcomes in clinical trials and practice (J Rheumatol 2017 Apr; 44(4):519– 534). A d v e r s e Dr. David N. Adam events such as Candida infections have been reported with the use of IL-17 inhibitors in patients being treated for psoriasis and psoriatic arthritis, when Dr. Catherine Zip compared to patients treated with placebo or ustekinumab (Br J Dermatol 2017 Jul; 177(1):47–62). Accordingly, it has been recommended that patients undergoing anti-IL-17 therapy be monitored for fungal infections and be appropriately managed if these infections occur, but it has not been recommended that patients discontinue IL-inhibition therapy because the Candida infections are mild-to-moderate and can be managed with standard therapy. recently, an extremely rare instance of psoriasiform eruption occurred with secukinumb therapy that involved the fingertips and nails but it was found to resolve with ustekPlease turn to Psoriasis page 6à


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an oral tablet for the treatment of moderate to severe plaque psoriasis

T:11” S:10”

Fictitious case. Individual results

may vary.

OTEZLA® (apremilast) is indicated for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

COVERED BY RAMQ (Exceptional Medication Status)¶4

Demonstrated efficacy in psoriasis clinical trials1,2 • PASI-75 response at week 16 with OTEZLA 30 mg BID: 33.1% vs. placebo: 5.3%, p<0.0001*

Over 140,000 patients

Proven safety profile1 • Most common adverse reactions (≥5%) were diarrhea (17.8%), nausea (16.6%), upper respiratory tract infection (8.4%), tension headache (7.3%), and headache (5.8%), which were mostly mild in intensity.† Incidences of these adverse events were higher in females than males.‡

have been treated with OTEZLA globally to date, combined across both psoriasis and psoriatic arthritis indications.3

Simplicity of oral dosing§1

Indications and clinical use: • OTEZLA® (apremilast), alone or in combination with methotrexate, is also indicated for the treatment of active psoriatic arthritis in adult patients who have had an inadequate response, intolerance, or contraindication to a prior disease-modifying anti-rheumatic drug (DMARD) OTEZLA has not been studied and is therefore not indicated in combination with other systemic (conventional or biologic) therapies or phototherapy for psoriasis. Should be used with caution in very elderly patients (≥75 years of age). Contraindications: • Pregnancy • Women who are breastfeeding Relevant warnings and precautions: • History of tachyarrhythmia or conditions worsened by increases in heart rate • Weight loss (monitor as necessary) • Diarrhea and nausea

• Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption • Severe immunological diseases, severe acute infectious diseases or patients treated with immunosuppressive medicinal products; experience in patients with latent infections is limited; not recommended in combination with potent immunosuppressants, including biological therapies and cyclosporine • Headache and migraine • History of depression and/or suicidal thoughts or behaviour • Severe renal impairment For more information: Please consult the Product Monograph at http://www.celgenecanada.net/ pdfs/Otezla_Product_Monograph_English_Version.pdf for important information relating to adverse reactions, drug interactions, dosing instructions and dosage adjustments in patients with severe renal impairment which have not been discussed in this piece. The Product Monograph is also available by calling us at 1-888-712-2353.

*A multicentre, randomized, double-blind, placebo-controlled study (ESTEEM 1) designed to evaluate the efficacy, safety, and tolerability of OTEZLA for the treatment of psoriasis. In ESTEEM 1, patients (N=844) with moderate to severe plaque psoriasis (PASI ≥12, BSA ≥10%, sPGA ≥3) were randomized 2:1 to OTEZLA 30 mg BID or placebo. At week 16, all placebo patients were switched to OTEZLA (placebo/OTEZLA) through week 32. At week 32, all patients who were randomized to OTEZLA at baseline and who achieved at least 75% reduction from baseline PASI score (PASI-75) were re-randomized (1:1, blinded) to continue OTEZLA or receive placebo. Upon loss of PASI-75 or at week 52, patients re-randomized to placebo resumed OTEZLA. The primary endpoint was the proportion of patients who achieved PASI-75 at week 16. Mean baseline PASI scores: OTEZLA 18.7; placebo 19.4. †

Nearly half of the adverse reactions of diarrhea, nausea, tension headache, and headache resolved within 2 weeks of onset.

The particular incidence rates for females experiencing nausea was 29.7% (vs. 9.9% for males), 24.0% for diarrhea (vs. 14.6% for males), 7.9% for vomiting (vs. 1.6% for males), and 11.5% for tension headache (vs. 5.2% for males).

§

OTEZLA is administered 30 mg BID after initial titration. Please consult the Product Monograph for complete dosage and administration instructions, including dose adjustments in patients with severe renal impairment (CLcr <30 mL/min).

For treatment of persons suffering from a severe form of chronic plaque psoriasis, before using a biological agent listed to treat this disease: in the presence of a score ≥15 on the Psoriasis Area and Severity Index (PASI) or of large plaques on the face, palms or soles or in the genital area; and in the presence of a score ≥15 on the Dermatology Quality of Life Index (DQLI) questionnaire; and where a phototherapy treatment of 30 sessions or more during three months has not made it possible to optimally control the disease, unless the treatment is contraindicated, not tolerated or not accessible or where a treatment of 12 sessions or more during one month has not provided significant improvement in the lesions; and where a treatment with two systemic agents, used concomitantly or not, each for at least three months, has not made it possible to optimally control the disease. Except in the case of a serious intolerance or contraindication, these two agents must be: methotrexate at a dose of 15 mg or more per week; or cyclosporine at a dose of 3 mg/kg or more per day; or acitretin at a dose of 25 mg or more per day. The initial request is authorized for a maximum period of four months. When requesting continuation of treatment, the physician must provide information making it possible to establish the beneficial effects of the treatment, specifically: an improvement of at least 75% in the PASI score; or an improvement of at least 50% in the PASI score and a decrease of at least five points on the DQLI questionnaire; or a significant improvement in lesions on the face, palms or soles or in the genital area and a decrease of at least five points on the DQLI questionnaire. Requests for continuation of treatment are authorized for a maximum period of six months. Authorizations for apremilast are given for 30 mg, twice a day. It must be noted that apremilast is not authorized if administered concomitantly with a standard or biological systemic treatment indicated for treatment of plaque psoriasis.

References: 1. OTEZLA Product Monograph, Celgene Corporation, June 9, 2015. 2. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37-49. 3. Data on file (medical letter dated December, 2016). Celgene Corporation. 4. RAMQ (official mark of the Régie de l’assurance maladie du Québec). List of Medications. 2016. Available at: http://www.ramq.gouv.qc.ca/en/regie/legalpublications/Pages/list-medications.aspx. Retrieved November, 2016.

OTEZLA® is a registered trademark of Celgene Corporation. © 2016 Celgene Corporation.

OTZ-PSO-16-039


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6 ¡ oct./nov. 2017

Psoriasis: New biologics on way Continued from page 4

inumab and topical methotrexate, underlining that other biologics can be considered when patients experience disease flares with another class of biologics (JAMA Dermatol 2017 Aug 2). Brodalumab, which was evaluated in three, randomized, controlled clinical trials involving more than 4,300 patients, carries a black-box warning in the u.S. with regard to an observed risk for suicidal thoughts and actions.

Different mechanisms of action Because brodalumab acts on the IL-17 receptor, it may prove to have a different impact than other IL-17 inhibitors like secukinumab and ixekizumab, explained Dr. David n. Adam, medical director, Baywood Dermatology, lead investigator, CCA Medical research, assistant professor, university of Toronto, active staff, St. Michaelâ&#x20AC;&#x2122;s hospital in Toronto, and president, Dermatology Association of ontario. â&#x20AC;&#x153;The real question is if the different mechanism of action ends up making a difference in overall efficacy or duration of response,â&#x20AC;? said Dr. Adam. â&#x20AC;&#x153;If you have a sub-optimal response to a monoclonal antibody that targets soluble IL-17, would targeting the receptor improve that response? We know that brodalumab blocks signalling through all of the IL-17 cytokine family, A through F.â&#x20AC;? The emerging therapies that selectively target IL-23, such as guselkumab, risankizumab, and tildrakizumab, are impressive in their efficacy and safety, said Dr. Lynde. â&#x20AC;&#x153;It is good for Canadian dermatology and our patients to have all these options,â&#x20AC;? said Dr. Lynde. â&#x20AC;&#x153;These new drugs can offer hope for people who have previously failed biologics.â&#x20AC;? An emerging therapy like guselkumab may present an alternative to patients who do not experience success with ustekinumab. A randomized, double-blind, Phase III investigation found that patients who did not have an adequate response to ustekinumab by week 16 obtained benefit to being switched to 100 mg of guselkumab (Br J Dermatol 2017 Jun 21). In addition, guselkumab may prove effective outside of the treatment of psoriasis. results from a Phase 2a study presented at the eADV meeting pointed to the positive and significant impact of guselkumab on joint symptoms, physi-

cal function, and psoriasis in patients who had active psoriatic arthritis with a minimum of 3% body surface area affected.

Other treatment options available Traditional treatments for psoriasis remain viable choices. Phototherapy, for example, is a choice for patients who do not want to be exposed to any systemic treatment, said Dr. Catherine Zip, a dermatologist in Calgary and clinical associate professor at the university of Calgary. â&#x20AC;&#x153;Some patients do not want to take anything internally,â&#x20AC;? said Dr. Zip. â&#x20AC;&#x153;For some patients, itâ&#x20AC;&#x2122;s great. Itâ&#x20AC;&#x2122;s time-consuming, however, to come in for phototherapy treatment two or three times weekly for months.â&#x20AC;? For pregnant women with extensive psoriasis, phototherapy is also the preferred treatment, said Dr. Zip. â&#x20AC;&#x153;narrow-band uVB is the treatment of choice for widespread psoriasis during pregnancy.â&#x20AC;? In patients with milder cases of psoriasis, where less than 10% of the body surface area is affected, a therapy like apremilast is an appropriate option, noted Dr. Lynde. â&#x20AC;&#x153;There is a good niche for this drug,â&#x20AC;? he said. Indeed, some of the advantages of apremilast include the fact that it does not require ongoing monitoring to evaluate for any organ toxicity, is administered orally, and produces weight loss (Am J Clin Dermatol 2017 Jun 8). Despite all the novel therapies emerging to treat psoriasis, roadblocks to access may exist depending on the decisions of payers to reimburse the costs of the therapies, according to Dr. Lynde. â&#x20AC;&#x153;We do not know where biosimilars will fit [in clinical practice],â&#x20AC;? he said. The integration of biosimilars into dermatology is not a uniquely Canadian challenge. The International Psoriasis Council has recommended that dermatologists take an active role in proposing prescribing policies vis-a-vis biosimilars in their respective jurisdictions (Br J Dermatol 2017 Jun 24). Non-proprietary and brand names of therapies: ixekizumab (Taltz, Lilly); secukinumab (Cosentyx, Novartis); ustekinumab (Stelara, Janssen); brodalumab (not approved in Canada); guselkumab (Tremfya, Janssen); risankizumab (not approved in Canada); tildrakizumab (not approved in Canada); apremilast (Otezla, Celgene).

CLARIFICATION

An article in the August, 2017 issue of The ChronICLe oF SKIn & ALLerGY (new therapies offer options for patients with Ih, page 11) incorrectly described two elements of oral propranolol 3.75 mg/mL (hemangiol, Pierre Fabre Dermo-Cosmetique Canada Inc.). The article should have noted that the branded product hemangiol became available in the Canadian marketplace in the second quarter of 2017. Additionally, the syringe provided with hemangiol is calibrated in millilitres, not milligrams as indicated in the report.


