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A DERMATOLOGY FOUNDATION PUBLICATION SPONSORED BY MEDICIS, THE DERMATOLOGY COMPANY® VOL. 30 NO. 1 SPRING 2011 DERMATOLOGY FOCUS ™ DF Also In This ...
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A DERMATOLOGY FOUNDATION PUBLICATION SPONSORED BY MEDICIS, THE DERMATOLOGY COMPANY® VOL. 30 NO. 1

SPRING 2011

DERMATOLOGY FOCUS ™

DF

Also In This Issue

DF Support Steady and Significant for 2010

DF Clinical Symposia: Proceedings 2011–Part I ADVANCES IN DERMATOLOGY The Dermatology Foundation presented its annual 3-day symposia series in March. This highly regarded cutting-edge program provides the most clinically relevant knowledge and guidance for making the newest research advances accessible and usable. A daily provocative keynote talk precedes topic-focused, peer-reviewed caliber presentations. This year’s topics were: Acne & Related Disorders; Autoimmunity & Inflammation; Human Appearance; Cutaneous Oncology; Women’s & Children’s Health; and Diseases of the Hair & Scalp. The Proceedings appear in the Spring (Part I) and Summer (Part II) issues. Stuart R. Lessin, MD, and Jack S. Resneck, Jr., MD—Program Co-Chairs

Stiefel — New Cornerstone Benefactor DF Honors Drs. Eugene J. Van Scott, Ruey J. Yu, Pearl E. Grimes New Insights on P. acnes. Subpopulations: A genetics analysis of 210 P. acnes isolates delineated three distinct evolutionary lineages and suggests that an epidemic clone is strongly associated with moderate to severe acne while the other two lineages are differentially associated with health and with opportunistic infection. Thiboutot believes that acne reflects an interaction between this epidemic clone and host response characteristics, which she discussed. Impact on monocytes: P. acnes induces patient-derived monocytes to differentiate into CD209+ macrophages that phagocytose these bacteria. (CD209 is an innate immune system cell-surface protein on monocytes and dendritic cells that recognizes a diverse spectrum of pathogens.) All-trans retinoic acid added to these monocyte cultures produces the same result; adding it along with P. acnes enhances this differentiation. This may be another means by which retinoids have anti-inflammatory actions. Host response: Adding P. acnes to cultured peripheral blood monocytes from acne subjects stimulates release of a greater volume and variety of inflammatory cytokines than

Insulin-R and IGF-1R Signaling WERNER K. STIEFEL LECTURESHIP Latest Developments in the Pathogenesis of Acne and Rosacea Diane M . Thiboutot, MD Introduction. The unusual variety of presentations characterizing both acne and rosacea patients makes these diseases extremely challenging. This range is so broad in rosacea that Thiboutot suspects it may not represent a continuum of disease. Resolving this issue requires significant progress in understanding the pathogenesis of both diseases, and Thiboutot discussed recent advances toward this end. Acne. After describing a small study documenting markers of oxidative stress in the tissue and blood of patients with severe acne—suggesting oxidative tissue damage—Thiboutot highlighted research addressing the pathogenetic role of Propionibacterium acnes, inflammation, the innate immune response, and the molecular control of sebum production.

Because the PI3 kinase pathway induces sebocytes to produce sebaceous lipids, it is a potential therapeutic target in acne.

Dermatology Focus Welcomes New Medical Editor Immunodermatologist Mary M. Tomayko, MD, PhD, has recently joined David J. Leffell, MD, as medical co-editor. expert in their clinical work, scientifically rigorous, Dr. Tomayko, Assistant Professor in the Departmultifaceted, and accessible.” Dr. Tomayko entered ment of Dermatology at Yale University School Yale for her residency, then completed a Postdocof Medicine, is a talented physician-scientist fascitoral Fellowship. A DF fellowship, and then a career nated with defining the mechanisms by which development award when she became junior faculty, B lymphocytes establish and maintain antibody enabled her to produce the research titers in both protective immunity and data that secured her independent fundautoimmune disease. She directs adult ing. An established physician-scientist dermatology at the Yale Primary Care now, she thrives on both the problemCenter, where she treats patients with solving challenges and the personal complex dermatologic conditions that interactions with patients, junior colinclude autoimmune and inflammatory leagues, and students her work involves. disorders. Dr. Tomayko also teaches residents and medical students, and is Dr. Tomayko finds her new role as a reviewer for two journals and for the co-editor for Dermatology Focus “a very Arthritis Research Council. special opportunity” to work on an important communication tool. “Our small Dr. Tomayko fell in love with imfield is comprised of many different submunology and memory B cells as an Mary M. Tomayko, MD, PhD specialties. As dermatologists we want undergraduate at the University of to know what is going on in all areas of our speMaryland, where she also won an NCI Research cialty. Dermatology Focus helps us do this by highFellowship. She chose dermatology while in the lighting exciting, interesting new developments and University of Pennsylvania’s Medical Scientist presenting them in a way that is accessible—and Training Program, where she completed her MD and fun to read.” She looks forward to the process of PhD in 2000. “The dermatology physician-scientists selecting important and intriguing developments there were all excited to be dermatologists,” she across the specialty to highlight for all our readers. recalls. “And they were great role models—

