November/December 2013 • Volume 11 • Issue 6 EDITORIAL Minor Cuts and Abrasions: Do They Need Our Help?
Dermatographic Fixed-Drug Eruption: Another Cause of Pseudo-Darier’s Sign
ORIGINAL CONTRIBUTIONS Prevalence of Depression in Vitiligo Patients
Recurrent Infantile Myofibromatosis in a 19-Month-Old Boy Presenting as Ulcerated Plaque
Lowthian and Parish
Al-Harbi
Androgenic Alopecia in Women: An Indian Perspective Sehgal, Srivastava, Aggarwal, and Midha
REVIEW What’s New in Infantile Hemangiomas: Current Insights and Future Perspectives Semkova, Kazandjieva, and Tsankov
DEPARTMENTS perils of dermatopathology Location, Location, Location: Proper Site Selection and Use of Direct Immunofluorescence Testing
Cosulich and Norton
Hocar, Sab, Akhdari, Amal, Ouladsiad, and Belaabidia
HIV/AIDS Kaposi Sarcoma: The Indian Perspective Sehgal, Verma, and Sharma
Borderline Tuberculoid Leprosy Mimicking Mycosis Fungoides
Rodríguez-Acosta, Esquivel-Pedraza, Saeb-Lima, Arenas-Guzmán, Granados-Arriola, and Domínguez-Cherit
BOOK REVIEW Dermatology at a Glance Petronic-Rosic
Patel, Wassef, Sharma, Mian, and Lambert
Photo capsule Inverse Lichen Planus Lee and Schwartz
new to the clinic New Drugs to Treat Hereditary Angioedema Scheinfeld
COSMETIC SCIENCE Will Epigenetics Change Our Approach to Treating Skin Conditions? Epstein
case studies From Mole to Scar: The Unintended Consequence of Treatment With an Over-the-Counter Mole Removal Cream
Lebanese Dermatological Society
Bronsnick, Kirkorian, Khan, Cole, and Rao Belarusian Society of Dermatovenereologists and Cosmetologists
North American Dermatologic Society
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TABLE OF CONTENTS November/December 2013 • Volume 11 • Issue 6
EDITORIAL
Minor Cuts and Abrasions: Do They Need Our Help?.................................................................................. 325
Peter Lowthian, MPhil, SRN; Lawrence Charles Parish, MD, MD (Hon)
ORIGINAL CONTRIBUTIONs
Prevalence of Depression in Vitiligo Patients ............................................................................................ 327
Mana Al-Harbi, MBBS
Androgenic Alopecia in Women: An Indian Perspective ............................................................................. 332
Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Reshmi Midha, MBBS
REVIEW
What’s New in Infantile Hemangiomas: Current Insights and Future Perspectives...................................... 341
Kristina Semkova, MD, MSc; Jana Kazandjieva, MD, PhD; Nikolai K. Tsankov, MD, PhD
Departments Perils of Dermatopathology W. Clark Lambert, MD, PhD, Section Editor
Location, Location, Location: Proper Site Selection and Use of Direct Immunofluorescence Testing ......... 351
Basil Patel, BS; Cindy Wassef, BS; Divya Sharma, BS; Kiran Mian, BS; W. Clark Lambert MD, PhD
Photo Capsule
Inverse Lichen Planus................................................................................................................................ 355
Michael D. Lee, MD; Laurel R. Schwartz, MD
New to the Clinic Noah Scheinfeld, MD, JD, Section Editor
New Drugs to Treat Hereditary Angioedema .............................................................................................. 357
Noah Scheinfeld, MD, JD
Cosmetic Science Howard A. Epstein, PhD, Section Editor
Will Epigenetics Change Our Approach to Treating Skin Conditions?.......................................................... 362
Howard A. Epstein, PhD
case studies Vesna Petronic-Rosic, MD, MSc, Section Editor
From Mole to Scar: The Unintended Consequence of Treatment With an Over-the-Counter Mole Removal Cream ................................................................................................................................ 364
Tara Bronsnick, BA; A. Yasmine Kirkorian, MD; Irfan Khan, BA; Allison Cole; Babar K. Rao, MD
Dermatographic Fixed-Drug Eruption: Another Cause of Pseudo-Darier’s Sign.......................................... 368
Michael T. Cosulich, BSE; Scott A. Norton, MD, MPH
321
TABLE OF CONTENTS July/August 2013 • Volume 11 • Issue 4
Recurrent Infantile Myofibromatosis in a 19-Month-Old Boy Presenting as Ulcerated Plaque.................... 371
Ouafa Hocar, MD; Imane Ait Sab, MD; Nadia Akhdari, MD; Said Amal, MD; Mohamed Ouladsiad, MD; Badiaa Belaabidia, MD
HIV/AIDS Kaposi Sarcoma: The Indian Perspective .................................................................................. 375
Virendra N. Sehgal, MD; Prashant Verma, MD; Sonal Sharma, MD
Borderline Tuberculoid Leprosy Mimicking Mycosis Fungoides.................................................................. 379
Elva Dalia Rodríguez-Acosta, MD; Lilly Esquivel-Pedraza, MD; Marcela Saeb-Lima, MD; Roberto Arenas-Guzmán, MD; Julio Granados-Arriola, MD; Judith Domínguez-Cherit, MD
Book Review Jennifer L. Parish, MD, Section Editor
Dermatology at a Glance ........................................................................................................................... 383
Vesna Petronic-Rosic
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EDITOR IN CHIEF
Lawrence Charles Parish, MD, MD (Hon) Philadelphia, PA
DEPUTY EDITORS William Abramovits, MD
W. Clark Lambert, MD, PhD
Larry E. Millikan, MD
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Newark, NJ Vesna Petronic-Rosic, MD, MSc
Meridian, MS Marcia Ramos-e-Silva, MD, PhD
Philadelphia, PA
Chicago, IL
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EDITORIAL BOARD Virendra N. Sehgal, MD Delhi, India
Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates
Jasna Lipozencic, MD, PhD Zagreb, Croatia Eve J. Lowenstein, MD, PhD New York, NY
Anthony V. Benedetto, DO Philadelphia, PA
Anthony A. Gaspari, MD Baltimore, MD
George M. Martin, MD Kihei, HI
Charles Steffen, MD Oceanside, CA
Brian Berman, MD, PhD Miami, FL
Michael Geiges, MD Zurich, Switzerland
Marc S. Micozzi, MD, PhD Rockport, MA
Michael H. Gold, MD Nashville, TN
Alexander J. Stratigos, MD Athens, Greece
George F. Murphy, MD Boston, MA
Orin M. Goldblum, MD Pittsburgh, PA
James S. Studdiford III, MD Philadelphia, PA
Venkataram Mysore, MD, FRCP (Hon, Glasgow) Bangalore, India
Robert J. Thomsen, MD Los Alamos, NM
Mohamed Amer, MD Cairo, Egypt
Howard A. Epstein, PhD Philadelphia, PA
Robert L. Baran, MD Cannes, France
Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Joaquin Calap Calatayud, MD Cadiz, Spain
Lowell A. Goldsmith, MD, MPH Chapel Hill, NC
Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan Aditya K. Gupta, MD, PhD, FRCP(C) Henry H.L. Chan, MB, MD, PhD, FRCP London, Ontario, Canada Joseph L. Pace, MD, FRCP Hong Kong, China Seung-Kyung Hann, MD, PhD Naxxar, Malta Noah Craft, MD, PhD, DTMH Seoul, Korea Art Papier, MD Torrance, CA Roderick J. Hay, BCh, DM, FRCP, FRCPath Rochester, NY Natalie M. Curcio, MD, MPH London, UK Johannes Ring, MD, DPhil Nashville, TN Warren R. Heymann, MD Munich, Germany Camden, NJ Ncoza C. Dlova, MBChB, FCDerm Roy S. Rogers III, MD Durban, South Africa Tanya R. Humphreys, MD Rochester, MN Bala-Cynwyd, PA Richard L. Dobson, MD Donald Rudikoff, MD Camila K. Janniger, MD Mt Pleasant, SC New York, NY Englewood, NJ William H. Eaglstein, MD Robert I. Rudolph, MD Abdul-Ghani Kibbi, MD Menlo Park, CA Wyomissing, PA Beirut, Lebanon Boni E. Elewski, MD Vincenzo Ruocco, MD Andrew P. Lazar, MD Birmingham, AL Naples, Italy Washington, DC Charles N. Ellis, MD Noah Scheinfeld, MD, JD Ann Arbor, MI New York, NY
324
Riccarda Serri, MD Milan, Italy
Julian Trevino, MD Dayton, OH Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Joseph A. Witkowski, MD Philadelphia, PA Ronni Wolf, MD Rechovot, Israel
November/December 2013
Volume 11 • Issue 6
Editorial: Part I of II
Minor Cuts and Abrasions: Do They Need Our Help? Peter Lowthian, MPhil, SRN;1 Lawrence Charles Parish, MD, MD (Hon)2
D
o minor wounds require attention? Should they be treated with antiseptics? For that matter, what is minor? This has caused us to reflect upon a variety of cutaneous insults, ranging from razor nicks and cooking knife stabs to scratches and abrasions. While doubting that anyone would follow a Boy Scout manual of yesteryear by scrubbing the wound with green soap or dousing with Merthiolate, we wonder how sensible it is to smear on an antibiotic ointment, to wrap the wound with a bandage, or even to apply the proverbial band-aid. We might also contrast letting nature do the healing, with a sterile dressing that includes antibiotic cream, bandaging, and a visit to an emergency room. The difference in cost between these two alternatives being obvious, we should be recommending an effective yet inexpensive treatment for these minor lesions. Even a small clinical improvement could benefit numerous people, not to mention the “bean counters” who would welcome a reduction in costs. The numbers involved are daunting. Take, for example, the number of minor wounds that occur each week in the United Kingdom, with 63 million residents. Even if just one minor wound was treated each week in each neighbourhood practitioner’s surgery, the United Kingdom would have 2 million of these to treat every year, and this does not include minor wounds treated elsewhere in that country, as well as those in the rest of the world. Deciding what to do may be more perplexing now, with our growing understanding of wound healing, and with the number of products we could discuss.1,2
Small Cuts At one extreme, a small needle puncture, by accident or design, will normally need no treatment, once it has stopped bleeding; this being nature’s way of cleansing the wound. This may also apply to minor cuts or scratches, while deeper cuts and abrasions that are more noticeable may need some attention. Needless to say, suturing may be best for wounds more than an inch in length and/or ones that penetrate past the dermis. Lest we forget, such wounds may also require tetanus prophylaxis. Not much cleansing is needed for small cuts, unless they are contaminated (eg, with feces or soil). Currently, we would recommend that they are washed with clean water before a dressing is applied. The traditional band-aid is likely to be the first treatment considered for small cuts. These adhesive dressings were invented in 1920, but whether the original design is still relevant is another matter. Over the years, manufacturers have produced many variations of the band-aid, some of which prevent skin maceration. This unwanted side effect, caused by inadequate ventilation and/ or absorbency of the dressing, may not only delay wound healing, but is also unsightly. Increasing the absorbency of a dressing is possible but is liable to increase its bulk. What is more practical seems to be to increase the dressing’s ventilation. The downside may be that bacteria can easily enter a well-ventilated dressing, especially when it is wet. As a result, it is better to have a waterproof (or water-resistant) dressing that is microporous, indicating that it has very small pores but not necessarily as small as microporous filters.3 In our experience, such a dressing will induce good wound-healing
From the Royal National Orthopaedic Hospital, Stanmore, United Kingdom (formerly);1 and the Department of Dermatology and Cutaneous Biology and the Jefferson Center for International Dermatology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Suite 301, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com
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EDITORIAL
conditions if it completely covers the wound: something that many band-aids do not do. Liquid-when-applied dressings, such as collodian and Liquid Skin, are sometimes used for minimal wounds or abrasions. Normally, these do have microscopic pores when dried; however, they would not be useful if hemorrhage is occurring or imminent. An advantage attributed to these dressings is transparency, but this is not always advantageous. In short, if a small wound is bleeding, some absorbent material is normally incorporated into the dressing. Small Burns Small burns need to be quickly cooled. If cool water is not available, a cool surface or even one’s own ear lobe, can help. Afterwards, they can be treated like small abrasions that are not bleeding. In both instances, the lesions should be covered to ease the stinging caused by fluid evaporating from the wound. The traditional butter application, preferably straight from the refrigerator, can still be used for minor burns, Even so, a dressing that hinders fluid evaporation may be preferred, as it is likely to stay in place longer.