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Lead article

8 · oct./nov. 2017

The ChronICLe of SKIN & A L L E R G Y

Vender on psoriasis Research

Assessing clinical advances in Pso care and research

PATIENT PREFERENCE FOR TOPICALS CAN VARY

Psoriasis patients have a wide range of needs and preferences in topical therapies, and being aware of these differences and choosing the right agent for a given patient may improve therapy adherence and better treatment outcomes, according to a paper published online ahead of print in the Journal of the European Academy of Dermatology and Venereology (Aug. 10, 2017). The authors set out to assess which attributes of topical treatments influenced patient preference of a fixed combination of calcipotriol 50 µg/g (Cal) and betamethasone 0.5 mg/g as Comment: Patients prefer to have treatments that dipropionate (BD) are cosmetically elegant, have no smell, feel comfoam vs. a gel formuforting, are non-greasy, and are easy to apply. Not lation, and also in only is safety and efficacy of critical and utmost comparison with the importance, but patient acceptance of different latest topical treatvehicles is necessary. This can increase adherment (LTT) each paence and compliance. However, having choices tient had received. A of different vehicles is also meaningful. This study Phase IIIb, prospecshowed that two different vehicles, foam and gel, were equally preferred and difference in age tive, multicentre, groups was a factor in their preference. open-label, randomized, two-arm crossover study (PSOINSIGHTFUL) was conducted. Patients 18 years or older who had mild-to-severe psoriasis were enrolled. After a washout period of up to four weeks, patients were randomized 1:1 to oncedaily Cal/BD foam for one week, followed by Cal/BD gel for one week, or vice-versa. The patients also completed six questionnaires to evaluate their preferences. Of the 213 total patients randomized into the study, 118 had received some topical treatment in the three months before the study. Based on the Subject’s Preference Assessment, 50% of the participants preferred Cal/BD foam, and 50% preferred Cal/BD gel. Overall mean scores on the Topical Product Usability Questionnaire (TPUQ) were high for both the foam and gel formulations, and were often significantly in favour of both study products compared with LTT. Greater differences between Cal/BD foam and gel vs. LTT were seen when the LTT was an ointment or a cream. Younger patients aged 18 to 39 years generally preferred the Cal/BD foam, while those aged 40 years and older generally preferred the gel formulation.

BSA HIGHER THAN 10% ELEVATES MORTALITY

A large cohort study that aimed to evaluate how direct measures of psoriasis severity influence risk of death has found that patients with psoriasis affecting more than 10% of their body surface area (BSA) are at an increased risk of death, even after controlling for standard mortality risk factors such as obesity. These findings come from a paper published online ahead of print in the Journal of Investigative Dermatology (Aug. 23, 2017). The source data came from The Health Improvement Network (THIN) electronic medical records database in the U.K., specifically the Incident Health Outcomes and Psoriasis Events (iHOPE) study. A physician survey was employed to confirm diagnosis of psoriasis and to classify the extent of disease. Data was collected prospectively from the date of the physician survey

until the patient died, was transferred out of practice, or reached the end of the collection period. Covariate examined included age, sex, BMI, alcohol use, smoking, and medical comorbities from the Charlson comorbidity index (CCI). A total of 8,760 Comment: It has been well established that more seadults with psoriasis vere psoriatic disease is associated with a higher risk and 87,600 adults of death. This severity is usually determined by the without psoriasis PASI score. This study shows that BSA is an important were included. The factor in determining morbidity and mortality. The impsoriasis patients portant question—that would take many patients and were more likely to years of study—would be: Would reducing the BSA be male and had a in psoriasis lead to lowered risk of morbidity and morslightly higher body tality, and would effective and safe agents like biomass index (BMI), logics contribute to this success? though average age was similar between the two groups. Rates of chronic kidney disease, chronic obstructive pulmonary disease, diabetes, and a history of MI were higher in the psoriasis patients. The risk of mortality remained higher in patients with BSA >10% after adjusting for CCI (HR: 1.79, 95% CI: 1.23–2.59).

GUSELKUMAB EFFECTIVE IN SUBPOPULATIONS

An analysis of data from the pooled guselkumab VOYAGE 1 and VOYAGE 2 psoriasis studies has shown a high degree of efficacy for the biologic in the treatment of moderate-to-severe psoriasis across a number of subpopulations. Published online ahead of print in the British Journal of Dermatology (Sept. 22, 2017), the analysis looked at sub-populations within a randomized group of 1,829 patients. Sub-populations were defined by demographics, baseline disease characteristics, and previous psoriasis treatment. The investigators found that the anti-interleukin (IL-23) antibody guselkumab proComment: Psoriasis patients are fortunate to vided substantial have many choices of safe and effective therapy benefit in the treatfor their moderate to severe psoriasis. ment of moderate-toGuselkumab offers a new safe and effective severe psoriasis in choice for these patients. This study confirms that almost all subpopulaguselkumab does not discriminate against tions examined. This weight or previous treatments used for these paincluded larger protients who have an increased weight or who have portions of patients had previous exposure to other biologics. achieving InvestigaGuselkumab therefore offers a great first choice tor’s Global Assessfor first line therapy and an alternative therapeutic choice for those who have had primary or secment (IGA) scores of ondary failure with previous treatments. This 0 (clear) or 1 (almost first-in-class biologic is a welcomed addition to clear) vs. placebo at the biologic world. week 16, and vs. the anti-tumour necrosis factor antibody adalimumab at week 24. Those patients treated with guselkumab also achieved greater efficacy—IGA 0/1 or IGA 0) vs. adalimumab at week 24 across all weight quartiles, particularly among patients weighing =>100kg.

We invite your comments and questions about this feature at www.derm.city. Dr. Ron Vender is a certified dermatologist with 23 years of clinical practice experience and over 50 clinical trials in psoriasis. He is founder and director of Venderm Innovations in Psoriasis, a centre of excellence for Psoriasis offering a comprehensive management solution for individuals with psoriasis. www.venderm.ca

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The ChronICLe of S K I N & A L L E R G Y

12 · oct./nov. 2017

Mosaic NF type 1 concerns can include learning disabilities

Continued from page 1 or more café au lait macules will meet the diagnostic criteria for neurofibromatosis type I and will meet that criteria by age six. others, with longer follow-up, will eventually meet the diagnostic criteria (Arch Dermatol 2009 Aug; 145(8):883–887). Dr. Lara-Corrales said that it is reasonable to recommend “further investigations and follow up” in patients who present with more than three café au lait macules, especially in the first year or two of life. In her own café au lait macules screening clinic, which was designed to expedite the diagnosis of the condition, many other conditions have also been observed, said Dr. Lara-Corrales.

Atypical presentations common “We are seeing so much more than just neurofibromatosis type I,” she said. “one of the most common things we are seeing are atypical presentations of neurofibromatosis type I. Mosaic neurofibromatosis type I is one of the most common presentations we see.” The estimated prevalence of mosaic neurofibromatosis type I in the general population is one in 36,000 to 40,000 individuals. “It is likely under-reported and underdiagnosed. It can be localized or generalized in the skin,” said Dr.

Lara-Corrales. “The phenotype will depend on the timing of when the cell lines are affected by the mutation. The majority of patients will have localized presentation but some will have a generalized presentation. A systematic review that Dr. LaraCorrales and colleagues conducted found three-quarters of 320 individuals with mosaic neurofibromatosis type I had localized disease confined to one segment while the balance of patients had generalized mosaic neurofibromatosis type I, meaning more than one segment of the body was involved but presented in a segmental configuration. In addition, most patients had pigmentary changes or neurofibromas only (Pediatr Dermatol 2016 Jan-Feb; 33(1):9–17). When the post-zygotic mutation relating to mosaic neurofibromatosis type I occurs will affect the presentation of the disease, said Dr. Lara-Corrales. “The earlier that the genetic change happens, the more likely that more of the skin will be affected,” she said. Genetic testing needs to be conducted via blood and skin samples, with samples from lesional and unaffected skin taken, said Dr. LaraCorrales. Thorough genetic testing allows clinicians to confirm mosaicism, she added.

Patients that have mosaic neurofibromatosis type I present with decreased clinical signs and complications compared to patients with complete neurofibromatosis type I. Still, complications associated with mosaic neurofibromatosis type I are not rare, said Dr. Lara-Corrales.

Other health impacts seen Apart from the impact of mosaic neurofibromatosis type I on the skin, the condition has other impacts on the patient, said Dr. Lara-Corrales. The systematic review published in 2016 found that among individuals who had pigmentary changes only, that about 30% of patients had hypertension, seizures, brain gliomas, and vascular malformations. “Patients that have mosaic neurofibromatosis type I can pass this mutation to the next generation as complete [not mosaic] neurofibromatosis type 1,” she said. “Many people think that if the mosaic neurofibromatosis affects the genital area there is a higher risk of passing it as a complete disease to the next generation and this is not true. There is no higher risk in this area, this is true for any area of the body identified to have the mosaic disorder. unfortunately, we are not able to predict if there is mosaicism in the gonads.”

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Another complication that can present is learning disabilities, which Dr. Lara-Corrales said she and colleagues have observed in children who have presented with mosaic neurofibromatosis type I at the hospital for Sick Children. It is important that patients with mosaic neurofibromatosis type I undergo genetic testing, as well as undergo a complete physical examination, counselling, and be monitored in terms of overall health. health surveillance is critical, she said. The risk of the same parents having more than one child with mosaic neurofibromatosis type I is extremely rare, she said, but the children of a person with mosaic neurofibromatosis are the ones that are at risk of having complete mosaic neurofibromatosis. “We are not able to predict the chances of this happening, but if the affected person has genetic testing and a mutation is identified, prenatal testing can be done in their pregnancies to determine if the mutation is present in their children.” The course of mosaic neurofibromatosis type I is not well-established, owing to the lack of long-term followup in case reports and case series, explained Dr. Lara-Corrales.

Share your knowledge and opinions with worldwide peers. Visit www.

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Vol. 20, No. 5

14 · Oct./Nov. 2017

Surveying the current

Dermatologic literature Cutaneous adverse drug reactions being driven by changes in clinical prescribing practice

SIBO appears to be the most relevant contributing factor to papulopustular rosacea

Epithelial stem cells ‘learn’ from initial inflammation

THE CHRONICLE of SKIN & A LLERGY

Recently come across something from the peer-review literature that you consider to be interesting or impactful? Share it with your colleagues. E-mail your clippings, along with your comments, to: health@chronicle.org

impacting cutaneous adverse drug reactions (CADRs) seen in clinical records, researchers conclude in a paper published in Cutaneous and Ocular Toxicology (Dec. 2017; 36(4):370-376). They also note that newer drugs can be culpable for CADRs, and that more CADRs are being documented with increased severity at clinical presentation.