occurs with control monocytes; now comparisons of patients with varying degrees of inflammation will be helpful. Impact on keratinocytes: Keratinocytes in culture respond to P. acnes by rapidly generating reactive oxygen species—especially superoxide anion—that inhibit bacterial growth. Adding retinoic acid, retinol, isotretinoin, zinc sulfate, or doxycycline inhibits superoxide anion. Retinoic acid and its derivatives completely abolish production of the inflammatory cytokine IL-8, further evidence of their antiinflammatory effects. Toll-like receptors (TLRs): In acne lesions, inflammatory cells surrounding the follicle express TLR2, the innate immune system component that first recognizes and responds to pathogens. These TLR2–expressing neutrophils exposed to P. acnes release a variety of inflammatory cytokines; adding retinoic acid inhibits this. Cultured keratinocytes with added dexamethasone or cortisol express more TLR2, explaining why glucocorticoids can exacerbate and sometimes cause acne and acneiform conditions. The Sebum Production Pathway. Thiboutot is especially intrigued with the parallel peaks of both acne and IGF-1 (insulinlike growth factor) during adolescence. After a study elsewhere found elevated IGF-1 in adult acne patients, Thiboutot and colleagues showed a strong correlation between IGF-1 level and acne severity in adult female patients. She knew that IGF-1 stimulates lipogenesis in cultured sebaceous glands and in the SEB-1 sebocyte model, and that this occurs via the transcription factor SREBP-1 (sterol response element-binding protein-1), part of a lipid homeostasis-regulating family. After pinning this down to the PI3 kinase pathway, Thiboutot determined that blocking it inhibited production of the kinase Akt, which blocked expression of the SREBP-1 2

Spring 2011

transcription factor and “stopped production of sebaceous lipids by our sebocyte cells.” This may provide a potential drug development target for agents that shut off sebum production in acne. Rosacea Pathogenesis. Thiboutot discussed research on the various factors thought to contribute to the inflammatory process central to rosacea pathogenesis. She noted in vitro

Progress in Understanding P. acnes • Oxidative stress is increased in severe acne: 앗SOD, 앖lipid peroxidation marker • P. acnes composed of 3 genetically distinct divisions; only the epidemic clone is associated with moderate-to-severe acne (the others with health or opportunistic infection) • P. acnes-induced CD209+ macrophages mediate host defense against this bacteria; all-trans retinoic acid induces these macrophages and enhances their induction by P. acnes • Host response to P. acnes differs in patients with and without acne–PBMCs from acne patients produce more inflammatory cytokines to all P. acnes strains. Thus, the inflammatory response in acne appears due to host responses, not P. acnes strain. • P. acnes stimulates ROS–especially superoxide anion– in keratinocytes. This is inhibited by retinoic acid, retinol, isotretinoin, ZnSO4, and doxycycline • In acne lesions, toll-like receptor 2 (TLR2)–part of the innate immune system’s pathogen-recognition network–is expressed on the surface of macrophages surrounding the follicle. P. acnesstimulated neutrophils release inflammatory cytokines, pointing to TLR2 activation enabling P. acnes-induced inflammation

Dermatology Foundation

research from the University of Michigan suggesting that photodamaged collagen can stimulate new blood vessel formation (telangiectasia), although a large study abroad found no relationship between sun exposure and the prevalence of papulopustular rosacea. Thiboutot cited two studies—one a meta-analysis—finding a significant presence of the Demodex mite among rosacea patients. Dr. Richard Gallo’s lab at UC-SD—which pioneered the identification and study of antimicrobial peptides (AMPs) in the skin—finds significantly higher levels of the AMP cathelicidin—both the common form and a variety of unique variants—in the skin of rosacea patients. Their skin also contains more kallikrein 5, the enzyme that breaks down cathelicidin’s precursor molecule into the active peptides. Injecting the unique cathelicidin peptides along with kallikrein 5 into mouse skin induces inflammation. Kallikrein 5 belongs to an enzyme class responsive to tetracycline antibiotics. Staphylococcus epidermidis—another suspect—has been found to colonize a significant number of rosacea pustules as well as (Continued on page 6)