can, of course, be purchased, but any tape closure entails some degree of risk, as bacteria can be trapped within the wound. The smaller lesions we are considering, however, will not need tape closures. For these, some simple dressing is clearly preferable to none at all, as leaving such wounds to dry causes some pain, as well as delayed healing. In addition, environmental contamination needs to be guarded against, and one’s blood may also contaminate other things, such as food. Conclusions Most minor wounds do need a dressing, and everything points toward a simple adhesive tape, or film, that is either waterproof or water-resistant (eg, Micropore). Waterproof, but vapor-permeable films (eg, Opsite) can be useful to guard against crosscontamination problems, but films are often tricky to cut and apply unless a roll version is used. An absorbent pad, placed on the wound will manage minor hemorrhage and/or wound discharge. It needs no special properties but should not stick to the wound. Also, like the adhesive tape, it should be clean, nontoxic, and, if possible, hypoallergenic. We hope to discuss this in more depth, in the near future. References
Simple Solutions Some dressings are ready-shaped to fit between fingers or toes. Sometimes, these can be in short supply; not to worry: with a pair of scissors, many varieties of adhesive tape can be similarly shaped, so that the ready-shaped ones are not needed. Sticky tapes can also be cut into thin strips to act as skin sutures. One of us (PTL) has often used Micropore for this purpose. Steri-strips
1 Eaglstein WH. Moist wound healing with occlusive dressings: a clinical focus. Dermatol Surg. 2001;27:175–182. 2 Weller C, Sussman G. Wound dressings update. J Pharm Pract Res. 2006;36:318–324. 3 A Century of Innovation: The 3M Story. Available at: http://multimedia.3m.com/mws/mediawebserver?66666 60Zjcf6lVs6EVs666IMhCOrrrrQ-. Accessed November 25, 2013.
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ORIGINAL CONTRIBUTION
Prevalence of Depression in Vitiligo Patients Mana Al-Harbi, MBBS Abstract Vitiligo is an acquired depigmentation disorder affecting 1% to 4% of the population worldwide. The chronic nature of the disease, long-term treatment, and lack of uniform effective therapy are demoralizing for patients with vitiligo, leading to decreased self-image and depression. Prevalence and severity of depression in vitiligo patients was studied by self-administered questionnaires distributed in dermatology departments in Qassim Region. Modified Beck Depression Inventory Scale was the tool used in the questionnaire to study and classify depressive symptoms. A total of 308 vitiligo patients participated in our study, including 59.7% men and 40.3% women. According to the Beck Depression Scale, 54.5% were found to be depressed, most with mild depression. Depression was more prevalent in single patients, especially women in the first few years of the disease (P<.05). Age, sex, duration of disease, marital status, and educational level were significant factors that influenced severity and prevalence of depression. Assistance of a psychiatrist or psychologist is of crucial importance in taking care of vitiligo patients, especially in high-risk individuals. (SKINmed. 2013;11:327–330)
T
he skin is the largest and most visible organ of the human body. It is an important aspect of attractiveness, sense of well-being, and self-confidence.1 Vitiligo is an acquired depigmentation disorder that affects 1% to 4% of the world’s population with an unpredictable course and variable response to treatment. It appears to be transmitted genetically in a polygenic/multifactorial manner. Depigmentation may be the source of severe psychological distress, diminished quality of life, and increased risk of psychiatric morbidity.12 The past decade has witnessed an increasing interest in psychological effects of various skin diseases and quality of life in affected patients.2 The self-image of vitiligo patients drops considerably and may lead to depression regardless of age, race, or sex.5 Many patients with vitiligo are sensitive to the way others perceive them and often withdraw from society because they anticipate being rejected. Vitiligo of exposed sites can adversely affect a person’s chance of getting a job after an interview and so restrict their career choices. Vitiligo beginning in childhood can be associated with significant psychological trauma that may have long-lasting effects on the self-esteem of children.6 Children with vitiligo usually avoid sports or restrict such activities. Vitiligo is thus an important skin disease that has a major impact on the quality of life of patients. The field of psychodermatology has developed as a result of increased inter-
est and understanding of the relationship between skin disease and various psychological factors.7 Method and Patients After departmental approval, self-administered questionnaires were distributed in dermatology departments of King Fahad Specialist Hospital, Buraidah Central Hospital, King Saud Hospital in Onaizah, and Al Bukairiyah Hospital in the Qassim region. Data collection occurred between December 2009 and February 2010. The questionnaire to assess depression was obtained from the department of psychiatry in Medical College Qassim University where the validity study was performed after translating it into Arabic. The Modified Beck Depression Inventory Scale was the tool used in the questionnaire to study and classify depressive symptoms in the patients. The questionnaire comprised 13 categories, each having 4 statements. The respondents were all patients who came into the dermatology clinic during the study period. Patients were asked to choose the statements that they considered the most relevant to their situation. The questionnaire also included some questions to elicit demographic data, duration of the disease, and type of treatment. The participants were patients with vitiligo who visited the dermatology departments for treatment .We excluded patients with other chronic
From private practice in Saudi Arabia Address for Correspondence: Mana Al-Harbi, MBBS, PO Box 295124 Riyadh, Saudi Arabia 11351 • E-mail: dr.badrani@hotmail.com
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ORIGINAL CONTRIBUTION
dermatological and psychiatric problems for minimization of bias. The returned questionnaires were entered and analyzed using SPSS version 17.0 (SPSS Inc, Cary, NC). A P value <.05 was accepted as the cutoff point for statistical significance. Results A total of 308 vitiligo patients who came for treatment and follow-up in the dermatology clinics in the selected hospitals participated in our study. Of these, 184 (59.7%) were men and 124 (40.3%) were women. The mean age was 27±14.5 years. About two thirds (63.6%) of patients were single and the rest were married. The majority of patients had secondary school education or less (75%) (Table I). According to the Beck Depression
Table I. Demographic Data Variable
Number (%)
Mean age, y
27±14.5
Male
184(59.7)
Female
124 (40.3)
Single
196 (63.6)
Married
112 (36.4)
Education Intermediate school or lower
116 (38.2)
Secondary school
112 (36.8)
University or higher
76 (25)
Duration of Disease <4 y
168 (54.6)
≥4 y
140 (45.4)
Scale, 168 (54.5%) patients were found to be depressed, more than half of them (52.4%) experienced mild depression, followed by moderate depression (33.3%), and then severe depression (14.4%). There was a direct relationship between age and depression (P<.05). The severity of depression was the highest during adolescence. Regarding the relationship between sex and depression, 68.2% of patients with mild depression were men, but among the patients with moderate and severe depression, the percentage of men and women was similar and the differences were not significant (P=.12). Depression was significantly more prevalent among single (unmarried) vitiligo patients: 64 (72.7%) of those with mild depression, 36 (64.3%) of those with moderate depression, and 20 (83.3%) of those with severe depression. The relationship between marital status and severity of depression was statistically significant (P=.006). Of patients who were depressed, the majority of educated patients (72.7%) showed mild depressive symptoms while the majority of patients with low educational level had moderate and severe depression (85.7% and 100%, respectively) (P=.002) (Table II). The prevalence and severity of depression were significantly higher in the first years of the disease: the majority of depressed patients had the disease for ≤4 years. These differences were statistically significant (P<.05) (Table III). When we studied the relationship between the affected part of the body and prevalence of depression, we found that among patients who had head and face depigmentation, 57.1% were depressed, while among those who had scattered lesions, 55.9% were depressed. Among patients who had acral vitiligo, 54.3% had depression; these differences were not statistically significant (P>.05) (see Table III for more details). Finally, there was a significant relationship between type of treatment used for vitiligo and prevalence of depression: 62.5 % of patients who used phototherapy and creams together showed signs of depression. On the other hand, only 51% of patients who were using creams had depressive symptoms (P<.05) (Table III).