C

HANGES IN PRESCRIBING PRACTICES ARE A MAJOR FACTOR

Researchers conducted a retrospective study of CADRs encountered in a single hospital-based population in Southern China during three time intervals from 1984 to 2015. Records from 306 patients with CADRs admitted to the hospital between 2011 and 2015 were compared to records from patients visiting the same hospital between 1984 and 1994, and between 2003 and 2010. From 2011 to 2015 the most common CADRs were exanthematous reactions (40.8%) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN; 17.0%). In the same period there were eight (2.6%) cases of CADRS related to targeted oncology therapy. In CADR cases due to single medications (n=205), the most common culprit medications were allopurinol (21.5%), cephalosporins (10.7%), and carbamazepine (10.2%). In the 2011 to 2015 time period, the percentages of CADR cases arising from allopurinol, carbamazepine, or epidermal growth factor receptor inhibitors were significantly higher than in either of the other two time periods studied. As well, the rate of SJS/TEN occurrence was significantly higher in the two more recent periods than in 1984 to 1994. —For more information visit http://tinyurl.com/y7tyrgwv

R

ESULTS FROM A PROSPECTIVE CASE CONTROL STUDY examining the etiopathogenesis of rosacea suggest

that small intestine bacterial overgrowth (SIBO) is the most relevant factor in papulopustular rosacea, with treatment of SIBO being crucial to improvement of rosacea and in the maintenance of clinical remission. These findings were published in Giornale Italiano di dermatologia e venereologia (Oct. 2017; 152(5):418-423).

The study included 60 patients with rosacea and 40 healthy controls. All patients underwent standardized skin surface biopsy to investigate Demodex folliculorum (DF), urea breath test for Helicobacter pylori (HP), and a glucose breath test for SIBO. Etiological therapy was then started in the following order: acaricidal treatment, then antibiotics for SIBO and HP. The three tests were repeated after three years, and statistical analysis was performed on the data. Of the 88 patients who completed the full follow-up, 47.7% were found to be positive for DF, 25% were positive for SIBO, and 21.6% were positive for HP. SIBO was significantly more associated with papulopustular rosacea, whereas HP was more strongly associated with erythrosis. At a six-month follow-up visit, 61% of the patients were in remission. After three years, 18% of patients had dropped out. At the final follow up, the majority of the patients were still in remission and negative for HP, while only five were positive for DF, and four for SIBO. —For more information visit http://tinyurl.com/yb6ajukf

(EPSCS) APPEAR TO HAVE A MEMORY FUNCTION FOR ACUTE INFLAMMATION which allows for more rapid skin barrier restoration after subsequent damage, though this enhanced sensitivity likely increases their susceptibility to autoimmune and hyperproliferative disorders, including cancers, according to findings of a study published online ahead of print in Nature (Oct. 18, 2017).

E

PITHELIAL STEM CELLS

The authors note that in spite of the known vulnerability of EpSCs to inflammatory pressures, there remains a relatively poor understanding of either the primary response to inflammation or its longer-term consequences in these cells. In order to gain better understaning of how EpSCs respond to inflammation, the researchers investigated the functions of these cells in a mouse model. In the study, they found the long-term memory to acute inflammation and were able to determine that this functional adaptation did not require either skin-resident macrophages or Tcells. Rather, the EpSCs maintain chromosomal accessibility at important stress response genes activated by the primary stimulus. Because of this action, when a future stimulus is encountered, relevant genes are transcribed more quickly. The researchers found that the AIM2 gene, which is involved in the production of an inflammatory protein, was key. When AIM2 or its downstream proteins caspase-1 and interleukin-1beta were absent, EpSCs could not recollect inflammation. —For more information visit http://tinyurl.com/ybtengwz


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Laser and light research

16 · oct./nov. 2017

The ChronICLe of S K I N & A L L E R G Y

Venous lake in Asians

Research

IPL, laser for CMN

Research

n not a good choice for first-line therapy

From the News Resources of The Chronicle

n Different laser parameters needed for safety From the News Resources of The Chronicle

Intense pulsed light (IPL) treatment alone or in combination with er:YAG laser therapy is not a definitive treatment for congenital melanocytic nevi (CMn) and should therefore not be considered as first-line therapy for the condition, investigators report in Annals of Dermatology (Feb. 2017; 29(1):39-47). Because there have been some promising early results published for the treatment of CMn with IPL, the authors set out to evaluate clinical and histological outcomes of small-to-medium sized CMn that had been treated with IPL alone or in combination with er:YAG laser, through a retrospective chart review of 26 CMns. Two independent clinicians evaluated any reduction in visible pigmentation, signs of recurrence, and any adverse skin changes. of the 17 patients who completed treatment and follow-up, 10 received IPL alone (mean 10.5 sessions) and seven had treatment with both IPL (mean 7.7 sessions) and er:YAG/IPL combination therapy (mean: 4.7 sessions). After initial treatment five patients were cleared and 12 had excellent improvement. however, 14 (82.4%) had recurrence one year after treatment completion, and histological results from one patient with an excellent clinical outcome revealed remnant nevus cell nests in the deep dermis.

Multi-wavelength laser treatment for venous lake (VL) is safe and highly effective in Asians with Fitzpatrick skin type IV, though much lower fluences of nd:YAG laser are needed compared to the fluences described in the literature for VL treatment in Caucasians. A pulse duration of 10 ms also ensures better outcomes in this patient population, according to a paper published in Photodermatology, Photoimmunology & Photomedicine (Sept. 2017; 33(5):267-270). The authors note that while multi-wavelength lasers have been reported in the literature as being effective for treating VL in Caucasians, it may not be appropriate to use the same laser parameters in Asian patients. They report their experience treating 17 episodes of VL in 15 Chinese patients. Treatment was with 595 nm pulsed dye laser (PDL) with a 7 mm spot size at 7 to 11.5 J/cm2, 2 to 10 ms, followed by 1,064 nd:YAG laser at 35 to 40 J/cm2, 15 to 40 ms. All laser treatments were performed in a single pass without overlap. There was complete resolution of 14 lesions after one to two treatment sessions with 10 ms PDL duration. The remaining three patients had 80% to 90% resolution after 1 to 2 ms PDL duration. There was only one recurrence after one year.

Laser and light update

RECURRENT LASER THERAPY IMPROVES ROSACEA PTS QOL recurrent treatment for rosacea using pulsed dye lasers improves patient quality of life and decreases symptoms, new research shows, a finding that investigators say supports the idea that chronic treatment is required for this condition. Publishing their findings in Journal of Cosmetic and Laser Therapy (June 2017; 19(3):160-164), the authors note that prior research into pulsed dye laser treatment of rosacea has emphasized a single series of laser treatments. To investigate how recurrent treatments might impact patient symptomatology and quality of life, researchers designed an eight-question survey about rosacea symptoms, prior treatments, effectiveness of prior treatments, benefit of the laser treatments, and the number of laser treatments. The survey was offered to all patients over the age of 18 years who were either beginning or currently undergoing pulsed dye laser treatments at a single clinic who had previously failed medical management for their erythematotelangiectatic rosacea. There were 50 patients who completed the survey. Significant improvement in symptoms was observed, and there was a statistically significant benefit from repeated pulse dye laser treatment for rosacea vs. a single series of treatments.

THULIUM FIBRE LASER FOR SCALP REJUVENATION IN MALE PATIENTS In a small case series, a 1,927 nm non-ablative fractional thulium fiber laser was effective, safe, and well tolerated for scalp rejuvenation in male patients, researchers report in Lasers in Surgery and Medicine (July 2017; 49(5):475479). The authors note that male scalps are prone to extensive photodamage as a result of the high prevalence of androgenic alopecia and associated exposure to ultraviolet radiation. This can include solar lentigines, fine rhytides, and keratosis, contributing to a patient’s appearance of age. In this series, four male patients with Fitzpatrick skin types II to III and extensive photodamage to the scalp underwent a single treatment with a fractional, non-ablative 1,927 nm thulium fibre laser. high density and high energy settings were used. Investigators observed a 60% to 90% improvement in dyspigmentation, lentigines, and keratosis in the four patients. no adverse events were observed, and the patients tolerated the procedure well.

Q-SWITCHED ND:YAG LASER EFFECTIVE FOR NEVUS OF OTA, IMPROVES SKIN QUALITY AS WELL Q-switched nd:YAG (QSnYL) 1064nm lasers not only effectively and safely remove pigment in nevus of ota, but also rejuvenate the skin in the treated area, according to a paper published in Lasers in Medical Science (May 2017; 32(4):765-769). The authors conducted a retrospective, randomized, split-face, clinical study including 29 patients with unilateral moderate to severe nevus of ota. each patient completed three to 13 sessions of QSnYL treatment, three to six months apart. Two independent physicians compared treated and untreated sides of the face, evaluating nevus of ota clearance, Wrinkle Severity rating Scale (WSrS), Global Aesthetic Improve-ment Scale (GAIS), and reported adverse events. The patients’ satisfaction levels were also considered. There were 28 (96.6%) patients who achieved nearly complete pigmentation clearance. As well the investigators observed a statistically significant improvement in wrinkles and skin texture on the treated side of the face after an average of 7.76±2.99 sessions, compared to the untreated side. There was a positive correlation between number of treatment sessions and degree of skin rejuvenation, and no clinically adverse effects.

EFFECTIVE TREATMENT OF NONPORT-WINE VASCULAR LESIONS IN CHILDREN WITH ND:YAG Long-pulsed nd:YAG (LP nd:YAG) laser treatment is well-tolerated and effective for some non-portwine stain vascular malformations in children, researchers report in the Journal of the American Academy of Dermatology (Sept. 2017; 77(3):473-479). The authors note that while vascular malformations manifest with pain, bleeding, disability, and disfigurement in a subset of children, there is little data in the literature on the utility and tolerability of laser surgery for symptomatic or disfiguring vascular malformations of this type. They conducted a retrospective review of 29 pediatric patients who had non-port-wine stain vascular malformations treated with 1064-nm LP nd:YAG laser at a single academic clinic, reporting patient characteristics, treatment parameters, outcomes, and complications. Blinded assessment of the clinical efficacy of the treatment showed good to excellent results in 66.7% of the patients treated, and poor to fair results in another 25%. overall, the complication rate was 27%, with the most common complications being minor skin breakdown and blistering.


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Lead article

18 · oct./nov. 2017

The ChronICLe of SKIN & A L L E R G Y

MI contact allergy incidence on increase in Western Canada

Continued from page 1 MCI and MI were found to be a strong sensitizer, based on initial studies in guinea pigs it was thought that the methylchloralisothiazolinone or the MCI portion was the stronger sensitizer. That led to the use of MI alone as a preservative.” unfortunately, MI also turned out to be a strong sensitizer, she said.

Evidence growing worldwide Dr. Guy and senior author Dr. Gillian de Gannes were spurred to look at their own clinical data on MI and MCI contact allergy by reports around the world of rising prevalence of MI contact allergy, as well as MCI contact allergy. This included clinical findings published by Dr. Melinda Gooderham in 2015 (Dermatitis July-Aug. 2015; 26(4):166-169). “That was the main impetus for us to then look at our clinic data and see if we could find a similar pattern, especially from 2013-onward, after we added the 2,000 parts per million MI to our screening series,” said Dr. Guy. She explained that prior to 2013, the contact allergy screen contained MCI and MI in a 3-to-1 ratio at 100

parts per million, which may have led to some false negatives compared to the more sensitive tests of MI at 2,000 parts per million, and the MCI/MI combination at 200 parts per million adopted in 2013.