Rosacea: Etiology • Unknown, controversial aspects • Genetics • Photodamage • Helicobacter pylori • Demodex folliculorum • Oxygen free radicals • Bacterial antigens (Bacillus oleronius) • Increased activity of kallikrein 5 • Staphylococcus epidermidis • Rosacea-like eruption with tyrosine kinase inhibitors

DF

DERMATOLOGY FOCUS A PUBLICATION OF THE DERMATOLOGY FOUNDATION Sponsored by

Medicis, The Dermatology Company ® Editors-in-Chief David J. Leffell, MD—Professor of Dermatology Yale School of Medicine, New Haven, CT

Mary M. Tomayko, MD, PhD—Asst Professor of Dermatology Yale School of Medicine, New Haven, CT

Executive Director Sandra Rahn Benz Communications Director Christine M. Boris Please address correspondence to:

David J. Leffell, MD & Mary M. Tomayko, MD, PhD Editors, Dermatology Focus c/o The Dermatology Foundation 1560 Sherman Avenue, Evanston, Illinois 60201 Tel: 847-328-2256 Fax: 847-328-0509 e-mail: [email protected]

Published for the Dermatology Foundation by Robert B. Goetz—Designer, Production Sheila Sperber Haas, PhD—Managing Editor, Writer This issue of Dermatology Focus is distributed without charge through an educational grant from Medicis, The Dermatology Company ®. The opinions expressed in this publication do not necessarily reflect those of the Dermatology Foundation or Medicis, The Dermatology Company ®. © Copyright 2011 by the Dermatology Foundation

New Annenberg Circle Members in 2010 Add Their Support to the Specialty’s Future The Dermatology Foundation is very grateful to the 29 forward-looking dermatologists who pledged $25,000 to the DF last year. They joined well over 500 of their colleagues in generously supporting advances in patient care through membership in the Annenberg Circle. Donald J. Adler, DO Julie A. Barber, MD Terry L. Barrett, MD Sidney Barsky, MD Anneli R. Bowen, MD Irwin M. Braverman, MD Ana M. Duarte, MD Pearl E. Grimes, MD James H. Herndon, Jr., MD Janine O. Hopkins, MD

www.dermatologyfoundation.org

Elizabeth Sanders Jacobson, MD Michael S. Kaminer, MD Gail A. Kleman, MD Neil J. Korman, MD, PhD James Lahti, MD Edgar Maeyens, Jr., MD Timothy D. Mattison, MD Andrew J. Mitchell, MD Ali Moiin, MD

Kishwer S. Nehal, MD Thomas Nicotri, Jr., MD Margretta A. O'Reilly, MD Mark P. Seraly, MD William K. Sherwin, MD, PhD Stuart Tafeen, MD Marguerite D. Thew, MD Gregory W. Thompson, MD Kalman L. Watsky, MD Schield M. Wikas, DO

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2010 Year in Review: Confidence and Support President Dr. Richard L. Edelson opened the Dermatology Foundation’s annual meeting of membership earlier this year with much good news to share. “Despite a year in which many philanthropic organizations continued to experience declining revenues, contributions to support the mission of the DF remained strong and steady. This accomplishment reflects the importance our colleagues and industry place on the Foundation’s work to help the most promising new physician-scientists and investigators develop into tomorrow’s leaders,” Dr. Edelson emphasized.

2010 Honorary Awardees

component of the DF’s individual giving revenue. The number of Annenberg Circle and AC Sustaining members continued grow. Annenberg Circle members now total 534 while AC Sustaining members, who give $5,000 each year beyond their $25,000 pledge, reached a high of 91.