Table II. Association of Depression to Educational Level and Marital Status Severe Depression
Moderate Depression
Mild Depression
No Depression
Studied Parameter
Intermediate or lower
52 (38.2%)
24 (27.3%)
48 (85.7%)
24 (100%)
96 (64.9%)
Secondary or higher
84 (61.8%)
64 (72.7%)
8 (14.3%)
0 (0%)
72 (46.2%)
Single
76 (54.3%)
64 (72.7%)
36 (64.3%)
20 (83.3%)
120 (61.2%)
Married
64 (45.7%)
24 (27.3%)
20 (35.7%)
4 (16.7%)
48 (42.9%)
Total Education Level
Marital Status
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ORIGINAL CONTRIBUTION
Table III. Relationship of Depression to Duration of the Disease, Depigmented Parts, and Type of Treatment No Depression
Total
Mild Depression
Moderate Depression
Severe Depression
Total
Duration of Disease, Y <4
56 (40%)
48 (54.5%)
44 (78.6%)
20 (83.3%)
112 (66.7%)
≥4
84 (60%)
40 (45.5%)
12 (21.4%)
4 (16.7%)
56 (40%)
Head and face
12 (8.7%)
4 (4.4%)
8 (14.3)
4 (16.7%)
16 (57.1%)
Hands and feet
68 (48.6%)
40 (45.6%)
24 (42.9%)
12 (50%)
76 (54.3%)
Cattered
60 (42.9%)
44 (50%)
24 (42.9%)
8 (33.3%)
76 (55.9%)
Local
96 (74.4%)
64 (72.7%)
24 (46.2%)
12 (60%)
100 (51%)
Phototherapy
36 (25.6%)
24 (27.3%)
28 (53.8%)
8 (40%)
60 (62.5%)
Affected Parts
Type of Treatment
Discussion Psychiatric comorbidity is one of the common issues that physicians encounter in their daily clinics.8 Skin disfigurement can be a source of emotional distress and psychiatric illness. Severe depression and suicidal tendencies have also been reported in vitiligo patients.9–11 Depending on the Beck Inventory Depression Rating Scale, 54.5% of vitiligo patients in our study were depressed. Age was one of the significant factors that influenced severity of depression, whereby the young adolescent vitiligo patients (≤14 years) were more likely to be severely depressed. Our study didn’t show a significant relationship between sex and prevalence of depression. Among patients with depression, 71.4% were single women; thus, depression is significantly more frequent in single patients, especially unmarried women. A young woman with vitiligo may have a reduced likelihood of getting married. Similarly, a married woman who develops vitiligo after marriage may have marital problems perhaps ending in divorce.12 We noticed that the severity and prevalence of depression were significantly much frequent in the first few years of the disease (Table III), which might be explained by psychological adaptation to their disease. Severity of depression was decreased in educated patients compared with noneducated patients (Table II). Depression was higher among patients who experienced acral and scattered depigmentation, but this relationship was not statistically significant (P=.32). It appears that depression is related to body image perception more than body surface SKINmed. 2013;11:327–330
area involved. Significantly, patients using phototherapy were more depressed compared with those who were using topical treatment; this may be because phototherapy is typically used for resistant cases.12 Response to treatment is one of the factors that affect depression in vitiligo patients. Conclusions Depressive symptoms self-reported by patients with vitiligo are influenced by severity and duration of the skin disease in addition to age, sex, marital status, and education level of patients. Depression in vitiligo patients may warrant referral to psychiatric services for proper psychiatric evaluation and management. Acknowledgment We are grateful to Dr Medhat Farid (and other colleagues) who assisted in the data collection and preparation of this manuscript. References
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1 Ongenae K, Beelaert L, van Geel N, Naeyaert JM. Psychosocial effects of vitiligo. J Eur Acad Dermatol Venereol. 2006;20:1–8. 2 Handa S, Dogra S. Epidemiology of childhood vitiligo: a study of 625 patients from North India. Ped Dermatol. 2003;20:207–210. 3 Kostopoulou P. Objective vs. subjective factors in the psychological impact of vitiligo: the experience from a French referral centre. Br J Dermatol. 2009;161:128–133.
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ORIGINAL CONTRIBUTION
4 Kent G. Psychological effects of vitiligo: a critical incident analysis. J Am Acad Dermatol 1996;35:895–898.
9 Noor SM, Khurshid K, Mahmmod T, Haroon TS. Quality of life in vitiligo. J Pak Assoc Dermatol. 2004;14:55–58.
5 Savin J. The hidden face of dermatology. Clin Exp Dermatol 1993;18:393–395.
10 Papadopoulos L, Bor R, Legg C, Hawk JL. Impact of life events on the onset of vitiligo in adults, preliminary evidence for psychological dimension in aetiololgy. Clin Exp Dermatol. 1998;23:243–248.
6 Ijaz A, Sohail A. frequency and pattern of psychiatric disorders in patients with vitiligo. J Ayub Med Coll Abbottabad. 2007;19:3. 7 Koo JY, Do JH, Lee CS. Psychodermatology. J Am Acad Dermatol. 2000;43(5 pt 1):848–853. 8 Hussain A, Khalid M, Shaheen JA, Ahmed I. Prevalence and pattern of psychiatric disorders among dermatological patients. J Pak Assoc Dermatol. 2005;15:13–17.
11 Parsad D, Dogra S, Kanwar AJ. Quality of life in patients with vitiligo. Health Qual Life Outcomes. 2003;1:58. 12 Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol. 2011;65:493– 514.
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November/December 2013
Volume 11 • Issue 6
Original contribution
Androgenic Alopecia in Women: An Indian Perspective Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Reshmi Midha, MBBS Abstract The authors sought to investigate androgenic alopecia (AA) utilizing clinical and investigative procedures to establish the pattern of AA in the Indian subcontinent. A total of 35 consecutive women presenting with AA were included. After obtaining informed consent, a detailed history/examination, hair pull test, trichogram, and a scalp biopsy were performed in patients. AA classification was attempted across Ludwig and Norwood guidelines. Of 35 women, 16 had grade I, 10 had grade II, and 1 had grade III Ludwig classification. In addition, 6 other women had Christmas tree baldness: 1 each of fronto-parietal and male pattern baldness. Several investigations including hormonal profile were inconclusive; however, hair pull test and trichogram may be helpful in understanding the sequence in AA in women. AA has infrequently been reported, particularly India and in Asia in general. (SKINmed. 2013;11:332–340)
H
air is a physical expression of personal and social wellbeing and is central to feelings of attractiveness and self-esteem.1 The pattern of hair loss in women is not easily recognizable as compared with that in men. Its diagnosis is often difficult to make.2 Androgenic alopecia (AA) is the most common hair loss in women.3,4 It differs from that in men due to susceptibility, age of onset, rate of progression, and morphology.5 Furthermore, the term AA in women has been used synonymously with male pattern alopecia in women, female pattern alopecia, diffuse hormonal alopecia, diffuse alopecia in women,6 common baldness in women,7 and female pattern baldness (FPB).5 AA is becoming more important in the spectrum of baldness, thus requiring more focused attention and extensive evaluation, so that the outcome may be applied in patients. Materials and Methods
system. Precipitating factors such as emotional stress, surgery, illness, thyroid dysfunction, iron deficiency, malignancy, and drug intake were also considered. In addition to detailed dermatological examination, complete general physical examination was also performed. Naked-eye hair analysis comprising its texture and structure was confirmed by microscopic examination. Routine, total, and differential leucocyte count, hemoglobin, and serum ferritin were also performed.9 Hair pull test10,11 was preformed in all 35 women, while trichography was performed in 5 patients. Approximately 60 hairs were grasped between the thumb, index, and middle finger and gently pulled. A test was interpreted as negative when a hair count was either ≤6, while a hair count of >6 was considered positive, indicating active hair shedding.
In all, 35 consecutive women presenting with thinning/rarefaction of the scalp hair irrespective of premenopausal or postmenopausal age group from the period 2007 to 2009 were included. While patients with AA, chronic telogen effluvium, cicatricial alopecia, scalp infections, and hair loss following chemotherapy were excluded.
Trichography/forcible complete hair pluck11 was used to evaluate around 50 hairs. The hair were cut 0.5 cm above the surface of scalp. They were then quickly pulled out with either epilating or artery forceps in groups of 5 to 10 hairs in the direction of hair growth.12 Subsequently, the roots were classified according to the findings given in Table I.
After informed consent was obtained, a detailed history and clinical examination were performed, including age, duration, age at onset, and progression of hair loss. Standardized hair photography8 of each patient was taken and recorded in the retrieval
A 10% potassium hydroxide mount for mycelia/spores were prepared from scrapings to exclude superficial mycosis. Hormonal profile constituting leutinizing hormone (LH), follicular stimulating hormone (FSH), prolactin, and dehydroepiandrosterone
From the DermatoVenereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati-Delhi, Skin Institute, School of Dermatology, Greater Kailash New-Delhi, India Address for Correspondence: Virendra N. Sehgal MD, DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033 India • E-mail: drsehgal@ndf.vsnl.net.in
SKINmed. 2013;11:332–340
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ORIGINAL CONTRIBUTION
Table I. Depicting the Salient Features of Various Phases of the Hair Cycle Anagen hair
Characterized by thick, dark base with preserved inner and outer sheaths. Bulb is at an angle of 20 degrees with the shaft, 80% to 95% adorn this phase.