2,177 patch tests reviewed A chart review found a total of 104 patients tested positive for MCI/MI or MI alone out of 2,177 total patients patch tested for the preservatives at a single community dermatology clinic in Vancouver from Jan. 2008 to Apr. 2015. overall, positive results increased over the study period. They peaked in 2015, with 9.41% testing positive for MCI/MI, 12.94% for MI, and 15.29% for either in that year. The initial positive patch testing prevalence for MI at 2,000 parts per million was 6.6% when it was introduced in 2013. This rose to 10.1% in 2014, and 12.9% in 2015. “Looking at our own data from 2013 to 2015, we had 71 patients who reacted to MCI/MI and/or MI,” said Dr. Guy. of those 71 patients, 31 reacted only to MI but not MCI, she said. “That shows 43.7 per cent of the

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Research

patients who were, in fact, sensitized to MI would have been missed and had a false negative result if they had only been screened for the earlier 100 parts per million MCI/MI allergen,” said Dr. Guy. This paper’s findings are concordant with those published by the north American Contact Dermatitis Group, said Dr. Guy (Zirwas MJ, hamann D, Warshaw eM, et al: epidemic of isothiazolinone allergy in north America: Prevalence data from the north American Contact Dr. Gillian de Dermatitis Group Gannes 2013-2014. Dermatitis 2017 May/Jun; 28(3):2004209). That paper looked at MCI and MI contact allergy prevalence in the 2013 to 2014 period, said Dr. Guy, and 10.7% of the patients were positive to MI contact allergy, compared to 9.0% in the 2013 to 2015 period covered by the paper written by Drs. Guy and de Gannes. “It just reinforces that this is an increasing allergy-causing sensitization in all kinds of personal products that people are exposed to,” Dr. Guy said. Family physicians and dermatologists who see patients with dermatitis, particularly when contact dermatitis is being considered and patch testing is available, should definitely consider screening for MI and MCI/MI, Dr. Guy said.

Top 10 list of allergens changing So prevalent have contact allergies to MI and MCI become that they have pushed other common contact allergens out of the north American Contact Dermatitis Group top 10 list, she said. “In the last publication this year

showing the data from 2013 to 2014, methylisothiazolinone went from being not on the list to now being number three. It has become a very significant allergen.” MCI/MI has also entered the list at number 10, displacing quaternium15, a formaldehyde-releasing preservative. In fact, other than formaldehyde itself, MI and MCI/MI are the only preservatives remaining on the north American Contact Dermatitis Group’s top 10 list.

Regulation of MCI/MI and MI health Canada is moving to more closely regulate MI and MCI/MI, said Dr. Guy, noting that currently MCI may not be used by itself, and the MCI/MI combination may not be used in leave-on products or in rinse-off products targeted for children under the age of three years. In rinse-off products for adults, MCI/MI is restricted to 0.0015% of the make up of the product, or 15 parts per million, she said. however, health Canada does not regulate either preservative in industrial products, only in personal care products. In the population sample of this study, mechanics were represented more than any other occupation, Dr. Guy said. “once [individuals] are sensitized, they can react to [these preservatives] in their personal care products—things like shampoos, soaps, creams, lotions, personal wipes—but also in industry or other uses where they are contacting industrial products,” she said. Dr. Guy noted that there have been cases where patients have reacted to interior house paint containing MCI or MI, causing the patient to develop generalized contact dermatitis. Some have had to leave their home for up to six months while the preservatives offgassed from the paint.

Study reveals clues into how staph evades immune system From the News Resources of The Chronicle via derm.city

researchers have discovered new insights into how staph bacteria elude the immune system, knowledge that could guide research into new avenues of therapy for the prevention of drug-resistant infections. The findings come from a paper published online in Cell Host & Microbe (Sept. 21, 2017). Widespread MrSA infections have prompted routine use of antibiotics that were once considerd last-line, and this is making the antibiotic resistance problem worse, co-lead author Dr. George Liu, said in a press release. Dr. Liu is a pediatric infectious diseases physician at the Cedars-Sinai Medical Center’s Maxine Dunitz Children’s health Center, and the F. Widjaja Foundation Inflammatory Bowel and Immunobiology research Institute in Los Angeles. “our study focuses on why MrSA is so common and why we never develop immunity to these bacteria,” he said. Typically the immune system learns to recognize key proteins from a pathogen, so can respond to future infections more quickly. But the human body can have repeated staph infections throughout life without developing a robust protective memory immune response. This study shows that staph bacteria are able to dodge this immune

response, as the bacterial cell walls of Staph. aureus do not break down and expose proteins that can be recognized by immune cells, so the body does not produce a defence against future exposure. “essentially, staph tricks the body’s T cells, which are white blood cells that fight infection, and prevents them from mounting an effective defense,” said co-lead author Dr. Gislaine Martins, an assistant professor at the F. Widjaja Foundation Inflammatory Bowel and Immunobiology research Institute and Departments of Biomedical Science and Medicine at Cedars-Sinai. “The study explains why our immune system is fooled by staph,” Dr. Martins said. “Staph evolved to have this enzyme that makes this modification in its cell wall. This modification protects the wall from degradation and therefore from being properly detected by the immune system, which won’t remember the bacteria the next time the body is infected.” The authors suggest that the findings provide clues about how to develop staph vaccines to make them more effective. Most staph vaccines that have been previously tried have attempted to stimulate antibodies—specialized molecules that recognize foreign bodies and help to mobilize the immune system. This study suggests that a successful vaccine should harness the body’s T cells, according to the release.


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POSTGRADUATE EDUCATIONAL SUPPLEMENT Chronicle

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Autoimmune aspects of psoriasis: Heritability and autoantigens Jörg Christoph Prinz1,*

ABSTRACT

from 1Department of Dermatology, University Clinics, Ludwig-Maximilian-University of Munich, Munich, Germany *Corresponding Author

Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation.

C

INTRODUCTION

hronic, immune-mediated diseases (IMDs) represent a heterogeneous group of multifactorial disorders.1–3 It comprises ankylosing spondylarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis vulgaris, type I diabetes mellitus (T1D), multiple sclerosis (MS), systemic lupus erythematodes, Behçet's disease, and many others.3,4 IMDs constitute the third-greatest burden for clinical treatment, after cardiovascular diseases and cancer.5 In IMDs the combined effects of a polygenetic predisposition and environmental influences eventually induce chronic and self-perpetuating inflammation that result in damage to organs, tissues, or cells. While much of the knowledge about immunological disorders is based on murine disease models, the pathomechanisms of human IMDs are still incompletely resolved. The strongest genetic association is seen with certain HLA alleles but the role of the HLA polymorphisms in disease pathogenesis has remained mysterious, because the extensive linkage disequilibrium within the major histocompatibility complex (MHC) did not allow for a precise risk allocation to a particular gene. Although being viewed as autoimmune or autoimmune-related in nature, final evidence of the autoimmune character of most IMDs is missing because precise target cells or Reprinted with permission from: Jörg Christoph Prinz Autoimmunity Reviews Sept. 2017; 16(9):970-979 © 2017 Jörg Christoph Prinz. Published by Elsevier B.V. Distributed under the terms of the Creative Commons Attribution License http://www.sciencedirect.com/science/article/pii/S1568997217301829?via%3Dihub Content may have been edited to conform with the Canadian Press Publication Style Guide.

autoantigens of the suspected autoimmune responses are still unknown. Accordingly, it has remained largely elusive how genetic traits cooperate with innate and adaptive immune mechanisms in driving IMD manifestation.4,6,7 Recent insights into the pathomechanisms of psoriasis now provide evidence that the disease-associated HLA alleles represent the key for resolving both missing heritability and missing autoantigens. This allows for redefining the pathogenetic concepts of HLA-associated IMDs.

IMDS: MISSING HERITABILITY

Familial clustering and genome-wide association studies Familial clustering and the concordance rate in monozygotic twins indicate that IMDs have a heritable etiology. Unlike rare monogenic autoimmune disease syndromes with highly penetrant mutations, however, IMDs are multifactorial.8–10 They involve the interaction of individual genotypes with environmental, infectious and lifestyle factors.11 Initially, identification of disease risk genes was based on candidate gene analyses and familybased linkage studies.12 Completion of the Human Genome Project and International HapMap Project and the introduction of array-based approaches then facilitated a hypothesis-free survey of the human genome for gene variants associated with disease susceptibility.12–15 For each IMD, genomewide association studies (GWAS) revealed a complex genetic predisposition and identified numerous diseaseassociated gene loci.12,13,16 The Major Histocompatibi-lity Complex (MHC) region on human chromosome 6, which harbours the HLA alleles, stands out as the most prominent susceptibility locus for all IMDs.12,17 Outside the

MHC region, GWAS revealed mainly common gene variants which exert only modest individual effects, explain only a small proportion of familial disease clustering and ostensibly act independently.18 Only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. While some of the susceptibility loci outside the MHC appear to be disease- or phenotypespecific, many others are shared across IMDs and implicate similar susceptibility pathways in multiple diseases.12,13,19–22 For particular IMDs 70 or more non-HLA risk loci were identified. They result in small increments with additive effects for disease risk but overall still explain only a minor proportion of the familial inheritance. Together the allelic variants usually make up for 20% to 50% of heritability.23 Thus, despite compelling genetic insights, much of the genetic contribution to complex traits remains unresolved. Proposed explanations for the missing heritability include that the effect size of common gene variants may be too small to be detected in cohorts with limited sample size, or that rare disease alleles are not covered by GWAS. Furthermore, non-additive epistatic gene-gene interactions might generate greater-than expected risk effects. 13,24 Polygenic disorders are therefore mainly interpreted as quantitative traits where the additive effects of hundreds of risk loci with moderate risk size account for a substantial part of inheritance.25–27 Because the identified associations are neither necessary nor sufficient for causing disease, and patient populations in any disease are inevitably heterogeneous19,28,29 it has been doubted, if single genes explaining a large proportion of heritability for complex diseases exist at all.24 HLA-association: the strongest genetic signal in IMDs

This conclusion turns the attention back to the HLA association of IMDs. Few, if any genetic signals of IMDs are stronger than the associations with the human MHC.13,30 This reflects the HLA association of IMDs that has been known for more than four decades: Virtually all autoimmune conditions are found in association with particular HLA-class I or class II alleles or both if large enough cohorts are being studied.17,31–33 The HLA alleles are localized in the MHC on chromosome 6p21. They are extremely polymorphic. By 2017 there are more than 16.000 HLA and related alleles described by the HLA nomenclature, comprising more than 12,000 HLA-class I alleles and 4200 HLA-class II alleles (IPD-IMGT/HLA Database). In view of this exceptionally high diversity it is particularly remarkable that only select HLA alleles are linked with autoimmune diseases: While IMDs share many of the non-

HLA loci, the associated HLA class I and/or class II alleles are usually disease-specific.34 This pleads for a direct causal role in IMD pathogenesis. The density of genes and the strong linkage disequilibrium within the MHC as well as the lacking functional implementation of disease-associated HLA alleles have hitherto thwarted an identification of the precise role of particular HLA molecules in IMD susceptibility. Only few experimental reports have assigned particular HLA-molecules with a direct role in disease pathogenesis. Transgenic expression of HLA-DRB1*1501, the main MS risk allele, caused a T-cell mediated MS-like disease in mice. 35 Humanized mice expressing another MS risk allele, HLA-A*03:01, and an HLA-A*03:01-restricted myelin proteolipid protein-specific T-cell receptor (TCR) isolated from MS patients developed a disease resembling human MS.36,37 Occurrence of arthritis in rats or mice transgenic for HLA-B27:05, the main risk allele for ankylosing spondylitis, indicated that the encoded HLA proteins and not genes in linkage disequilibrium with HLA-B27 are responsible for joint inflammation.38–40 Because HLA-B27 molecules present peptides from cytoplasmic proteins on the cell surface41,42 and act as restriction elements for CD8+ T-cell responses43,44 it was proposed that HLA-B27 may induce autoimmune responses through presentation of arthritogenic self-peptides. Aberrant cell-surface expression of HLA-B27 heavy chain homodimers or HLA-B27 misfolding inside the endoplasmic reticulum were considered as alternative causes for innate immune dysregulation.45,46 Yet, despite these intense investigations the pathogenic mechanisms by which HLA alleles cause disease remained elusive.