Corporate Generosity Increases Industry stayed the course and directed significant support to the DF. Dr. Edelson was pleased to announce that “contributions from all of our industry supporters increased almost 7% from last year.” This speaks both of their commitment to meaningful innovation in the field and confidence in the DF’s ability to ensure the presence of leaders in the specialty. Dr. Edelson pointed to the exceptional dedication and support of Cornerstone Benefactors Top: DF President Richard L. Edelson, MD, with Discovery Awardees Ruey J. Yu, PhD, OMD Galderma Laboratories and (left) and Eugene J. Van Scott, MD. Left: Paul R. Gross, MD (Clark W. Finnerud Award) presented by George W. Hambrick, Jr., MD (left). Right: Roy S. Rogers III, MD (Lifetime Career Unilever, whose contributions for Educator Award) presented by Mark R. Pittelkow, MD (left). Bottom: Pearl E. Grimes, MD 2010 each totaled a half million (Practitioner of the Year) presented by Jag Bhawan, MD (left). dollars. He expressed the DF’s gratitude for all industry support, Dermatologists: and recognized those companies who are also A Powerful Force for the Future members of the DF’s Corporate Honor Society: Abbott; Amgen Pfizer; Medicis, The Dermatology Dr. Edelson noted that “the DF’s greatest Company®; The Allergan Foundation; Ortho supporters continue to be dermatologists who are Dermatologics; Stiefel, a GSK company; Astellas committed to the specialty’s future. I am pleased to Pharma US, Inc.; Avon Products, Inc.; Centocor report that individual member contributions to the Ortho Biotech Inc.; Coria Laboratories; Intendis, Foundation this year totaled $3 million—nearly Inc.; Merz Pharmaceuticals, LLC; Obagi Medical half of the DF’s total revenue.” Leaders Society Products, Inc.; and SkinMedica, Inc. member dues approached $1.6 million, the largest

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Dermatology Foundation

$3.1 Million for Dermatology’s Future Unwavering support from individual dermatologists, corporations, and societies in 2010 enabled the Dermatology Foundation to award $3.1 million in research funding to 67 promising individuals and research projects that span the full range of dermatology. Bruce U. Wintroub, MD, Chairman of the DF Board of Trustees, announced the 2011 research awards at the annual meeting in New Orleans. The 67 awards included 47 career development awards, multi-year awards that have become the heart of the DF’s research support program. “These career development awards are the most significant investment the DF can make, and are bestowed on those with the potential to have an impact on the scientific and teaching base of the specialty,” Dr. Wintroub pointed out. Ten fellowships and 10 research grants rounded out the research awards. Dr. Wintroub thanked the Foundation’s many supporters, and expressed the DF Trustees’ gratitude for the ability to fund these awards. “We all look forward to watching these recipients progress and become tomorrow’s experts.” He also stressed that “the need for research funding is tremendous and ongoing, and it is the Foundation’s goal to continue increasing its ability to fund research awards that will respond even more fully to the comprehensive needs of the specialty.” For a list of the 2011 award recipients and projects, visit www.dermatologyfoundation.org

Society Partners Continue Their Research Support Dr. Edelson thanked the DF’s many society partners “who believe their contributions to the DF are a significant way to keep dermatology progressive.” He recognized the following society contributors for their substantial support of the Foundation’s Research Awards Program: The American Academy of Dermatology; Women’s Dermatologic Society; Society for Investigative Dermatology; Society for Pediatric Dermatology; and The American Society of Dermatopathology.

Contributions Are Effective Dr. Edelson shared highlights from the recently completed survey of Career Development Award recipients, designed to assess the impact of these highly competitive 3-year awards. The results show

www.dermatologyfoundation.org

Bruce U. Wintroub, MD 47 Career Development Awards ($55,000 annual salary support)

13 5 1 3 8 2 15

Physician Scientist Dermatologic Surgery Health Care Policy Science of Human Appearance Medical Dermatology Women’s Health Research Career Development

10 Fellowships ($30,000 to $45,000 salary support)

9 1

Dermatologist Investigator Pediatric Dermatology

10 Grants (up to $20,000 project/program support)

6 3 1

Basic Science Research Patient-Directed Investigation Dermatopathology Grant

that 80% of these awardees have remained in academic dermatology, and that over 80% of awardees went on to obtain independent funding. The survey results are a powerful validation of the DF’s ability to identify and launch the careers of individuals who will lead the specialty. Asked to state how their DF CDA impacted their career, this response summarizes the answers with precision and simplicity: “It was essential!” These results were made possible by the individual members, industry supporters, and society partners who have shared in realizing the Foundation’s mission, ensuring a strong specialty and the continual advancement of patient care. “We are grateful to everyone who has made the DF’s mission a priority this past year,” Dr. Edelson remarked. “Contributions at all levels are appreciated and important to our ability to support the people who will lead dermatology in the future.”