Telogen hair
Thin, club-shaped, smooth contour, and nonpigmented bulb. More than 25% telogen count is considered abnormal. The preceding features are seen in 10% to 20% of plucked hair.
Catagen hair
The hair is similar to that of telogen hairs except that the bulb is rough and covered by loose and thick outer and inner sheath. 1% to 2% of the hairs are in this phase.
Dystrophic/aplastic/ traumatized anagen hair
Lack of outer and inner sheath and angulated bulb
Table II. Clinical Definitions of Female Pattern Baldness According to Ludwig Classification Grade I
Perceptible thinning/rarefaction of hair on the crown, limited in front by a line situated 1 to 3 cm behind the frontal hair line
Grade II
Pronounced thinning/rarefaction of the hair on the crown within the area seen in grade I
Grade III
Full baldness/total denudation within the area seen in grade I and II
Table III. Female Pattern Baldness: Duration Duration Range
Frequency
Percentage
3 mo to 5 y
24
68.57
6 y to 10 y
9
25.71
11 y to 15 y
1
2.86
16 y to 20 y
0
0
21 y to 25 y
0
0
26 y to 30 y
1
2.86
(DHEAS) were performed on the first or second day of the menstrual cycle. Thyroid-stimulating hormone, triiodothyronine, and thyroxine were performed in select patients along with serum ferritin.9 Five women underwent scalp biopsy from the representative lesion. Hematoxylin-eosinâ&#x20AC;&#x201C;stained transverse and horizontal section were examined to exclude AA due to other causes.13,14 Lower abdomen ultrasonography was undertaken to define the possibility of polycystic ovaries. Ultimately, FPB was classified into grade I, II, and III in accordance with criteria stipulated by Ludwid3 and Norwood (Table II).15 Observations Several pertinent parameters were considered for evaluating AA, such as demographic profile, pattern of hair loss, and laboratory investigations including hormonal profile, serum ferritin, and ultrasonography of lower abdomen. SKINmed. 2013;11:332â&#x20AC;&#x201C;340
The age of the 35 women ranged from 16 to 50 years, of which 25 (71.42%) were in the age range of 16 to 30 years, 8 (22.86%) were in the age of 31 to 45 years, and 2 were older than 45 years. Of the 35 women, 19 (54.29%) were unmarried and 16 (45.71%) were married. Duration of hair loss was variable (Table III), with the majority in the range of 3 months to 5 years, followed by 6 to 10 years. Six (17.14%) of the women gave a history of using henna and one each of hair color use, miscarriage, and AA. History of stress was recorded in 15 women (42.86%). Of the 35 women, 18 (51.43%) were nonvegetarians and 17 (48.57%) were vegetarians. Seven (20%) of the patients had early menarche and 28 (80%) had menarche after age 11. Twenty-four (68.57%) of the women had regular menstrual periods, while 9 (25.71%) had irregular periods and 2 had menopause. Family history of hair loss was recorded in 23 women, of which
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ORIGINAL CONTRIBUTION
Table IV. Female Pattern Baldness: Comprehensive Details of Each Patient
No.
Age, y
Duration, y
Age at Onset, y
Marital Status
Age at Menarch, y
1 2
20 30
6 1.5
14 28.7
U M
9 13
3
25
4
21
M
10
4
17
0.5
16.7
U
5 6 7 8
20 29 16 20
2 13 0.25 2.5
18 16 15.9 17.7
9
30
2
10
25
11
Family History
Hairpull Test
Trichogram
Mother Mother Father, brother
+Ve –Ve
Done
–Ve
-
12
-Ve
–Ve
U M U U
12 13 12 12
-Ve -Ve Sister Sister, aunt
+Ve –Ve –Ve –Ve
28
M
11
Niece
–Ve
6
19
M
14
-Ve
+Ve
31
10
21
M
17
Brother
–Ve
12 13 14 15 16 17 18 19 20
33 39 30 30 31 34 37 41 23
10 5 3 2 4 5 0.5 0.5 3
23 34 27 28 27 29 36.7 40.7 20
M M U U U M U M U
16 14 9 13 14 12 13 13 11
Brother Brother Brother Mother -Ve -Ve Mother Brother -Ve
+Ve –Ve –Ve –Ve +Ve –Ve –Ve –Ve –Ve
21
23
8
15
U
14
Mother
–Ve
22
29
4
25
M
14
-Ve
+Ve
23 24 25 26
28 25 22 33
2 0.7 9 4
26 24.5 13 29
U U U M
16 14 11 12
–Ve –Ve –Ve –Ve
-
27
27
2
25
U
11
+Ve
-
28
26
1.5
24.7
U
14
–Ve
-
29
29
2
27
M
13
-Ve Mother, sister -Ve -Ve Father, brother Father Father, brother
–Ve
-
30
50
30
20
M
16
Father
–Ve
31
20
6
14
U
15
Father
–Ve
32
20
7
13
U
13
Father
–Ve
33 34
18 24
5 4
13 20
U M
13 12
Mother, sister -Ve
–Ve +Ve
35
49
10
39
M
13
Sister
–Ve
Done Done Done -
Done -
Abbreviations: +Ve, positive; –Ve, negative; DHEAS, dehydroepiandrosterone; FSH, follicular stimulating hormone; LH, leutinizing hormone; M, married; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; S. Fe, serum ferritin; U, unmarried.
November/December 2013
ORIGINAL CONTRIBUTION
Table IV. Female Pattern Baldness: Comprehensive Details of Each Patient Thyroid Profile
Hormonal Profile
S. Fe, ng/mL
LH, mIU/mL
FSH, mIU/mL
Prolactin, ng/mL
Testosterone, ng/mL
DHEAS, µg/dL
T3, ng/dL
T4, µg/dL
TSH, µIU/mL
Ludwig Grades
36.9 40
12 5.9
5.1 8
10 15
1.1 1.1
3 1.1
0.9 1.5
5.6 7.2
1.3 6.6
I II
35
4.6
3.5
38
0.6
2.3
1
5.4
6
I
20
5
4
15
0.7
0.9
1
8.2
1.4
22.85 24.2 9.08 29.8
5 7.3 5.2 4.8
4 6.2 5 3.8
11 9.5 20 12
0.9 0.8 1.1 0.9
0.9 1.1 1.3 1.4
0.8 0.9 0.7 1.1
5.2 5.5 8 1.2
1.9 1.7 3.3 5.6
31.2
5.9
5.4
9
0.7
1.9
1.4
4.3
4.4
33
6.1
5
13
0.5
1.7
0.8
5.6
1.6
30.18
6.1
4
21
0.6
1.1
0.6
8.6
0.9
21.26 46 15 15 20 18.6 30.4 28.7 28
7.7 7.1 5.9 6.3 6.9 4.5 5.2 5.3 10
9.8 6.2 5 4.8 5.2 4 4.1 3.9 6
10 16 8 12 13.5 19 21 23 24
0.9 0.8 0.7 0.6 0.8 1 0.9 0.5 0.7
1.2 1.4 0.8 1.2 1.5 1.6 1.8 0.7 0.8
1 1 1.5 1.5 1.6 1.7 1.7 1.7 1.2
5.1 8.2 6.6 6.7 6.8 6.9 7 7.1 10
4 2.9 2 2.1 2.2 2.3 2.4 2.5 3.8
382
18
21
15
0.7
2.8
1.5
2.7
2.7
20
11
11
20
0.6
0.8
1.4
1.9
2
I
21.57 61 56 42
5.85 5.6 13.78 5.4
4.18 6.9 3.2 9.1
16 12 22 15
0.8 0.4 0.6 2.1
2.1 2.2 1.6 1.7
1.1 1.5 2.4 1.5
1.9 8.7 1.3 9.1
2.8 2 4.1 5.1
II I II II
21
6.3
6.9
16
1.9
0.6
1.1
1.4
4.7
III
7.3
6.8
4.1
16.4
0.6
2.1
1.4
6.2
4.3
18.2
4.8
3.9
11
0.5
1.4
0.6
5.2
1.6
II Christmas tree
113.5
7.5
4.4
10.2
2.5
5
2.5
12.9
0.4
57
4.19
7.57
15.02
1.8
1.68
1
5.5
4.7
45.6
15
6.1
23
0.5
3.24
0.8
8
1.4
20.2
4.7
5.1
20
1
2.14
1
10.1
5.8
32.5
5.7
6.2
35
1.1
1.89
0.8
6.4
3.9
56
21
25
19
5.2
3.1
1.1
7.7
4
Frontotemporal I I I I Christmas tree II Christmas tree II I I I I I I I I Christmas tree
II Christmas tree Christmas tree II II Male pattern receding hairline
Associated Disorder PCOS – – – Acne Nil – – – – – – – Acne – – – – – – – Hypothyroid – -PCOS Hirst – – Acne NIDDM, RA Htn – Acne – Infert
November/December 2013
ORIGINAL CONTRIBUTION
Figure 1. Thinning of the hair on the crown of a 22-year-old woman, limited in front by a line situated 1 to 3 cm behind the frontal hair line (left). A similar change is seen in the occipital region conforming to Ludwig’s grade I (right).
11 (31.43%) were of maternal and 12 (34.29%) of paternal origin, the details of which are reflected in Table IV. The scalp surface examination was apparently normal in 23 patients (65.71%), while it was seborrhoeic in 12 (34.29%). Hair pull test was positive in 8 patients (22.86%), while it was negative in 27 (77.14%). Anagen/telogen ratio was found to be reversed in all the 5 women in whom trichography was performed. Histopathological findings were found to be consistent with the diagnosis of FPB in all the 5 patients, where biopsy was taken from the representative lesion. There was no associated dermatological disorder in 24 (68.57%) patients; however, 4 women presented with acne, 2 with polycystic ovary syndrome (PCOS) and 5 had other disorders, which included hirsuitism, primary infertility, rheumatoid arthritis, non–insulin-dependent diabetes mellitus, and hypertension.