CHALLENGES FROM HLA ANTIGEN PRESENTATION AND TCR ANTIGEN RECOGNITION HLA antigen presentation and autoimmune responses

The natural immunological function of HLA molecules is presentation of peptide antigens to the TCRs for cognate antigen recognition by T cells.47,48 HLA polymorphisms mostly refer to pockets of the peptide binding groove which determines the peptide repertoires by specific acceptor sites or pockets that bind side chains of particular amino acids localized at certain positions within the peptide. The peptide residues in between the anchor amino acids may be flexibly occupied. A single HLA molecule can theoretically display between 6 × 205–7 (HLA class I) and 12 × 2010 (HLA class II) different peptides. 47,49,50 Different HLA molecules select different peptide repertoires for presentation, 51,52 although the binding specificities may overlap.53,54 Accordingly, induction of T-


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POSTGRADUATE EDUCATIONAL SUPPLEMENT cell mediated autoimmune responses through presentation of self-peptides by select HLA molecules would be the most straightforward explanation for the HLA association of IMDs.55 HLA-class I- and II-molecules differ regarding their expression patterns and the origin and length of the peptide antigens they present. This should have essential consequences for potential autoimmune responses. HLA-class I molecules are expressed on all nucleated cells. They present peptide antigens of usually eight to 10 amino acid lengths to aß TCRs of CD8+ T cells.56 The peptides are derived from intracellular, i.e., cytoplasmic proteins generated within cells that were degraded by the proteasome, translocated into the endoplasmic reticulum and subjected to N-terminal trimming by the endoplasmic reticulum peptidases 1 and 2 (ERAP1/2).56–58 This reflects the primary role of HLA-class I-molecules to present antigens from viruses that replicate intracellularly within infected cells and otherwise would escape immune recognition.47 Consequently, an HLA-class Irestricted autoimmune response by CD8+ T cells should be directed against a particular target cell expressing the protein which is the source of the autoantigenic peptide.57,58 Expression of HLA-class II molecules is mostly restricted to professional antigen-presenting cells including macrophages, dendritic cells and B cells.57 HLA-class II-molecules screen the environment for antigenic danger signals. The antigenic peptides are primarily derived from extracellular proteins degraded in the endocytic pathway. They have a 9-amino acid core but the peptides vary greatly in length, because the flanking residues may extend out of the HLA-class IIbinding groove and.59 HLA-class II-antigen presentation activates CD4+ T cells which promote inflammation and antibody formation. Hence, HLA-class IIassociated autoimmune diseases are usually characterized by formation of autoantibodies.60 Unlike HLA-class Ipresented cytoplasmic antigens, which should be derived from the proteome of a particular cell, neither source nor length of autoantigens for CD4+ T cells can be anticipated. TCR antigen recognition and polyspecificity The TCRs of pathogenic T cells hold the clue to defining the role of HLA alleles in autoimmune diseases. They determine both HLA-restriction and antigen specificity and thus define the precise reactivity of adaptive immune responses. A T-cell mediated immune response begins with the formation of a trimolecular complex between the TCR of a T cell and a peptide presented by the appropriate HLA molecule. Upon antigen recognition, T cells become activated and undergo clonal expansion at the site of antigen exposure. Due to TCR diversity, any two T cells expressing the same TCR likely arose from a common progenitor T cell.7 TCR clonotypes designate the T cells involved in pathogenic circum-

stances that have expanded in response to local antigen stimulation.7,61 Clonal T-cell expansions characterize inflammatory infiltrates of IMDs such as MS, ankylosing spondylitis, coeliac disease, Crohn's disease, rheumatoid arthritis, and type I diabetes mellitus. 62–72 The TCR clonotypes from tissue infiltrates can be used for analyzing HLA restriction and antigen specificity of pathogenic T-cell responses. As several aspects limit the availability and experimental use of pathogenic T cells in human diseases, such approaches currently rely mainly on cloned TCRs. 7 This requires identification and isolation of the clonally expanded pathogenic T cells from complex inflammatory infiltrates and analysis of their TCR rearrangements. Conventional T cells express unique aß TCRs composed of an a- and ß-chain, each generated by somatic recombination of diverse V(D)J gene segments and random addition or deletion of nucleotides at the recombination sites.73 The comparatively small size of the human TCR repertoire of an estimated 107 to 108 different aß TCRs,61 which faces the huge peptide antigen diversity presented by HLA molecules, is compensated by the fact that TCRs are polyspecific.49,50,74–76 A single TCR can recognizes more than one million distinct decamer peptides in the context of a single HLA-class I molecule once they share amino acid anchor and TCR contact residues defining them as TCR ligands.77 While this principle guarantees the recognition of a broad antigen spectrum it creates a major challenge for antigen identification: the precise peptide antigen of a pathogenic autoimmune response has to be unequivocally identified from the universe of potential TCR ligands.76,77 In this context HLAclass I-associated IMDs may offer advantages over HLA-class II-risk genes. The origin of HLA-class I-presented molecules from cytoplasmic proteins limits the spectrum of potential autoantigens to the target cell proteome. This makes the identification of the target cells of HLA-class I-restricted autoimmune responses an essential precondition. The first HLA-class Iassociated IMD, in which resolving this experimental challenge successfully determined the role of the main HLA risk gene, defined the autoimmune target cell type and identified an autoantigen by using a pathogenic TCR, is psoriasis vulgaris.78

HLA-C*06:02 AND T-CELL RESPONSES IN PSORIASIS

HLA-C*06:02 and CD8+ T cells in psoriasis Psoriasis vulgaris [MIM177900] is a common inflammatory skin disease characterized by T-cell driven epidermal hyperplasia. T cells infiltrating psoriasis skin lesions display a Thelper/cytotoxic cell (Th/c) 17 phenotype and drive psoriatic inflammation through a complex cytokine pattern

with the signature cytokines interleukin (IL)-17A, IL-22 and IFN-Y.79,80 Psoriasis is multifactorial and has a complex genetic predisposition. HLAC*06:02 is the major psoriasis risk gene in Caucasian populations.81–83 It is located in the psoriasis susceptibility locus 1 within the MHC on chromosome 6 (PSORS1 on 6p21.3), which accounts for approximately 50% of disease risk.84–86 Other psoriasis associated HLA variants with lesser Odds ratios are HLA-C*07:04, HLA-C*12:03, HLA-B*27, HLA-B*57, HLA-B amino acid positions 67 and 116, HLA-A amino acid position 95, and HLADQA1 amino acid position 53, and others. 82,87,88 Psoriasis heritability explained by GWAS variants outside the MHC was estimated at about 20%, 89 while the remaining 30% of disease risk are attributed to environmental factors.90 HLA-C*06:02 defines familial clustering, early onset and a more severe course of psoriasis.91–93 Accordingly, HLA-C*06:02 is a paradigmatic HLA-risk gene. The HLA-C*06:02 association of psoriasis would be consonant with the presentation of self-antigens to pathogenic CD8+ T cells. Indeed, CD8+ T cells play a prominent role in psoriasis. The formation of psoriasis lesions depends on the epidermal influx, activation and clonal expansion of CD8+ T cells, which predominate the epidermal infiltrate and preferentially rearrange Vß3 or VB13S1 TCR genes.94–98 Together with the persistence or reappearance of the same clonal T cells in chronic or relapsing psoriasis lesions99,100 and sharing of lesional TCRs between monozygotic twins concordant for psoriasis101 these findings emphasize that dominant tissue autoantigens drive lesional psoriatic T-cell activation and inflammation. Accordingly, understanding the immunopathogenesis of psoriasis demanded answers to two fundamental but tightly linked issues: What is the role of the main psoriasis risk gene, HLA-C*06:02, and which are the antigens of the lesional psoriatic CD8+ T-cell response? Use of a TCR hybridoma to identify the target cells of the psoriatic autoimmune response We had addressed these two issues by the use of a paradigmatic pathogenic psoriatic Va3S1/Vß13S1 TCR. It had been obtained by single-cell TCR analysis from a pervasive epidermal CD8+ T-cell clone identified in the lesional infiltrate of an HLA-C*06:02positive psoriasis patient. 95 The Va3S1/Vß13S1 TCR was expressed as recombinant TCRs along with human CD8 a and ß chains in an NFAT-sGFP T-hybridoma cell line that reports on TCR signalling by robust sGFP expression. 102,103 Consequently, this functional TCR hybridoma carried the specificity of the lesional psoriatic Tcell response. The reactivity of the Va3S1/Vß13S1 TCR was characterized in a two-armed strategy: arm I determined HLA-restriction and target cell

type, while arm II recovered artificial peptide ligands of the Va3S1/Vß13S1 TCR from combinatorial peptide libraries, determined the conserved amino acid pattern of Va3S1/Vß13S1TCR ligands and searched for corresponding peptide epitopes in the proteome of the target cells. We then combined the results from both arms and tested the antigenicity of candidate peptide antigens identified in arm II in the context of the full-length parent proteins within the target cell type identified in arm I.78 These experiments revealed that the Va3S1/Vß13S1-TCR reacted specifically against melanocytes or melanomaderived melanocytic cell lines in an HLA-C*06:02-restricted manner. High frequencies of CD8+ T cells in direct contact with melanocytes in psoriasis skin lesions indicated that the Va3S1/Vß13S1-TCR reactivity is representative of the lesional psoriatic T-cell response in general. These CD8+ T cells polarized granzyme B-containing granules towards the melanocyte contact sites indicating TCR-mediated activation without signs of cytotoxicity.78,104 Hence, the unbiased analysis of the lesional psoriatic Va3S1/Vß13S1 TCR had allowed for two fundamental novel insights into psoriasis pathogenesis: the protein encoded by HLA-C*06:02, the main psoriasis risk gene, mediates an autoimmune response against melanocytes as target cells of the lesional psoriatic CD8+ T-cell response. HLA-class I-presented autoantigens are determined by antigen processing Identification of melanocytes as specific target cells of the HLA-C*06:02restricted autoimmune T-cell response in psoriasis provided the key for identification of the causative autoantigen from various antigen candidates. After having determined the conserved amino acid pattern of peptide ligands recognized by the Va3S1/Vß13S1-TCR in the context of HLA-C*06:02 we searched the transcriptome of melanocytes and the human proteome for proteins containing corresponding peptides. Of approximately 200 self-peptide candidates tested, peptides from six human proteins stimulated the Va3S1/Vß13S1-TCR hybridoma when presented by HLAC*06:02. In the context of the fulllength parent proteins however, only a peptide epitope from ADAMTS-like protein 5 (ADAMTSL5) kept its antigenicity for the Va3S1/Vß13S1 TCR, and this property depended on expression of the ADAMTSL5-parent protein in melanocytes as psoriatic target cells, but not in other cell types. These data document that the human proteome may contain many peptide antigens that can be recognized by an autoreactive TCR. The actual immunogenicity of self-peptides, however, is limited by antigen-processing and may be cell-type specific. For presentation under natural conditions antigenic peptides need to be generated from the full-length parent protein by proteasomal degradation. 58,105 This


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involves preferred proteasomal cleavage sites and cell-type dependent differences in antigen processing and limits the spectrum of potentially autoantigenic self-peptides to select proteins and tissues or cell types. 58,106,107 Accordingly, for final validation of HLA-class I-presented candidate peptide autoantigens the antigenicity of the full-length protein has to be verified within the target cell. Only this approach may finally confirm that a TCR peptide ligand from a natural protein is an actual autoantigen.