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• Like the acneiform rash with inhibitors of epidermal growth factor receptor signaling, a rosacea-like eruption has been reported with other tyrosine kinase inhibitors • Imatinib (Gleevec®) and nilotinib (Tasigna®)– used to treat CML–are TK inhibitors that target the ABL kinase, PDGFR kinases, and c-kit kinases • These drugs can cause a rosacea-like eruption See Yang et al. J European Acad Derm Venerol. 2010 DOI: 10.1111/j.1468-3083.2010.03764.x

Malassezia— The Result, Not the Cause, of SD

MINI-SYMPOSIUM: ACNE & RELATED DISORDERS

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Introduction. Leyden presented the accepted view of dandruff and seborrheic dermatitis—ie, they represent a continuum of symptoms with a common etiology, the yeast Malassezia—and countered it with the perspective derived from his extensive research with the late Ken McGinley in the 1960s and 1970s. The Two Conditions. Leyden described the basic sequence of events in dandruff (pityriasis simplex) that culminate in a crust of nucleated corneocytes, with clusters of parakeratotic cells shed as visible flakes. Seborrheic dermatitis is more widespread with more chronic epidermal involvement that includes acanthosis and spongiosis, and occasionally a psoriasiform-like appearance. Although the distribution and name imply a role for sebaceous glands, he and McGinley found lipid trapping by the accumulating scale and no evidence for increased sebum production. The continuum concept persists despite the reality that no one has seen people transition from one to the other. The Underlying Mechanism. Current wisdom holds that the yeast Malassezia (formerly called Pityrosporum), which resides on human skin, causes the problem by hydrolyzing SG triglycerides into fatty acids to free saturated fatty acids (FFAs) for their nutrients. The unsaturated fatty acid residue—oleic acid especially— induces flaking and inflammation in vulnerable people, ie, those with a dysfunctional stratum corneum. Leyden’s observation of a significantly increased predominance of Malassezia in dandruff and seborrheic dermatitis helped give rise to this view. Another of Leyden and McGinley’s studies from that time, however, led them to conclude that this Malassezia overgrowth is actually a consequence of the underlying pathophysiology, which results in shedding of clumps of corneocytes, sebum trapping, and then subsequent yeast proliferation. Leyden outlined the technique enabling them to assess clinical grade, corneocyte count, and Malassezia counts over 9 weeks under 4 conditions. Using nonmedicated shampoo alone after clearing the scalp provided baseline values. Adding topical amphotericin at week 3 rapidly reduced the yeast count to practically zero, yet the disease persisted, making it “difficult to argue that the organism is responsible

Percent Recovery

Seborrheic Dermatitis James J. Leyden, MD

Medicated I Nonmedicated Shampoo

Nonmedicated Shampoo 100

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Rosacea and Tyrosine Kinase Inhibitors

for the disease.” When 3 weeks of selenium sulfide shampoo— which had reduced clinical grade and corneocyte count and almost eliminated the yeast—was followed by 6 weeks of nonmedicated shampoo—a marked increase in Malassezia followed the return of clinical grade and corneocyte count, not the other way around. When topical amphotericin was also begun at week 3, “the yeast did not return, but the disease did—the nail in the coffin for the current thesis.” Leyden also documented the cellular antiproliferative effect of the medicated shampoos in addition to their anti-yeast properties. Conclusion. Leyden views seborrheic dermatitis as an inflammatory process—with the primary events basically a mystery— with little bursts of nucleated corneocytes that come off in clumps (scaling). The scaling traps sebum, enabling the increase in Malassezia, which may amplify the process via the fatty acids and other mechanisms. Medicated shampoos and topical antiinflammatory agents are very effective, and shampooing with any type of shampoo is effective if done frequently enough.

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the eyelid margin of many patients, suggesting a possible role in the pustular and ocular forms of this disease. Rosacea-like eruptions are reported with the tyrosine kinase receptor inhibitors imatinib and nilotinib, adding to the more wellknown acneiform eruptions observed with inhibitors of the epidermal growth factor receptor pathway.

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Pityrosporum = Malassezia. Reprinted with permission from Leyden JJ et al. Arch Dermatol. 1976;112:333–8.