Figure 2. Progressive pronounced thinning of the hair occupying the crown confirming to Ludwig’s grade II.
Total and differential leukocyte count and hemoglobin were within the normal range. Serum ferritin was also found to be in the normal range in 34 (94.28%) women, while it was margin- Discussion ally elevated in 1 woman. FPB in women is a common disorder characterized by a diffuse In addition, serum testosterone levels were elevated in only 5 pa- reduction in hair density, which largely affects the crown and tients (14.29%), whereas 30 (85.71%) patients had normal tes- frontal scalp. It is equivalent to male balding and accordingly are tosterone levels. LH, FSH, prolactin, and DHEAS serum levels both referred to as androgenetic alopecia. The frontal hairline is usually retained in FPB and the hair loss seldom progresses to were largely within the normal range (Table IV). complete baldness. The history of hair biology and its classificaThe various patterns of baldness among women was formed and tion in FPB have been described elsewhere.16 FPB affects more classified into Ludwig grade I in 16 patients (45.71%) (Figure than 50% of women older than 50 years. 1), grade II in 10 patients (28.57%) (Figure 2), grade III in 1 patient (Figure 3), Christmas tree pattern (Figure 4) in 6 patients In the current study, the age of the women ranged from a mini(17.14%), fronto-temporal recession (Figure 5), and male pat- mum of 16 years to a maximum of 50 years. A majority of the cases of FPB were in the second and third decade, followed by the tern baldness in 1 woman each. SKINmed. 2013;11:332–340
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ORIGINAL CONTRIBUTION
Figure 3. Full baldness/total denudation confined to the area seen in grade I and II Ludwigâ&#x20AC;&#x2122;s grade III.
Figure 4. Christmas tree pattern baldness.
Figure 5. Male pattern baldness in a woman marked by severe frontal and fronto-temporal recession and sparseness of hair on the vertex (right) extending in involve the occipital region (ponytail) (4). SKINmed. 2013;11:332â&#x20AC;&#x201C;340
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fourth decade, a finding that confirms earlier observations;2,17,18 furthermore, it has been noted that thinning/rarefaction of FPB is progressive and is directly proportional to its duration, with the longer the duration, the more overt the baldness. This finding has been presented well in the present study. Most of the women in the studied group presented within 3 months to 5 years of the onset of hair fall. Consequent upon the increase in duration, there was a perceptible decline in their reporting, perhaps because the patients accepted the baldness, became less concerned about the problem, or there were financial constraints. History of active hair loss was not volunteered by most of the women, instead they complained of progressive thinning and shortening of hair over the years, apparent with center parting confined to the vertex. This may indicate that affected individuals are more concerned in the initial stages of hair loss. Although the majority of patients had no obvious precipitating factor(s) contributing to their hair loss, application of henna in a few patients may have been responsible. Subsequent washing of dried henna at frequent intervals might cause permanent damage to the hair bulb that leads to hair loss; moreover, AA is known to mimic FPB, the confirmation of which is possible only through histopathology in which marked lymphohistiocytic infiltrate is seen around the hair follicle (swarm of bees) without miniaturization of hairs.4,19 Similar features were seen in a single case where AA preceded FPB. Another case of AA was recorded in a woman 3 years after the use of hair color/dye. Melanocytes damage to the hair papilla may lead to miniaturization and subsequent FPB. Stress, a well-known cause of diffuse hair loss, has not yet been established in FPB. Its probable mechanism is neuro-immune modulation with a direct effect on or contributing to the hormonal imbalance ultimately resulting in FPB. Stress was not a regular feature in our study patients. Menarche and subsequent menstrual cycle were largely inconclusive but should not be overlooked in a study of FPB. Unmarried women outnumbered married women, emphasizing the cosmetic nature and psychologic stress of the problem.1 Of the several semi-invasive techniques available thus far, the hair pull test has been one of the most credible office procedures; however, it has sparingly been used in day-to-day practice. Its step-by-step technique and subsequent interpretation has precisely been outlined (vide supra).10 Its credibility as a feasible tool for the diagnosis of FPB has again been reiterated and is recommended for use in future studies of this nature. The preceding procedure with trichography should be supplemented with the guidelines of which have already been described.20 This procedure was undertaken only in 5 patients. It indicated a reduction SKINmed. 2013;11:332–340
in the ratio of anagen/telogen coupled with breaking of a few hair shafts during the process of plucking. It was seen that the few hair shafts also broke during the process of plucking. These hairs had thinned out to such an extent that they could not take the force of plucking, suggesting miniaturization of hair.13 Phototrichography20 and phototrichography vediomicroscopy21 for the evaluation of scalp hair has recently been suggested. Paternal or maternal family history of baldness was elicited; however, their ratio in two groups was equal, an observation similar to that of previous work.22 This aspect is still speculated in AA in women in contrast to that in men, in whom history of firstdegree relatives with male pattern hair loss13,23 was positive. The importance of adequate serum ferritin levels during oral cyproterone acetate and ethinyl estradiol treatment of diffuse androgen-dependent alopecia in women has also been emphasized,9 but it was inconclusive in the current study. Iron deficiency is speculated to cause telogen effluvium and may also interfere with the efficacy of treatment of FPB. A low serum ferritin is diagnostic of iron deficiency; however, depleted iron stores may not be detected by serum ferritin measurements since ferritin is an acute-phase reactant and active infections increase its synthesis, which gives a false sense of normal iron stores. The majority of women with AA have no clinical or biochemical evidence of androgen excess, which is in concordance with this study. A subset of women with AA and those with concomitant signs/symptoms of hirsutism, and/or treatment refractory adult acne, acanthosis nigricans, irregular menstruation, and/or galactorrhea, however, should be adequately screened for hyperandrogenemia.24,25 Moderately high levels of circulating androgens is associated with a Ludwig type of hair loss, while grossly elevated testosterone levels would produce “male patterning.”12 Patients with testosterone >2.5 times the normal limit or >200 ng/dL, or DHEAS >2 times the normal limit or >700 µg/dL in premenopausal or >400 µg/dL in postmenopausal women12 should undergo additional investigations such as ultrasonography of the abdomen, computerized tomography of the head and abdomen, and magnetic resonance imaging to rule out the presence of any hormone-secreting tumor. Serum DHEAS and prolactin were marginally raised in 4 and 8 women, respectively. The latter had no other signs of galactorrhoea and 5 had irregular menstruation and mildly raised testosterone levels, an outcome consistent with past findings.12 Serum prolactin levels are warranted in irregular menstruation. LH:FSH ratio was found to be normal in all except 2 patients in whom it was more than 2:1. Diagnosis of PCOS was established
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ORIGINAL CONTRIBUTION
in these 2 women. In one study,26 61.5% of 109 women 14 to 47 years of age had early-onset, moderate to severe FPB, in whom no biochemical evidence of androgen excess could be elicited. Despite normal blood androgens in the majority of women with AA, another report revealed that 27 showed ultrasound evidence of PCOS compared with 27% in the control population. The demonstration of hormonal levels in the normal range is indeed intriguing and may be because of microenvironment of the hair follicle, which may be responsible for deciding about miniaturization, which is influenced by androgen receptors, 5α-reductase, stem cell factors, drugs, and cytokines.28
whereas the latter was described earlier.15,40 In addition, an objective clinical technique for establishing early diagnosis consists in comparison of “part width” on the crown with part width on the occipital scalp. The part width on the crown of the scalp is wider than that of the occiput in female pattern hair loss. This patterned change, one of the earliest clinical signs, is caused by preferential miniaturization of hairs on the crown of the scalp.41 References
The role of androgens in AA is still speculative. It is interesting to mention that in women with normal androgen levels, the mean sebum excretion was found to be greater in hirsute than in nonhirsute women, suggesting that sebum excretion can be used as a marker of the hair follicle end organ response to androgens.29 The observation was worthwhile and was subsequently reiterated with a proviso that interindividual variation might be wide.30 Hormonal profile is suggested in women having both hirsuitism and FPB. Scalp biopsy was considered essential not only to exclude chronic telogen effluvium,31 diffuse alopecia areata19 or cicatricial alopecia,32,33 central centrifugal cicatricial alopecia,34 and trichotillomania,35 but also to outline: • Miniaturization of terminal into vellus-like hair. • Increase in percentage of tellogen hairs from a normal of 5% to 10% to 15% to 20% on average with a corresponding decrease in the percentage of anagen hairs. • Hair shafts >0.03 mm in diameter and thicker than follicles inner root sheath on horizontal section terminal, and the vellus or vellus-like hair shafts ≤0.3 mm in diameter and thinner than follicles in the inner root sheath. • The ratio of terminal to vellus or vellus-like hair <4:1. (A study by Whiting36 showed that the normal terminal to vellus hair ratio of 7:1 decreased to 1.5:1 for men only and around 2.2:1 for women only.) • Mild perifollicular infiltrate predominantly lymphohistiocytic was present around the follicle.37 Conclusions There are several classifications of FBD that are outlined elsewhere38,39; however, the Ludwig3 and Norwood15 classifications are fairly comprehensive and are practiced around the world. The definitions of the former are provided in the current study, SKINmed. 2013;11:332–340
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1 Cash TF. The Psychology of hair loss and it’s implications for patient care. Clin Dermatol. 2001;19:161–166. 2 Olsen EA. Female pattern hair loss. J Am Acad Dermatol. 2001;45:S70–S80. 3 Ludwig E. Classification of types of androgenetic alopecia (common baldness) occurring in female sex. Br J Dermatol. 1977;97:247–254. 4 Biondo S, Goble D, Sinclair R. Women who present with female pattern hair loss tend to underestimate the severity of their hair loss. Br J Dermatol. 2004;150:750– 752. 5 de Berker DAR, Messenger AG, Sinclair RD. Disorders of hair. In: Burns T, Breathnach S, Cox N, Griffiths C, eds, Rook’s Textbook of Dermatology. 7th ed. United Kingdom; Blackwell Publishing: 2004:63.1–63.36. 6 Suzberger Mb, Witten VH, Kopf AW. Diffuse alopecia in women. Its unexplained apparent increase in incidence. Arch Dermatol. 1960;81:556–560. 7 Muller SA. Common baldness. Minn Med. 1974;57:809– 812. 8 DiBernardo BE, Giampapa VC, Vogel J. Standardised Hair photography. Dermatol Surg. 1996;22:945–952. 9 Rushton DH, Ramsay ID. The importance of adequate serum ferritin levels during oral cyproterone acetate and ethinyl oestradiol treatment of diffuse androgen dependent alopecia in women. Clin Endocrinol. 1992;36:421– 427. 10 Olsen EA, Bettencourt MS, Cote N. The presence of loose anagen hairs obtained by hair pull in the normal population. J Invest Dermatol. 1999;4:258–260. 11 Olsen EA. Clinical tools for assessing hair loss. In: Disorders of Hair Growth: Diagnosis and Treatment. New York, NY: McGraw-Hill; 1994:59–69. 12 Olsen EA, Messenger AG, Shapiro J, et al. Evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol. 2005;52:301–311. 13 Solomon AR. The transversely sectioned scalp biopsy specimen: The technique and algorithm for its use in the diagnosis of alopecia. Adv Dermatol. 1994:9:127– 157. 14 Sinclair R, Jolley D, Mallari R, Magee J. The reliability of horizontally sanctioned scalp biopsies in the diagnosis of chronic diffuse telogen hair loss in women. J Am Acad Dermatol. 2004;51:189–199.