(Table 1). Overall, they reflect the different stages of the innate and adaptive immune activation cascade for mounting the CD8+ T-cell response in psoriasis. The following paragraph briefly summarizes the function of these gene variants and how they might impact on the psoriatic autoimmune response. The precise effects of most GWAS risk loci on biological pathways however, are still not sufficiently clarified and their role remains largely hypothetical. Because the GWAS results have been extensively discussed in various reviews 130–135 only specific aspects related to the focus of this manuscript are addressed here.

In 1993 N. R. Rose and C. Bona had revisited the criteria for establishing the autoimmune etiology of a human disease. 108 In psoriasis, HLA association,81,83 oligoclonal lymphocytic infiltration of the target organ and restricted TCR Vß-gene usage96,98 as well as the favourable response to immunosuppression109 represent circumstantial evidence. Indirect evidence for an autoimmune pathogenesis results from triggering psoriasis onset through checkpoint inhibition110,111 which may induce various autoimmune-related adverse drug reactions,112 and from the adoptive transfer or resolution of psoriasis by bone marrow or autologous stem cell transplantation.113–116 The findings from the unbiased analysis of a pathogenic psoriatic TCR now define an HLA-restricted autoimmune response as a central and disease-specific event in psoriasis pathogenesis. They show that the HLA molecule, which is encoded by the main psoriasis risk gene, HLA-C*06:02, mediates an autoimmune response against melanocytes through autoantigen presentation. The identification of melanocytes as organ-specific autoimmune target cells and of ADAMTSL5 as a melanocytic autoantigen provides direct experimental evidence for the autoimmune nature of psoriatic inflammation. Because melanocytes are a selectively skin-resident cell population and account for five to 10% of all epidermal cells117 this also explains why psoriasis primarily targets the skin.

Gene loci related to innate immunity

AUTOIMMUNE DISEASE CRITERIA IN PSORIASIS

CORRELATING GWAS RESULTS AND IMMUNE PATHOMECHANISMS IN PSORIASIS

Defining the functional role of HLAC*06:02 in psoriasis may now help to understand how gene variants identified by GWAS may affect autoimmune disease manifestation and allow for redefining the architecture of the pathogenic immune response. GWAS and more targeted candidate gene approaches have identified more than 40 psoriasis-associated SNPs at a genome wide significance level.89,118–129 Except for the MHC locus they mostly represent common genetic variants with low effect size. They can be grouped into genes affecting innate immune pathways, antigen presentation, activation and differentiation of CD8+ T cells and the IL-23/IL-17 axis

Initiation, magnitude and quality of adaptive immune responses require proinflammatory signals from the innate immune system.136 Various psoriatic risk loci point to an increased responsiveness of innate immunity to trivial or unspecific triggers, which may enhance type-I interferon and NF-KB signalling pathways and hereby promote the initiation of T-cell responses. IFN-a is a strong activator of adaptive immunity. 137 The initial phase of psoriasis involves the production of IFN-a by plasmacytoid dendritic cells.138 Various candidate gene loci related to type I interferon induction and signalling are associated with psoriasis risk (Table 1). ELMO1 encodes the engulfment and cell motility protein 1 which interacts with DOCK2 and is essential for Tolllike receptor-induced IFN-a induction in plasmacytoid dendritic cells.139,140 Suppressor of cytokine signalling, SOCS1, reduces IFN responses through inhibition of Tyrosine kinase 2 (Tyk2)-mediated STAT signalling and negatively impacts IFN-a receptor 1 surface expression.141 The ubiquitin binding protein RNF114 regulates a positive feedback loop that enhances production of type I IFN induced by cytoplasmic double-stranded RNA (dsRNA).142 DNA sensing by plasmacytoid dendritic cells through LL37 and endosomal Toll-like receptors is a potent trigger of interferon production in psoriasis.143 Proteins encoded by two psoriasis-associated variants, IFIH1-encoded MDA5 (melanoma differentiation-associated gene 5) and its paralog retinoic acid-inducible protein 1 (RIG1/DDX58) are cytoplasmic nucleic acid-sensing receptors which coordinate with each other to evoke downstream signalling events that promote robust type I-IFN responses and NF-KB activation.144,145 NF-KB is a key transcription factor in immune responses. NF-KB activity is inducible in all cell types and regulates transcription of many genes which encode cytokines and other proinflammatory mediators. NF-KB is activated by TNF-a and other members of the TNF-a family. 146 TNF-a blockade is highly effective in psoriasis treatment and other IMDs. 147 Hyperactivation of NF- K B in skin

induces a T-cell dependent psoriatic phenotype in a mouse model of inflammation. 148 Various gene variants of the NF-KB pathway contribute to psoriasis risk (Table 1). TYK2, REL and CARM1 encode proteins essential for NF- K B activation and signalling.119,149,150 Proteins encoded by NFKBIA, FBXL19, UBE2L3, TNIP and TNFAIP3 have inhibitory effects on NF-KB activation.151–155 The best characterized variants represent gain of function mutations in CARD14. CARD14 encodes Caspase recruitment domain-containing protein 14 that activates NF- K B. It is the causative gene at PSORS2. 156,157 CARD14 is mainly expressed in keratinocytes and dermal endothelial cells. 156,158 Psoriasis-associated gain-of-function mutations in CARD14 lead to unopposed NF-KB activation and transcription of inflammatory mediators in keratinocytes in response to proinflammatory triggers or physical injury.156 The association with psoriasis but also another inflammatory skin disease, Pityriasis rubra pilaris, 159 indicates that CARD14 mutations exert an organ-selective proinflammatory effect which may precipitate epidermal immune reactions. Gene loci related to antigen presentation All major HLA-class I-associated disorders including ankylosing spondylitis, 160 MS, 161 T1D 162 and Behçet's disease163 show associations with distinct variants of ERAP1, a gene encoding the endoplasmic reticulum aminopeptidase 1. ERAP1 governs the final step of peptide antigen generation by N-terminal trimming of antigenic precursors to the length appropriate for binding to HLA-class I molecules. Different ERAP1 variants show different cleavage activities and fine substrate preferences and hence may influence the antigenic peptide repertoire.164–167 HLA-C*06:02 in psoriasis is found in epistasis with certain ERAP1 variants.126,168 A variant protective for psoriasis reduced the antigenicity of the ADAMTSL5 peptide

and melanocytes (unpublished result). This verifies for a defined autoantigen how the genetic interaction between an HLA-class I allele and ERAP1 variants may affect disease risk through peptide destruction. Gene loci affecting activation and differentiation of CD8+ T cells Epidermal infiltration, activation and expansion of CD8+ T cells are key events in psoriasis onset. Various psoriasis risk loci involve genes related to the generation and differentiation of CD8+ T cells (Table 1). The transcription factor ETS1 enhances expression of RUNX3. RUNX3 cooperates with ETS1 in regulating the development of CD8+ T cells by repressing CD4 expression and initiating cytotoxic gene expression during the differentiation of MHC-class Irestricted thymocytes.169–172 TNFRSF9 (alternative nomenclature CD137, 4-1BB, ILA) is a member of the TNF receptor family. It is primarily expressed on activated T cells and promotes the expansion and memory formation of CD8+ T cells.173,174 Methyl-CpG-binding domain protein 2, MBD2, is involved in the efficient generation of memory effector cells from naïve CD8+ T cells.175 Interferon regulatory factor 4 (IRF4) is vital for the expansion and effector differentiation of CD8+ T cells.176 Gene loci related to IL23/T17 pathways The IL-23/T17 axis has a sentinel role in psoriasis.177 Blocking IL-23 or IL-17 has strong efficacy in psoriasis treatment. 178–181 IL-6 and transforming growth factor ß (TGF-ß) released by dermal DCs elicit Retinoic Acid Receptor-Related Orphan Receptor Gamma-t (RORYt)-dependent differentiation of naive T cells into Th/c17 cells.182–185 IL-23 sustains the phenotype and expansion of Th/c17 cells.186 Psoriasis susceptibility is associated with SNPs in both subunits of IL-23, IL12Bp40 and IL23Ap19, in IL23R,124,187,188 TYK2,126 JAK2125 and STAT389 (Table 1). The IL-23 receptor is a heterodimer composed of IL12Rß1 and IL-23R. 189 A prominent

Table 1: Major non-MHC psoriasis GWAS loci in European and Chinese populations.89,118-129


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POSTGRADUATE EDUCATIONAL SUPPLEMENT associated HLA alleles, and it may inspire attempts to identify the missing autoantigens using similar approaches in other IMDs as well. This may finally allow for the development of biomarkers and novel causal therapies.

TAKE-HOME MESSAGES

The association of IMDs with particular HLA-alleles may reflect the capacity of the encoded HLA proteins to present self-peptides and induce an autoimmune response.

Clonal T-cell expansions within the inflammatory tissue infiltrate of IMDs may reflect the activation and expansion of pathogenic T cells through stimulation by local tissue antigens.

Because HLA-class I-molecules present antigens from cytoplasmic proteins, an HLA-class I restricted autoimmune response should naturally be directed against a particular target cell type.

• Figure 1: Model of psoriasis pathogenesis. Select HLA-molecules, in particular HLA-C*06:02, predispose for an autoimmune response against melanocytes through presentation of autoantigenic peptides, which are generated in melanocytes from cytoplasmic proteins and trimmed to the appropriate size by certain ERAP1 variants. The complex of peptide and HLA-class I molecules is recognized by CD8+ T cells, which have been conditioned for an increased responsiveness during thymic T-cell development under the influence of gene variants related to CD8+ T cell differentiation. In the afferent upstream phase of the melanocyte-specific autoimmune response gene variants related to increased IFN-a signalling and NF-KB activation induce an increased inflammatory response which recruits various immune cells and provides the secondary signals for autoreactive T-cell activation upon unspecific proinflammatory triggers. In the efferent downstream phase of the autoimmune response gene variants related to the IL-23/IL-17A axis maintain CD8+ T cell differentiation into a Tc17 phenotype which promotes psoriatic inflammation through the psoriasis signature cytokines IL-17A, IL-17F, IFN-Y and TNF-a and enhanced IL-17A signalling. coding SNP in IL23R reduces IL-23 signalling and is protective against psoriasis and other autoimmune diseases.190 IL-23R associates with Jak2 and STAT3 while IL-12Rß1 interacts directly with Tyk2. 189 Proteins encoded by TYK2, STAT3, SOCS1, and ETS1 are involved in downstream signalling of IL23. 191,192 IL-23 induced activation of STAT3 induces transcription of IL-17A and IL-17F.193 STAT3 up-regulates the expression of the Th17-specific transcriptional regulator ROR Y t. A SNP within the gene for TRAF3 interacting protein 2 (TRAF3IP2) may influence NF-KB activation downstream of IL-17 receptor signalling and promote IL-17 induced effects.121,194,195 Other genes (ZC3H12C, IL12B, STAT5A/5B, ILF3) refer to Th1 signalling pathways and interleukin 2 expression.132