SD Pathophysiology • Inflammatory process; primary events unknown • Inflammation produces scaling • Scales trap sebum 씮 increase in Malassezia • Increased Malassezia amplify process by FFAs & other mechanisms, eg, complement activation

SD Treatment • Shampooing to remove scales as fast as they develop. ZPT and SeS suppress Malassezia and are cytostatic • Topical anti-inflammatory agents Dermatology Foundation

Acne Revisited: Is Acne a Manifestation of Systemic Disease? Kanade Shinkai, MD, PhD Introduction. The significant pathogenetic factors in acne have been identified—androgens, diet (insulin and insulin signaling), medications, alterations in follicular keratinization and differentiation, bacteria (especially P. acnes), genetics, sebum production, and innate immunity—but their interconnections remain murky. Acne associated with systemic disease is helping to clarify the different pathways producing the acne phenotype. Presenting 4 challenging cases, Shinkai highlighted the respective composites of factors/pathways involved and raised the possibility that acne can be an autoinflammatory disease.

The Pathogenesis of Acne Propionibacterium acnes Genetics

Androgens Diet

Sebum production

Medications Alteration in follicular keratinization, differentiation

Innate immunity, cytokines

Acne Can Be An Autoinflammatory Disease 3 features of acne support this classification: • Chronic, intermittent inflammation with cytokines • Key role for commensal organisms (P. acnes) • Dysregulation of pathogen-recognition pathways Illustrative Cases. PCOS: A woman in her early 30s presented with severe scarring facial acne, subtle hirsutism, and with what was determined to be PCOS (polycystic ovary syndrome). Prior isotretinoin failures (clearing with rapid relapse) were an important clue to her underlyling hormonal disease. Her acne involves excess androgens, diet (IGF pathway stimulation), sebum production (via IGF signaling), and possibly genetics. EGF receptor inhibitor: Two weeks after beginning cetuximab treatment for metastatic lung cancer, this patient broke out in the acneiform rash on his chest—due to progressive keratinocyte alterations and necrosis—affecting ≤80% of patients given these drugs. Because the rash is associated with a good cancer prognosis, dermatologists can enable therapy to continue by helping patients prevent or manage this complication. (For Lacouture’s clinical approach, see: Balagula Y et al. Clinical presentation and management of dermatological toxicities of epidermal growth factor receptor inhibitors. Int J Dermatol. 2011;50:129–46.) Apert’s syndrome: This genetic disease involves mutations in the FGF (fibroblast growth factor) receptor 2 gene affecting the skin—including sebaceous gland stimulation—and skeleton. This FGFR2 mutation impairs follicular keratinization and stimulates sebum, producing severe acne that can affect very unusual sites. Lesional skin in nevus comedonicus www.dermatologyfoundation.org

involves this FGFR2 mutation and may be mosaic for Apert’s. Acne fulminans: Six days after beginning isotretinoin therapy, an adolescent boy with a long history of papulopustular acne erupted with severe ulcerating lesions. Shinkai discussed the spectrum of causes in genetically susceptible individuals. She also noted its association with Crohn’s disease, among other systemic diseases, an autoinflammatory disease that turned out to affect this patient and his family. Inherited and nongenetic autoinflammatory diseases associated with significant acne carry a common immunologic signature that acne partly shares. “Our normal mechanisms for recognizing pathogens and inducing inflammation may be inappropriately upregulated in autoinflammatory diseases, and may be turned on by commensal organisms.” P. acnes may trigger autoinflammation in acne—rather than infection—supported by data showing the associated upregulation of TLR2. Conclusion. Although not always a systemic disease, acne is a clinical spectrum that includes autoinflammatory disease, with distinct molecular pathways producing the acne phenotypes. Ideal treatment targets the specific pathway(s) involved.

Latest Developments and Controversies in Isotretinoin Therapy Diane M. Thiboutot, MD Introduction. Isotretinoin improves acne significantly for the majority of patients, but there are controversies regarding its ability to induce other health problems. Thiboutot summarized current findings, then described her lab’s exploration of isotretinoin’s mechanism of action and added data demonstrating that a reduced dosage can avoid isotretinoin flares.

Gene Changes in the Skin of Patients Receiving Isotretinoin • At 1 week: – Genes encoding differentiation markers, tumor suppressors, serine proteases, innate immune proteins, and proinflammatory molecules were upregulated. • At 8 weeks: – Extracellular matrix genes were upregulated – Numerous genes encoding lipid-metabolizing enzymes were downregulated. See Nelson et al. Dermato-Endocrinology. 2009;1:177-87; Nelson et al. JID. 2009;129:1038-42.