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15 Norwood OT, Lehr B. Female androgenetic alopecia: a separate entity. Dermatol Surg. 2000;26:679–682. 16 Sehgal VN, Srivastava G, Aggarwal A, Midha R. The imperative of hair biology, its comprehensive sequence in female pattern/pattern baldness, diagnosis and treatment modalities. Skinmed. [VOLUME NO. ETC?] 17 Venning VA, Dawber RP. Patterend androgenetic alopecia in women. J Am Acad Dermatol. 1988;18:1073–1077. 18 Birch MP, Messenger JF, Messenger AG. Hair density, hair diameter and prevalence of female pattern hair loss. Br J Dermatol. 2001;144:297–304. 19 Sehgal VN, Jain S. Alopecia areata: clinical perspective and an insight into pathogenesis. J Dermatol. 2003;30:271–289. 20 Guerrera M, Ciulla MP. A quantitative evaluation of hair loss: the phototrichogram. J Appl Cosmetol. 1986;4:61– 66. 21 D’amico D, Vaccaro M, Guarneiri F, et al. Phototrichogram using vediomicroscopy: a useful technique in the evaluation of scalp hair. Eur J Dermatol. 2001;11:17–20. 22 Kuster W, Happle R. The inheritance of common baldness: two B or not two B? J Am Acad Dermatol. 1984;11:921–926. 23 Smith MA,Wells RS.Male type alopecia, alopecia areata and normal hair in women: family histories. Arch Dermatol. 1964;89:95–98. 24 Kuhn BH. Male pattern alopecia and/or androgenetic hirsutism in women, part III: definition and etiology. J Am Med Women’s Assoc. 1972;27:357–364. 25 Carey AH, Waterworth D, Patel K, et al. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet. 1994;3:1873–1876. 26 Futterweit W, Dunaif A, Yeh H-C, et al. The prevelance of hyperandrogenism in 109 cosecutive female patients with diffuse alopecia. J Am Acad Dermatol. 1988;19:831– 836. 27 Cela E, Robertson C, Rush K, et al. Prevalence of polycystic ovaries in women with androgenetic alopecia. Eur J Endocrinol. 2003;149:439–442. 28 David A. Whiting. Possible mechanisms of miniaturization during androgenetic alopecia or pattern hair loss. J Am Acad Dermatol. 2001;45:S81–S86. 29 Strauss JS, Pochi PE. The hormonal control of human sebaceous glands: Observations in certain endocrine disorders. Clin Endocrinol. 1968;2:798–808.
30 Birch MP, Lashen H, Agarwal S, Messenger AG. Female pattern hair loss, sebum excretion and the organ response to androgens. Br J Dermatol. 2006;154:85– 86. 31 Whiting DA. Chronic telogen effluvium. Dermatol Clin. 1996;14:723–731. 32 Sehgal VN, Srivastva G, Bajaj P. Cicatricial (scarring) alopecia. Int J Dermatol. 2001;40:241–248. 33 Olsen EA. Female pattern hair loss and its relationship to permanent/cicatricial alopecia: a new perspective. J Investig Dermatol Symp Proc. 2005;10:217–221. 34 Gathers RC, Lim HW. Central centrifugal cicatricial alopecia: past, present, and future. J Am Acad Dermatol. 2009;60:660–668. 35 Sehgal VN, Srivastava G. Trichotillomania +/– trichobezoar: revisited. J Eur Acad Dermatol Venereol. 2006;20:911–915. 36 Whiting DA. Diagnostic and predictive value of horizontal sections of scalp biopsies in male pattern androgenetic alopecia. J Am Acad Dermatol. 1993;28:755– 763. 37 Whiting DA, Waldstreicher J, Sanchez M, et al. Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizontal sections of serial scalp biopsies: results of finasteride 1 mg treatment of men and postmenopausal women. J Investig Dermatol Symp Proc. 1999;4:282–284. 38 Hamilton JB. Patterned loss of hair in man: types and incidence. Ann N Y Acad Sci. 1951;53:708–728. 39 Lee WS, Ro BI, Hong SP, et al. A new classification of pattern hair loss that is universal for men and women: basic and specific (BASP) classification. J Am Acad Dermatol. 2007;57:37–46. 40 Sehgal VN, Kak R, Aggarwal A, et al. Male pattern androgenetic alopecia in an Indian context: a perspective study. J Eur Acad Dermatol Venereol. 2007;21:473–479. 41 Miller JJ. Medical pearl: comparing crown part width to occipital part width to diagnose female pattern hair loss. J Am Acad Dermatol. 2005;53:331–332.
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What’s New in Infantile Hemangiomas: Current Insights and Future Perspectives Kristina Semkova, MD, MSc;1 Jana Kazandjieva, MD, PhD;1 Nikolai K. Tsankov, MD, PhD2 Abstract Infantile hemangiomas are the most common benign vascular tumors of infancy. Their hallmark feature is the spontaneous involution over months to years after an initial rapid proliferation. The exact origin of infantile hemangiomas and the pathogenetic mechanism(s) of their life cycle are still unknown, but recent findings, including multipotent hemangioma-derived stem cells, vasculogenic activity, and response to hypoxic stimuli, give new insights into this common yet puzzling vascular tumor. β-Blockers have been recently introduced as effective therapy alongside conventional modalities, such as corticosteroids and lasers. Better understanding of the pathogenesis is needed in the future to ensure a more focused treatment approach with high efficacy and good safety. (SKINmed. 2013;11:341–349)
I
nfantile hemangiomas (IHs) are common benign vascular tumors of infancy with a natural history of spontaneous involution over months to years after an initial phase of proliferation. The well-programmed life cycle of IHs has given many clues to the pathogenesis, but the exact triggering mechanisms at each phase are still unknown. Given the wide variety in terms of clinical presentation, localization, life cycle, and associations, it is highly likely that several different endogenous and exogenous factors determine the occurrence, development, and final outcome of IHs.
Inconsistent nomenclature was a serious problem in the past that has partially been resolved after the acceptance of a general classification dividing vascular anomalies into vascular tumors and vascular malformations. Nevertheless, the term hemangioma is still commonly misused to describe any type of vascular lesion, primarily in specialties other than dermatology.1 Proper diagnosis is important to decide on adequate treatment because different vascular anomalies have different behavior and prognosis. The purpose of this review is to present the scientific and clinical findings from the past several years that give a better insight into our understanding of what induces IHs and why, what treatments work for the individual patient, and what can be done in the future to help our hemangioma patients and their parents.
Clinical Presentation Most IHs present as sporadic, single, tumor, or plaque-like cutaneous lesions with a predilection for the head and neck (60%– 80%) (Figure 1).2 Facial distribution is non-random. Tumor-like IHs are localized along the lines of embryological fusion, mainly on the cheek, upper lip, and upper eyelid, while diffuse IHs follow a segmental distribution pattern.3 Multiple hemangiomas are present in approximately 20% of affected children. IHs have a characteristic natural course with spontaneous involution over months to years after initial proliferation. A precursor lesion may be present at birth in about 50% of children. In the rest, hemangiomas appear de novo a few days or weeks after birth. The growth phase is usually completed within the first 6 to 10 months of life followed by gradual involution with complete regression in as much as 90% by the age of 9.4,5 Nevertheless, some hemangiomas might have minimal or arrested growth,6 while others (mainly deep and segmental lesions) show a tendency for a prolonged growth phase.7 Residual lesions, including teleangiectasia, fibro-fatty tissue, and depigmentation, are reported in 25% to 69% of untreated hemangiomas, depending on the studied population. The growth pattern has no predictive value on the residual outcome, while epidermal invasion, clinically presenting as a cherry red color, is the main risk factor for residual lesions.4
From the Department of Dermatology and Venerology, Medical University-Sofia, Bulgaria;1 and the Clinic of Dermatology and Venerology, Tokuda Hospital Sofia, Bulgaria2 Address for Correspondence: Kristina Semkova, MD, MSc, Department of Dermatology and Venereology, University Hospital “Aleksandrovska,” Medical University-Sofia, 1 G. Sofiiski, Sofia 1431, Bulgaria • kristina_semkova@yahoo.com
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Figure 1. Clinical types of infantile hemangiomas. Localized superficial early proliferative (a). Localized superficial proliferative (b). Localized nodular (c). Undetermined mixed superficial and deep (d). Segmental (e).