THE PATHOGENETIC CASCADE OF HLA-ASSOCIATED IMDS

Together these insights propose an HLAcentred pathogenetic model for psoriasis and other HLA-associated IMDs. In this model a particular HLA allele represents the causal risk gene. It constitutes the essential disease prerequisite because it predisposes for a tissue- and antigen-specific autoimmune response through its capacity for autoantigen presentation. The HLA allele alone, however, is not sufficient for disease manifestation but requires the additive effects of common gene variants, which provide the func-

tional environment for manifestation and differentiation of the actual autoimmune response. From the perspective of the HLAC*06:02-restricted T-cell mediated autoimmune response as central event in psoriasis pathogenesis, the pathogenic cascade can be differentiated into a proximal afferent and distal efferent phase (Fig. 1). In the upstream phase gene variants related to type-I IFN signalling and NF- K B activation may potentiate the innate immune response to trivial environmental triggers. This may promote the recruitment of inflammatory cells and production of proinflammatory mediators and chemokines, providing ample secondary signals for the HLA-restricted activation of potentially autoreactive non-cytotoxic CD8+ T cells that may have been conditioned by certain gene variants during thymic CD8+ T cell development and recognize peptides generated under the influence of certain ERAP1 variants. The efferent downstream phase involves gene variants related to the IL23/IL-17 axis. They act on the maturation and differentiation of autoreactive CD8+ T cells into a Tc17 phenotype, which is maintained by IL-23. Together with enhanced IL-17 signalling, the Tc17 cytokine pattern promotes keratinocyte hyperplasia, inflammation and recruitment of inflammatory cells. In this pathogenetic cascade the combination of particular risk gene activities may determine disease manifestation

and phenotype in a polygenic manner.12 In a case-case study HLA-C*06:02 associated equally strong with mild and severe psoriasis. Strong additive effects for severe disease were observed when HLA-C*06:02 combined with gene variants of IL23A, IL23R, IL12B, NFKB1 or TNIP1. Thus, HLA-C*06:02 confers an overall risk for psoriasis, while gene variants related to innate immune activation and the IL-23/T17 axis may modify disease expression.196

CONCLUSION

Psoriasis is the first major IMD where the pathogenic role of the main HLArisk gene could be unequivocally identified through the unbiased analysis of a pathogenic TCR. The HLA-C*06:02restricted autoreactivity of the Va3S1/Vß13S1-TCR obtained directly from tissue-infiltrating psoriatic T cells provided direct evidence that diseaseassociated HLA-alleles can confer autoimmune susceptibility by facilitating tissue-specific autoimmune responses through presentation of particular autoantigens. These insights propose a concept for complex HLA-associated immune mediated disorders, where the genetic predisposition of IMDs combines a causative HLA-risk allele with the additive effects of many modifier genes that finally facilitate disease manifestation and modulate disease phenotype. This model attributes much of the missing heritability of IMDs to disease-

The particular target cell type may define the organ or tissue which is affected by the HLA-restricted autoimmune response.

Identification of the autoimmune target cell type may be a prerequisite to identify and validate potential autoantigens, because the immunogenicity of particular self-proteins may be cell-type dependent.

Because of TCR polyspecificity and cell-type specific differences in antigen processing, for a precise identification of disease-relevant HLA-class I-presented autoantigens it is not sufficient to determine peptide ligands for select TCRs but necessary to prove the immunogenicity of the peptide in the context of the parent protein within the target cell.

The number of autoantigens relevant for an autoimmune disease is probably much smaller than the broad TCR reactivity against various natural peptide ligands would predict.

HLA-alleles may account for the missing heritability of IMDs and facilitate the identification of autoimmune target cells and autoantigens.

ACKNOWLEDGEMENTS

This work was supported by the Deutsche Forschungsgemeinschaft [grant number Pr241/5-1]. I am grateful to Ulla Knaus for critical discussion of the manuscript, and to Yehuda Shoenfeld for valuable comments that improved the manuscript.

KEYWORDS

HLA-association; Genetic predisposition; Immune-mediated inflammatory disorders; Psoriasis vulgaris; Autoimmune response; T-cell receptor specificity

REFERENCES

Complete list of references available online at: https://tinyurl.com/ydcrpxwq


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The ChronICLe of S K I N & A L L E R G Y

oct./nov. 2017 · 25

Think Skin project helps explain cosmecetical research

Continued from page 1 In addition to the written content, the blog features unique illustrations created by Dr. Liu. In a post titled “What’s up with Manuka honey?,” Drs. Guo and Liu wrote about the growing popularity of cosmeceuticals containing manuka honey. They identify that there is some research demonstrating that manuka honey might have a role in wound healing because of its antibiotic effects; that it may have potential to degrade existing biofilms and prevent construction of biofilms; and that it might stimulate collagen production and new blood vessel formation. They noted that while manuka honey has positive effects in certain medical scenarios that does not necessarily mean those benefits are carried to daily life. They concluded, “let’s be honest, manuka honey has some early scientific evidence for wound healing and antimicrobial properties, but if you are basing your choice of cosmetics for those reasons alone, then perhaps you should look elsewhere. . . . We are not trying to discourage you from buying manuka honey based cosmetic products. Instead, as always, we just want consumers to be aware of what’s fact and what’s fiction.” other topics they have tackled include “adult vs. baby skin: why adults can not have skin as smooth as a baby’s bum,” “what’s up with moisturizer’s?,” “What’s up with BB, CC, and DD creams?,” “What’s up with acronyms in sunscreens?,” and

more. examples of their approach to answering these questions are illustrated on this page. T h e C h r o n I C L e ’s emily InnesLeroux spoke with Drs. Guo and Liu to discuss their Think Skin MD blog.

What was your motivation behind creating the Think Skin MD blog? Dr. Guo: I initially had the idea when a lot of patients that I was seeing were asking me questions about general skin care and products related to cosmetics and cosmeceuticals as opposed to medicine and actual skin disease. These are topics that we are not taught so much about as part of residency or in medical school, but I think we kind of go out there and learn. I found it was such a prominent part of what the patient wanted to know that I decided to create this project to act as an unbiased source of reference for patients who are interested in learning more about these things in a readerfriendly manner. And I recruited [Dr. Liu], so that we could start this project together. She is the artist and I do the writing and together we make the Think Skin MD website.

I was very young, but I do not have any formal training. I just did some art classes during high school . . . I find that there is so much I can do with illustrations, [such as using] it for teaching other people like in the illustrations of studies in this project . . . So

I continued to draw and developed my style throughout university and I was very happy to hear that [Dr. Guo] had this project and this vision in mind. I thought that I was a good fit.

How do you determine your topics? Dr. Liu: When we first started the project we obviously did not have too many recommendations from people, just a few, so we made a list of topics based on what we thought was most important and also based on my own experience of what patients wanted to know about. As we went along, we both began doing a bit more reading to determine some [of the] common myths and common misunderstandings out there, and we decided to tackle Dr. Liu, how did you develop your those. We also look at cosmetic and artistic talent? Dr. Liu: I have enjoyed drawing since cosmeceutical products to see what ingredients are hot and popular at this time and we do a scientific review of those products to see if there is actually some benefit in a lot Continued from page 3 tion of the committee including Drs. of the claims that are being made. robert Bissonnette, Jan Dutz and Alain Brassard. This program has been extremeWhat has been the response to ly successful in developing mentorship for academic dermatologists. I am sure the committee will miss the work of Dr. Alain Brassard who has your blog posts? accepted a new position in the u.S. as Professor of Dermatology, at uC Davis, Dr. Guo: From my experience, the Sacramento, Calif. on behalf of all Canadian dermatologists we would like to people who have read this blog are congratulate Professor Brassard for the significant contributions he has made primarily patients that have been recto teaching research, wound care, and through his major leadership role at the ommended by family physician colroyal College of Physicians and Surgeons. he will truly be missed here in leagues, as well as my own colCanada, but we wish him all the success in his new role. leagues, . . . and from hearing from Finally, I invite readers to turn to page 19 for the new Chronicle Patient Primer. my colleagues they say it is a great This new graphic feature is a tool for patient counselling and adherence. each fea- source of information [and] they ture is designed to provide clear and simple information for patients, and can be themselves did not know the answers downloaded and printed at no cost from www.derm.city. This instalment provides to the questions that we post. So they information on AD, and other conditions will be highlighted throughout the year. found it helpful. They also find that As always, we invite your comments at www.derm.city. their patients seem to like it. —Wayne P. Gulliver, MD, FRCPC, Medical Editor Dr. Liu: A lot of the feedback that I

Message from the Medical Editor

received is from my fellow residents and the residents’ families, and they really appreciated how the overall information is tailored to them as consumers in the products that they see everyday in the grocery stores or other health product stores. And they find that it is a good guide at least for them to start thinking about how these products can impact their own health and how to be smart in choosing the right products.

There are so many health blogs these days, how does Think Skin MD stand out? Dr. Guo: That is something that I really had to think about clearly and I talked to [Dr. Liu] about this in the beginning, ‘what makes us different? Why should people listen to this?.’ So first of all we declared right off the bat that this is not funded by anyone, because a lot of websites that have product reviews, they got the product from the sponsor and even if that person wants to be as neutral as possible there is still some inherent bias. Secondly, as medical professionals who have trained in the scientific area and also regularly review medical and scientific literature, we have access to a body of knowledge that the general public also has access to, but may [not] be able to interpret as much. Because we do this on a regular basis, I think we can see the takeaway messages from the literature and convey what is important and translate it for the public. What I find is there are not a lot of doctors who take the time to review medical literature and turn it into a consumer friendly product as we have done. Dr. Liu: I agree that there are lot of blogs out there that are sort of consumer-to-consumer products and reviews. In terms of the medical field, medical professionals-to-medical professionals use a lot of jargon that the lay public would not be able to fully appreciate, nor [would they] be able to interpret the data for themselves. We found a nice synergy between having the medical knowledge, but also pursuing our passion for health literacy to be able to combine both into something that the lay person can understand.


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PLASMA BIOMARKERS THAT PREDICT MEK INHIBITOR RESPONSE IDENTIFIED

n preclinical models, researchers identified 21 plasma metabolites, including amino acids, propionylcarnitine, phosphatidylcholines, and sphingomyelins, that were significantly altered in two B-rAF-mutant melanoma xenografts, both of which were reversed after a single dose of a potent, selective MeK inhibitor (ro4987655). Treatment of animals without tumours, and of mice with PTen-null u87MG human giloblastoma xenografts resulted in changes in amino acids and propionylcarnitine only. When patients with advanced melanoma were treated with ro4987655, on-treatment changes in amino acids were only observed with disease progression. Changes in phosphatidylcholines and sphingomyelins were seen in responders. Pretreatment levels of seven lipids identified in the preclinical screen predicted objective responses to ro4987655. Treatment-related changes were greater than the baseline physiological variability in nontreated individuals. The authors conclude they have evidence of a translational exo-metabolomic plasma readout which predicts efficacy and pharmacodynamic utility following treatment with a signal transduction inhibitor. Ang J.E., et al: Modulation of plasma metabolite biomarkers of the MAPK pathway with MEK inhibitor RO4987655: Pharmacodynamic and predictive potential in metastatic melanoma, in Molecular Cancer Therapeutics (Oct. 2017; 16(10):2315-2323)..