Isotretinoin Effects 앗SEBUM PRODUCTION 앗Lipid metabolism 앗Cholesterol metabolism

Isotretinoin

앖APOPTOSIS/CELL CYCLE ARREST 앖NGAL 앖Tumor suppressors Time (weeks)

(Continued on page 10)

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DF Honors the Specialty’s Finest The Dermatology Foundation paid tribute to specialty leaders and role models at its Annual Meeting this past February in New Orleans. The 2010 award recipients nominated by their peers for their outstanding contributions to dermatology are:

Eugene J. Van Scott, MD and Ruey J. Yu, PhD, OMD—Discovery Award Pearl E. Grimes, MD—Practitioner of the Year Drs. Paul R. Gross (Clark W. Finnerud Award) and Roy S. Rogers III (Lifetime Career Educator Award) were highlighted in the Winter 2010/11 issue.

2010 Discovery Award: Eugene J. Van Scott, MD and Ruey J. Yu, PhD, OMD This award recognizes those outstanding investigators whose research discoveries have had major impact on the treatment of skin disease. A landmark publication in the October 1974 Archives of Dermatology introduced the newly coined term ␣-hydroxyacids (AHAs) to the dermatology community and described their profound therapeutic effects on epidermal keratinization in ichthyosis. In what had been a virtually untreatable and devastating disease, just a single week of applying these compounds transformed gray, scale-covered skin to a normal appearance. The pioneering co-authors—dermatologist and skin biologist Eugene J. Van Scott, MD, and dermatopharmacologist/skin chemist Ruey J. Yu, PhD—were enormously excited about their discovery and planned to explore the therapeutic value of these AHAs in other diseases of hyperkeratinization. They never dreamed of the multiple ways in which these gentle acids would impact how the specialty cares for the skin. James J. Leyden, MD, Professor Emeritus of Dermatology at the University of Pennsylvania, presented their contributions. “Van Scott and Yu found that these small molecules have multiple effects on skin, including enhanced corneocyte desquamation, increased epidermal proliferation, dispersal of melanosomes in keratinocytes, and upregulated hyaluronic acid in the epidermis and dermis. Recognizing the similarity to the effects of topical retinoids, they studied the AHAs in other skin disorders and found significant benefit in acne, photodamage, and aspects of aging skin. Forty years after their original observations, AHAs in various formulations and applications are used daily by dermatologists around the world. Van Scott’s and Yu’s discoveries led to the genesis of a whole industry based on AHAs.”

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Drs. Van Scott and Yu began their enduring collaboration in 1969, when their professional lives intersected in the Dermatology Department at Temple University’s Skin and Cancer Hospital. Yu had arrived in 1967 after his PhD in chemistry at the University of Ottawa and post-doc at Canada’s National Research Council. He was fascinated with the effects of natural substances on the skin and proceeded to develop his expertise in dermatology. Van Scott arrived in 1968 after 15 high-impact years with the NIH. They shared a passion for science and exploration, a thirst for new knowledge, a fascination with skin biology and therapeutic substances, and the desire to help patients with difficult skin diseases. They had traveled very different routes to reach this meeting of the minds. Yu—born into extreme poverty in rural pre-war Taiwan—saw education as his escape route. He eventually studied chemical engineering in a nearby vocational high school, then taught himself the academic courses he needed for applying to National Taiwan University. Yu ultimately earned his MSc in chemistry there Ruey J. Yu, PhD, OMD and then went to the University of Ottawa for his PhD—all on full scholarship. Van Scott, who grew up on a farm in upstate New York, had always been interested in science and discovery. His interest in skin had begun with his frequent poison ivy dermatitis, “as there was simply no answer to it.” His intense interest in dermatology was inspired by the legendary Dr. Stephen Rothman at the University of Chicago. Van Scott began working in Rothman’s research lab during medical school. After completing his residency there in 1952 and an interim year at the University of Pennsylvania, Van Scott established the Dermatology Service at the NCI and orchestrated its growth