The most common complication of IHs is ulceration, which occurs with an incidence of 15% to 25%, at a median age of 4 months. Early grey-white discoloration has been found to be a predictive sign for impending ulceration and a sign of forthcoming nasal cartilage destruction in columella involvement.8,9
velopment and evolution of IHs. Whether these are a result of embolization of placental cells, increased angiogenic and/or vasculogenic activity, tissue hypoxya or an intricate combination of all known and still unknown mechanisms, is yet to be elucidated.
Pathogenesis
Role of the placenta
Clinical and basic molecular studies have provided much new information on IHs over the past several years. Still, the complete pathogenetic cascade remains unknown. Clinical characteristics such as the non-random distribution, the inevitable proliferation-involution life cycle, and the morphology of the precursor lesions give clues to the pathogenesis and allow for targeted cellular and molecular research.
The idea of placental origin caused by embolization of placental stem cells to receptive fetal tissues during gestation is vastly supported by the unique immunohistochemical similarities between the placenta and IHs. IH endothelium coexpresses with placental microvasculature-specific surface markers such as glucose-transporter protein 1 (GLUT-1), Lewis Y antigen (CD14), CD32, CD15, merosin, and indoleamine 2,3-deoxygenase (IDO).10,11 Moreover, these proteins are not found in other vascular anomalies and nonhemangioma tumor vasculature.
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Additional evidence for placental origin is provided by a genomebased analysis comparing transcriptomes of placenta and hemangioma by hierarchical and nonhierarchical clustering analysis of >7,800 genes.11 The level of similarity between placenta and IHs in this study was strikingly high and paralleled that observed between a given tissue and its derived tumor. The correlation was remarkably higher for a subset of endothelial-specific genes and the similarity of hemangioma to placental samples exceeded that among placental samples themselves. Placental origin could well explain the programmed lifespan of IHs that resembles the natural progression of the placenta with initial proliferation followed by a subsequent stable phase. Transcervical chorionic villus sampling is associated with a significantly increased incidence of IHs.12,13 The most likely reason for this relation is the increased number of placental cells into the fetal circulation following tissue trauma. Placental abnormalities that may result in shedding of placental cells also lead to a higher risk of hemangioma development.14,15 Several studies, however, question the maternal origin of hemangioma endothelial cells. No evidence for maternal-fetal microchimerism was detected via fluorescent in-situ hybridization on surgical specimens of infantile hemangiomas.16,17 Nevertheless, the placenta has both a maternal and a fetal component and hemangioma endothelium cells might be derived from any of these two. The restricted sample of the above-mentioned studies does not allow for strong conclusions, but they should be taken into consideration. Angiogenesis and/or vasculogenesis IHs have long been considered a disease of abnormal angiogenesis because of the disorganized and rapid growth of blood vessels and the presence of hemangioma endothelial progenitor cells (HemEPCs) along with angiogenic factors such as basic fibroblast growth factor and vascular endothelial growth factor A (VEGF-A) within the tumor.18 The recent finding of hemangioma-derived stem cells (HemSCs),19 however, favors an alternative concept of initial de novo formation of vessels, ie, vasculogenesis, with further angiogenesis. HemEPCs were isolated from proliferating hemangiomas and defined as potential precursors of hemangioma endothelial cells (HemECs) by coexpression of the human stem cell marker CD133 and the endothelial marker CD34.20 HemEPCs, HemECs, and cord blood EPCs proved to be similar in in vitro assays including mRNA transcriptional profiling for expression of cell-cell and cell-matrix adhesion molecules.18 Additionally, an increased number of circulating CD133+/CD34+ EPCs in SKINmed. 2013;11:341–349
children with hemangioma has been reported.21 Whether these cells are recruited into proliferating hemangiomas or generated locally is yet to be elucidated, but their contributory role to promote angiogenesis in tumor formation is further confirmed by their decreasing count with involution.20,21 Hemangioma-derived stem cells HemSCs are multipotent progenitor-like cells that have both proliferative and clonogenic ability and multi-lineage differentiation potential.19 Current evidence suggests that all cell lines detected in IHs, including HemEPCs, very likely originate from these cells. HemSCs express CD90, VEGFR-1/Flt-1, and neuropilin-1, but do not express the endothelial markers CD31/PECAM-1 or VE-cadherin. Their further differentiation into ECs, however, is characterized by cell surface CD31 expression and retained vasculogenic activity when implanted into secondary recipients. The stem cell origin of IHs is further supported by the ability of hemangioma cells to form labeled non-murine–derived adipocytes in a murine model.19 Involution of IHs results in a fibro-fatty deposition that was thought until recently to be caused by recruitment of mesenchymal stem cells from bone marrow or/and adjacent niches.22 Recent studies have shown that hemangioma endothelial cells coexpress primitive mesodermal, mesenchymal, and neural crest markers and might differentiate into mesenchymal cells to form the fibro-fatty tissue. Investigators reported that hemangioma endothelial cells express neurotrophin receptor (p75), a cell surface marker identifying neural crest cells, brachyury, a transcription factor in cells of the primitive mesoderm23 and the mesenchymal stem cell markers, CD29 and vimentin.24 Furthermore, strong expression of preadipocyte factor-1 (Pref-1), an epidermal-growth factor-like inhibitor of terminal adipocyte differentiation in premesenchymal cells, was detected in the endothelial layer cells of proliferating, but not in involuted IH.24 These findings are suggestive of a primitive mesodermal origin of the capillary endothelium of IHs. Terminal mesenchymal differentiation is most probably inhibited during the proliferative phase by Pref-1 and angiotensin II, and downregulation of these cytokines at a later stage might account for a default adipogenesis during involution, as shown in cultures of hemangioma endothelial cells recovered from IH explants.24 Signaling pathways Abnormalities in a novel pathway of regulation of VEGF-A signaling in HemECs cells were recently found to be a major underlying factor for the occurrence of IHs. Reduced VEGFbinding VEGF receptor (VEGFR) 1 “decoy” function results in a constitutive VEGF-dependent activation of VEGFR2 and downstream signaling triggering angiogenesis.25 VEGFR1 tran-
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scription in microvascular endothelial cells is controlled by the VEGFR2/TEM8/β1 integrin complex through an NFAT-dependent mechanism. The low-level expression of VEGFR1 was attributed to suppressed NFAT activation due to abnormalities in this complex. Investigators provided evidence that some patients with hemangioma carry heterozygous germ-line missense mutations in the genes for VEGFR2 or TEM8. Somatic mutations in a phosphatase have also been described in sporadic hemangioma specimens and it was hypothesized that somatic mutations might trigger hemangioma formation in patients with an underlying germline mutation.26,27 An alternative theory is that reversible pathophysiological events, including hypoxia and placental emboli, trigger hemangioma formation by stressing the VEGFR2/TEM8/β1 integrin-dependent VEGFR1 control mechanisms.26 Tissue hypoxia A precursor lesion may be found in as many as half of IHs. Most commonly it is a pale or blanched area with or without teleangiectasia, clinically suggestive of tissue hypoxia. Recent studies have shown an association between placental ischemic abnormalities and an increased incidence of IHs.15,28 Placental insufficiency usually results in low birth weight, which is a well established risk factor for development of localized hemangiomas.29 Low levels of oxygen prompt cells to modify gene expression, stimulating the growth of new vessels as a survival mechanism. The major regulator of the cellular response to tissue hypoxia is the hypoxia-inducible factor 1α, which upregulates several proteins known to be associated with his—VEGF, GLUT-1, and insulin growth factor-2.14,30 GLUT-1 is a specific marker of IHs and is expressed normally only by microvasscular endothelia at sites of blood-tissue barriers, such as the placenta.31 Investigators showed that in tissue cultures of monocyte-derived endothelial-like cells hypoxia induces a 14-fold increase in GLUT-1 that persists for 2 days after normoxic recovery.32 The highly increased levels of GLUT-1 enhance glucolysis and facilitate proliferation. In vitro studies have shown that estrogens and hypoxia have synergistic effect to stimulate hemangioma endothelial cell proliferation.21 This could be the explanation for the female predominance of IHs. An additional hypoxia-favoring finding is the currently recognized strong association between IHs and the retinopathy of prematury (ROP). ROP is an ischemic retinopathy caused by abnormal hypoxia-triggered neovascularization.33 IHs and ROP share the same microscopic and epidemiologic features. SKINmed. 2013;11:341–349
Two major hypoxia-related pathways have been suggested as important for the development of IHs.33 Generalized pre-delivery hypoxia in placental insufficiency or preeclamsia is a potential risk factor for the occurrence of small, localized hemangiomas, while regional hypoxia secondary to abnormal vasculature carries a risk for segmental hemangiomas. The different timing and type of hypoxic stimuli most probably account for a different timing of deposition of precursor cells and hence a different characteristic pattern of tissue involvement.3 Involution Notwithstanding the current scientific advancement that helps to partly elucidate the origin of IHs, the mechanisms responsible for the inevitable involution are still vague. Apoptosis is enhanced in involuting compared with proliferative lesions, but the exact apoptotic triggers still remain unknown. Whether involution is a passive process due to the programmed lifespan of HemECs similar to the placenta or an active process of immune cells recruitment is yet to be found. Loss of various critical proliferation proteins has been proposed to play a role in a passive involution, one of them being IDO that protects IHs from immune surveillance. Investigators showed that HemECs undergo a spontaneous differentiation to adipocytes with time that correlates with a loss of Pref-1 expression.24 A recruitment of VEGFR1-expressing CD45-positive myeloid cells into the tumor was recently suggested as a contributory mechanism for involution through reduction of VEGF and subsequent reduction of VEGFR2 signaling activation.26 Treatment The characteristic course of natural involution of IHs is the reason for the wide acceptance of “active nonintervention” as the primary approach for the majority of IHs. Treatment is warranted to prevent or improve scarring or disfigurement and functional and life-threatening complications.34 Until recently, the treatment repertoire was limited to relatively aggressive systemic therapy (corticosteroids, interferon, chemotherapeutics), topical therapies such as steroids and imiquimod, and laser and surgical interventions. Nevertheless, since propranolol, a nonselective β-blocker, was serendipitously found to be highly effective for the treatment of IHs in both the proliferative and involution phase, it has become the standard of care in many centers worldwide (Table). Systemic corticosteroids Corticosteroids have been the mainstay of treatment for IHs for many years and several dermatologists still prefer them as