T

TOPICOP SCORE VALID FOR ASSESSING STEROID PHOBIA ACROSS COUNTRY DATA

he feasability of applying the validated ToPICoP score for assessing topical corticosteroid phobia (TCP) across different countries was investigated. The researchers asked patients older than three months with atopic dermatitis, or their parents or legal representatives, complete a validated translation of the ToPICoP questionnaire, and collected opinions on the feasibility and acceptability of the ToPICoP questionnaire. Some 1,564 participants from 15 countries were included. of those, 81% considered the questions clear or very clear, and 79% reported the ToPICoP took less than five minutes to complete. each item on the questionnaire was considered to be not at all difficult to answer by 49% to 74% of participants. Mean ToPICoP score was 44.7±20.5%, and mean ToPICoP subscores were 37±22.8% for knowledge and beliefs, 54.7±27.8% for fears, and 50.1±29.1% for behaviours. While global scores and subscores differed between countries, subscores did not always vary in parallel, which suggests there are different levels of, and drivers of, TCP in each country. The authors say the ToPICoP score can be applied across countries and may be useful for collecting qualitative data from international studies, and for adapting patient education and treatment. Stalder J.F., et al: Topical corticosteroid phobia in atopic dermatitis: International feasibility study of the TOPICOP score, in: Allergy (Nov. 2017; 72(11):1713-1719)

Diagnostic Quiz http://tinyurl.com/y8mcotwg

I

Research of Note

The ChronICLe of S K I N & A L L E R G Y

A. Fibrous papule of the face B. Bowen disease C. Actinic keratosis D. Basal cell carcinoma

THE EDITORS invite your participation in this regular feature of the journal. Please send all images and correspondence to: Medical Editor, The Chronicle of Skin & Allergy 555 Burnhamthorpe Road, Suite 306, Toronto, Ont. M9C 2Y3. Telephone: (416) 916-2476 E-mail: health@chronicle.org

What THE LAY PRESS is saying about . . .

THERAPY STOPS RESECTED MELANOMA FROM SPREADING results from two international trials show a new medication successfully prevented the spread of cancer in patients with stage III melanoma whose tumours had been surgically removed, a finding one of the participating researchers says is a ‘breakthrough’ that will change how melanoma is treated, reports The Daily Mail (Sept. 13, 2017). until now, patients with stage III melanoma were at a high risk—40 to 70%—of their disease progressing to advanced and fatal melanoma, the news outlet reports. The treatments studied included a combination of dabrafenib and trametinib vs. placebo in the CoMBI-AD trial, and nivolumab vs. ipilimumab in the CheckMate 238 trial. In the CoMBI-AD trial the treatment prevented resected Stage III melanoma from recurring and also increased overall survival of BrAF positive patients, according to the researchers. results of the CheckMate 238 trial showed nivolumab decreased the chance of relapse, and this benefit was seen in patients regardless of BrAF mutation status.

CLINICAL REPORT ON BODY ART IN YOUNG PATIENTS RELEASED The American Academy of Pediatrics (AAP) has released its first ever clinical report on piercing, tattooing, and scarification, detailing changing trends and demographics as well as providing recommendations to those seeking body art on how to minimize risk of complications, reports the New York Times (Sept. 18, 2017). A Pew research Center report cited in the new AAP report said that in 2010, among 18- to 29-year-olds, 38% had at least one tattoo and 23% had a piercing somewhere other than the earlobe. one of the report’s lead authors, Dr. Cora Collette Breuner, a professor of pediatrics and adolescent medicine at Seattle Children’s hospital, and the chair of the AAP Committee on Adolescence, was quoted saying, “It should be brought up at adolescent visits: ‘have you considered getting a tattoo, a piercing, where?’” Dr. Breuner said that pediatricians should be asking adolescent patients if they have talked to their parents about body art, and if they understand that the changes are permanent. She also suggests temporary tattoos as a way to trial the experience of having body art, and that parents should recommend a waiting period.

MECHANISM OF MINERAL IONS CAN WORSEN ECZEMA A new study has shown how calcium and magnesium ions in hard water can worsen the symptoms of eczema, reports Express U.K. (Sept. 25, 2017). The paper, from university of Sheffield and King’s College London, reveals the mechanism by which the ions in hard water, surfactants, and the protein filaggrin interact to damage the skin barrier. These findings provide new information about how exposure to hard water could potentially contribute to the development of eczema. The calcium and magnesium ions bind to potentially irritating surfactant molecules in cleaning products and cause them to precipitate out onto the skin. As well, hard water is somewhat alkaline, and so raises the skin’s ph which also disrupts the skin barrier function. “By damaging the skin barrier, washing with hard water may contribute to the development of eczema—a chronic skin condition characterised by an intensely itchy red rash,” said Dr. Simon Danby, lead study author and a research fellow, Sheffield Dermatology research, Department of Infection, Immunity & Cardiovascular Disease, university of Sheffield.

Correct answer: Basal cell carcinoma

Journal Club

26 · oct./nov. 2017

ANT VENOM MOLECULE MAY BE AN ALTERNATIVE TO CERAMIDES Topical creams containing solenopsin compounds—derived from fire ant venom—could be used to treat psoriasis in conjunction with other therapy, reports The Sun U.K. (oct. 2, 2017). The news outlet reports that solenopsins are chemically similar to ceramides, molecules native to the skin that play a role in maintaining skin barrier function and an ingredient in many skin creams. however, the study authors note that ceramides can sometimes degrade into sphingosine–1-phosphate, which promotes cell growth but may also lead to inflammation. The research team prepared a 1% cream formulation and tested it in a mouse model of psoriasis. After a 28-day treatment period, the mice treated with the solenopsin cream had approximately 30% less skin thickening, and approximately 50% less immune cell infiltration than the control mice who had not received treatment. When tested in vitro with mouse immune cells, the cream reduced the inflammatory reaction of the cells and increased production of anti-inflammatory molecules. Department Editor: John Evans


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In adult patients with moderate to severe PsO

Consider STELARA for the long run

®

®

STELARA has demonstrated efficacy with long-term continuous use in PsO * †‡

1

• At 1.5 years (76 weeks), among adult patients who were PASI 75 responders at both Weeks 28 and 40 and re-randomized to 45 and 90 mg STELARA or placebo maintenance treatment, 56.6% of patients (90/159) combined over the STELARA arms were PASI 90 responders vs. 5.8% (9/156) for placebo1*† (secondary endpoint) ®

®

Indication and clinical use • STELARA® is indicated in adult patients for the treatment of chronic moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. • STELARA® is indicated for the treatment of chronic moderate to severe plaque psoriasis in adolescent patients from 12 to 17 years of age, who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies. STELARA® should be used only by physicians who have sufficient knowledge of plaque psoriasis, psoriatic arthritis, and/or Crohn’s disease and who have fully familiarized themselves with the efficacy/safety profile of the drug. Contraindications • Severe infections such as sepsis, tuberculosis and opportunistic infections Relevant warnings and precautions • Potential to increase the risk of infections and reactivate latent infections • Patients should be evaluated for tuberculosis infection prior to therapy and monitored for active tuberculosis during and after treatment • Potential to increase the risk of malignancy • All patients, in particular those greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy or those with a history of PUVA treatment, should be closely monitored for skin cancer

• Serious allergic reactions, including anaphylaxis and angioedema, have been reported • The needle cover on the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex • Concurrent use with live viral or bacterial vaccines is not recommended • Caution should be exercised when considering concomitant use of immunosuppressive agents and STELARA® • STELARA® may affect allergy immunotherapy • If Reversible Posterior Leukoencephalopathy Syndrome is suspected, administer appropriate treatment and discontinue STELARA® • STELARA® should be given to a pregnant woman only if the benefit clearly outweighs the risk • Studies of STELARA® in pediatric patients below 12 years of age have not been conducted For more information Please consult the Product Monograph at http://www.janssen.com/canada/products#prod-428 for important information relating to adverse reactions, drug interactions, and dosing that has not been discussed in this piece. The Product Monograph is also available by calling 1-800-567-3331.

Now indicated in Crohn’s disease STELARA® is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease, who have had an inadequate response, loss of response to, or were intolerant to either immunomodulators or one or more tumour necrosis factor-alpha (TNFα) antagonists, or have had an inadequate response, intolerance or demonstrated dependence on corticosteroids.

®

For more information, please contact your STELARA representative PASI: Psoriasis Area Severity Index; PsO: plaque psoriasis. * PHOENIX 1 was a multicentre, randomized, double-blind, placebo-controlled, phase 3 study in 766 adult patients (≥18 years) with chronic (>6 months) plaque psoriasis who had a minimum body surface area involvement of 10% and PASI score ≥12 and who were candidates for phototherapy or systemic therapy. Patients in all treatment groups had a median baseline PASI score ranging from 17 to 18. Patients were randomized to receive subcutaneous injections of either STELARA® 45 mg (n=255) or 90 mg (n=256) at Weeks 0 and 4, then q12w through Week 76 or placebo (n=255). Patients receiving placebo crossed over to STELARA® 45 mg or 90 mg at Weeks 12 and 16, then followed the same dose q12w through Week 76. The use of low-potency topical corticosteroids on the face and groin was permitted after Week 12 but was not mandatory. At Week 40, among patients who were PASI 75 responders at both Weeks 28 and 40, 162 patients were re-randomized to receive STELARA® at 45 mg and 90 mg given every 12 weeks (maintenance treatment) and 160 were re-randomized to receive placebo treatment (withdrawal). Patients were followed for at least 76 weeks. † In the PHOENIX 1 study, 42% and 37% of patients receiving STELARA® 45 and 90 mg, respectively, achieved a PASI 90 response at Week 12, compared with 2% of patients receiving placebo (p<0.001 for 45 mg or 90 mg vs. placebo). In subjects randomized at Week 40 to either placebo or STELARA® 45 or 90 mg, the percentage of patients achieving PASI 90 at Week 76 was 49.4% and 7.0% for STELARA® 45 mg and placebo, respectively, and 63.4% and 4.7% for STELARA® 90 mg and placebo, respectively. ‡ Safety and efficacy beyond 5 years have not been established. Reference: 1. STELARA® Product Monograph. Janssen Inc. December 12, 2016.

The image depicted contains models and is being used for illustrative purposes only. 19 Green Belt Drive | Toronto, Ontario | M3C 1L9 | www.janssen.com/canada © 2017 Janssen Inc. | All trademarks used under license. | STBR160592E


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See what HUMIRA can do for your patients • Treatment of active moderate to severe hidradenitis suppurativa (HS) in adult patients, who have not responded to conventional therapy (including systemic antibiotics). Please consult the Product Monograph at abbvie.ca/content/dam/abbviecorp/ ca/en/docs/HUMIRA_PM_EN.pdf for contraindications, warnings, precautions, adverse reactions, interactions, dosing and conditions of clinical use. The Product Monograph is also available by calling 1-888-704-8271. Reference: 1. AbbVie Corporation. Data on file.

PsA

2008

DATES OF INTRODUCTION IN CANADIAN PRACTICE:1

2006

THE ABBVIE DERMATOLOGY PORTFOLIO

ESTABLISHED EXPERIENCE*

Ps

2015

HUMIRA is indicated for: • Treatment of adult patients with chronic moderate to severe plaque psoriasis (Ps) who are candidates for systemic therapy. For patients with chronic moderate plaque Ps, HUMIRA should be used after phototherapy has been shown to be ineffective or inappropriate. • Reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis (PsA) patients. HUMIRA can be used in combination with methotrexate (MTX) in patients who do not respond adequately to MTX alone.

* Clinical significance has not been established. © AbbVie Corporation Printed in Canada HUM/3822A – August 2017

abbvie.ca 1-888-703-3006

HS

The Chronicle of Skin & Allergy October/November 2017  

The Chronicle of Skin & Allergy October/November 2017

The Chronicle of Skin & Allergy October/November 2017  

The Chronicle of Skin & Allergy October/November 2017

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