Dermatology Foundation

to the Dermatology Branch that we know today. He also become the NCI’s Director of Intramural Research and then Scientific Director for General Laboratories and Clinics before returning to academic medicine at Temple. Looking for a research collaborator, “when Ruey and I first met, we clicked,” Van Scott recalls. They chose to search for compounds affecting keratinization because it is disordered in the majority of skin diseases. They began with ichthyosis. When Van Scott asked Yu to suggest a nontoxic compound that could Eugene J. Van Scott, MD penetrate the thick scales and epidermis of these patients, “I thought physiologic, and prepared organic acids from apples, oranges, and other natural sources,” Yu recalls. He incorporated each one into a cream base, including salicylic acid, then the sole (and inadequate) treatment for ichthyosis. Patients applied the coded compounds on their arms—several times daily for a week—in small numbered circles. Yu and Van Scott were astonished and elated to see each patient return with normal skin in certain test areas. Clearing there was due to what they decided to call the ␣-hydroxyacids. After successfully treating acne and turning to the thickened stratum corneum of seborrheic keratoses, the before and after photographs unexpectedly showed disappearing wrinkles. Pursuing this uncovered their substantial value in treating skin damage from both sun exposure and aging. Van Scott and Yu developed polyhydroxy acids for sensitive skin. And along the way, they co-founded NeoStrata. After their landmark article appeared, the course of their careers changed. Van Scott entered private practice and Yu went on to study Oriental Medicine and become a licensed acupuncturist. Their vigorous research collaboration, however, continued to flourish. They now have more than 110 patents. Yu has published over 50 papers. Van Scott has published close to 200, and his broad imprint on the specialty has been recognized by various honors. Van Scott and Yu continue to find “excitement in the search” as they look for ways to normalize diseased skin more permanently. Their ultimate focus—from the very start—has been psoriasis. “Dr. Yu and I had agreed that, in our lifetime, we are going to find that answer.”

www.dermatologyfoundation.org

2010 Practitioner of the Year Award: Pearl E. Grimes, MD This award recognizes dermatologists who are committed to the highest levels of clinical care. “Dr. Grimes has dedicated her career to studying and treating pigmentary disorders and unique ethnic skin and hair conditions,” Jag Bhawan, MD, noted while highlighting her career achievements at the DF’s annual membership meeting. She speaks worldwide on these topics and has published widely. Dr. Grimes has spurred fundamental research-based progress in vitiligo, introducing her view of it as an immunologic T-cellmediated disease in 1986, and in 2002 publishing her therapeutic success with tacrolimus. Dr. Grimes brings 30 years of extensive research and clinical experience with vitiligo to her patients. “I have seen and treated virtually every permutation of this disorder,” she says. Her work with vitiligo began during her residency at Howard University and intensified during her years as a fulltime faculty member at Pearl E. Grimes, MD UCLA (where she remains a clinical professor of dermatology). Earning a DF research grant for Immunologic Aberrations in Vitiligo early in her career enabled her to gain NIH funding and establish her research program. In 1990, she founded her private practice in southern California to provide cutting edge treatment to patients suffering from vitiligo and other pigmentary disorders, and continue her research. Commitment to each patient is a hallmark of Dr. Grimes’ practice. “I’m not going to leave the examining room until the patient is happy and feels that I have answered every question.” Six years ago, her concern and compassion for patients suffering with skin disorders resulted in the founding of CARRY, the nonprofit Coalition for At-Risk Youth. Through this organization, Dr. Grimes provides dermatologic treatment and arranges for other needed medical attention to adolescents and young adults in foster care, group homes, and shelters. Dr. Grimes’ contributions to the specialty and constant concern for quality patient care was summed up nicely by Dr. Bhawan at the DF meeting: “It is no surprise that Dr. Grimes has been chosen as Practitioner of the Year.”

Spring 2011

9

Risk of Other Health Problems. The claim that isotretinoin can induce IBD is “an ever-evolving situation that began with case reports” suggesting a possible link. A populationbased study from Canada found no difference, then Seth Crockett’s comprehensive review found insufficient evidence for either side. His subsequent large case-control study documented a significant relationship only with ulcerative colitis, which was heightened with both increasing dose and use beyond 2 months. David Margolis’ recent study of the tetracycline antibiotics found a significant risk between doxycycline use and ulcerative colitis. Mechanisms of Action. Thiboutot’s lab has determined that isotretinoin induces apoptosis within sebaceous glands, not within keratinocytes, and does this via NGAL, the antimicrobial peptide neutrophil gelatinase-associated lipocalin. She hopes to upregulate NGAL activity in sebaceous glands to maintain isotretinoin’s efficacy without its adverse effects. Gene array expression analyses after initiating isotretinoin treatment identified many proinflammatory genes at 1 week, but predominantly reparative genes by 8 weeks. “We suspect that the reparative response to this initial inflammation causes long-term remission.” In addition, her lab has found that isotretinoin reduces the activity of tolllike receptor 2 on monocytes in affected skin. “We hypothesize that isotretinoin has some relatively persistent effects on the immune system that produce a permanent or close to permanent improvement in the acne.” Isotretinoin Flares. In a study in Europe that compared 0.5 mg/kg with