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Table. Treatment Options for Infantile Hemangiomas: A Phase-Specific Approach Proliferation
Involution
Large, life- and function-threatening or deforming infantile hemangiomas
Systemic β-blockers Systemic corticosteroids Intralesional corticosteroids Laser treatments Surgical intervention Interferon-α Vincristine
Systemic β-blockers Laser treatments Surgical intervention
Small, cosmetically disfiguring infantile hemangiomas
Topical β-blockers Topical corticosteroids Imiquimod
Topical β-blockers Laser treatments Surgical intervention
a more predictable and better known alternative to β-blockers. The main advantage of corticosteroids over other treatments is the long-term experience in IHs. Nevertheless, their potential side effects, including adrenal insufficiency, diabetes, osteoporosis, and cataracts, have always been a concern when considering this therapeutic option, even without a huge body of evidence for such events in the literature.35 Corticosteroids inhibit the expression of VEGF-A, monocyte chemoattractant protein-1, urokinase plasminogen activator receptor, and interleukin 6 by targeting the NF-κB in HemSCs, but not in HemECs in a murine model and in vitro.36,37 Downregulation of VEGF-A in these cells translates into vasculogenesis inhibition in vivo. This may explain the higher rates of effectiveness in the early proliferative phase when the ratio of immature stem cells to mature endothelial cells is higher. Corticosteroids are suggested to be effective and safe when dosed properly, administered for an adequately long period, and when a positive response is recognized as a stabilization, and not only a reduction, in tumor size.35 The optimal dose is 3 mg/kg per day, tapered gradually every 2 to 4 weeks to avoid rebound and discontinued after the proliferation phase at the age of 9 to 12 months. The reported effectiveness, even with optimal dosing, is between 30% and 60% and the therapeutic effect is noted after the 2nd or 3rd week.38 Long-term systemic side effects are quite uncommon because of the relatively short course and the dose waning, but the potential for serious cardiac events should be taken into consideration. Oral steroids have more clinical and biological benefits over pulse steroids, but with an increased risk of side effects.39 Very few recent studies evaluate the safety of systemic corticosteroids in the context of IHs. Researchers studied the prevalence of adrenal insufficiency in 18 children with IHs treated with prednisolone at a starting dose of 2 to 3 mg/kg per day for 4 weeks, followed by a tapering period, for a mean duration SKINmed. 2013;11:341–349
of 7.2 months.40 Only one patient showed abnormal results on corticotropin testing that were reversed to normal 3 months after discontinuation. These data suggest that the risk of long-standing adrenal suppression is relatively low and, although existent, should not be a reason to neglect this treatment modality. Immunosuppression was assessed in another study that showed a significant reduction in the numbers and function of all Band T-lymphocyte subpopulations after corticosteroid administration. Compared with baseline, CD19(+) B lymphocytes, CD4(+) T cells, and CD8(+) T cells were significantly reduced after 8 to 16 weeks of therapy. Protective diphtheria titers and tetanus titers were also decreased. The authors recommend prophylaxis with trimethoprim/sulfamethoxazole and tetanus and diphtheria antibodies checks with a consideration for an additional immunization in these patients; however, the clinical implications of these results are debatable as no increased risk of infections has been shown in children receiving systemic corticosteroids for IHs.35 Systemic beta-blockers Propranolol is a well-known, nonselective β-adrenergic antagonist that competitively inhibits the β1- and β2-adrenoreceptors expressed on endothelial cells. It has been used in pediatric cardiology for more than 40 years. Its antiproliferative effect in IH has was observed in 2008 while managing a secondary hypertrophic obstructive cardiomyopathy induced by systemic corticosteroid treatment for a nasal capillary IH.41 This first report of the index case was followed by numerous reports and case series of remarkable efficacy and good safety, and propranolol has since become the first choice of therapy for complicated and/or large IHs. Even so, currently there is not a generally accepted concept regarding the exact mechanism of action or a standardized application protocol.
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Rapid regression with propranolol 2 to 3 mg/kg per day was observed in segmental and complicated cutaneous hemangiomas42; airway hemangiomas43; vision affecting periorbital and orbital hemangiomas44,45; posterior fossa abnormalities, facial hemangioma, arterial abnormalities, cardiac and aortic defects, eye anomalies, and sternal agenesia (PHACES)46,47; hepatic hemangiomas48,49; and hemangiomatosis.50 Propranolol is similarly effective in involuting hemangiomas and could be used in patients who fail to respond to other active interventions during the proliferative phase or have not sought adequate early therapy.51 The safety profile of propranolol is relatively benign and wellknown as a result of its long-term use as chronic therapy for children with hypertension and cardiovascular diseases, with no fatalities reported in the literature thus far.52 Most adverse events are expected and caused by receptor blockade, but the risk of toxicity cannot be predicted because bioavailability of propranolol in children is inconsistent and not dose-related.53 In children with IHs taking propranolol, the adverse events most commonly reported are hypotension, sinus bradycardia, hypoglycemia, and bronchospasm that are not life-threatening but require patient monitoring at baseline and during treatment.54 Other minor side effects include restless sleep, nightmares, agitation, constipation, and cold legs.38,55 Special attention is required in patients at risk for cardiac compromise, including patients with very large hemangiomas; PHACES syndrome; perineal hemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag (PELVIS) syndrome; and miliary hemangiomatosis.54 Physicians prescribing propranolol to infants with IHs should be aware of the signs and symptoms of hypoglycemia and of risk-decreasing measures such as feeding after dosing and dose adjustment/discontinuation during illness or periods of restricted food intake.56,57 Treatment should be started after baseline investigations at a lower dose that is gradually increased to 2 to 3 mg/kg per day divided into 3 applications. The recommended starting dose is 0.17 mg/kg for 2 administrations, followed by doubling of the dose after every 2 administrations until the optimal dosing is reached.54 Nevertheless, some authors58 do not support initiation of treatment at lower doses since, on one hand, the therapeutic dose of 2 to 3 mg/kg per day is already at the low end of the dosing range and, on the other, propranolol side effects are not doserelated.53 Dosing is revised periodically to reflect weight gain in the child. Baseline monitoring should include examination of vital signs (heart rate, blood pressure, weight), history of respiratory problems, and a thorough cardiology evaluation including a detailed cardiovascular history, physical examination, and electrocardiography and/or echocardiogram at discretion of the SKINmed. 2013;11:341–349
cardiologist.53,58 During treatment, monitoring is focused on the commonest problems associated with propranolol administration. Heart rate and blood pressure should be measured hourly for 3 hours after dosing, as the maximum decreases are usually observed at 2 hours after dosing.58 Caution is advised for signs and symptoms of hypoglycemia, but routine blood glucose measurements are not required.56,57,58 Therapy should be administered until the end of the proliferative phase, but treatment duration depends on the individual response. Several months are usually required until full effect is attained. Since chronic use of propranolol results in upregulation of the β-receptors, the treatment should be discontinued in a tapering fashion during a 2-week period to prevent a withdrawal syndrome.58 The current knowledge of the mechanism of action of propranolol in IHs is incomplete. Three different pharmacodynamic characteristics are thought to be important for its effectiveness at different stages. These are early vasoconstriction, angiogenesis inhibition, and apoptosis induction. Clinically, these mechanisms translate into early change of surface color within the first 24 or 72 hours, growth arrest, and regression, respectively.30 Acebutalol, a selective β1-blocker, has been advocated as a similarly effective and less toxic alternative to propranolol. Researchers reported four 4 of steroid-resistant IHs with good response to acebutalol 10 mg/kg per day. Further, 3 cases of effective treatment of subglottic and cutaneous hemangiomas with acebutalol 8 mg/kg have been reported.59 Despite these promising results, no definite recommendations or conclusions can be drawn without a trial in a larger population. Topical Beta-blockers Timolol maleate, a topically applied β-blocker licensed for treatment of open-angle glaucoma, has been reported to be effective for small, superficial IHs in few case reports/series.53,60 Dramatic response to timolol 0.5% solution has also been observed in a patient with a hemifacial hemangioma associated with PHACES syndrome.61 Patients taking topical timolol with suboptimal response after 2 to 6 weeks or lesions that grow regardless of treatment could be switched to oral propranolol.53 The systemic bioavailability of timolol after application in the eye is about 50% in healthy volunteers. Reported side effects after glaucoma treatment in children include drowsiness, bradycardia, pruritus, Cheyne-Stokes breathing, apnea, and serious exacerbation of underlying asthma.62 The pharmacokinetics of cutaneous application has not been studied in detail and, although systemic absorption is a possibility for each topical formulation and the
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Figure 2. Treatment of infantile hemangiomas with topical timolol 0.1% gel before start of therapy (age 3 months; a). Regression after 8 weeks of treatment (age 5 months; b).
ophthalmic administration could have systemic side effects,63 so far timolol has not shown any adverse reactions when used to treat his.53,60 Larger prospective studies are necessary, however, to assess the actual level of toxicity after cutaneous application and until more safety data are available, treating specialists should be alert to all known β-blocker side effects and monitor infants respectively.
tive phase (in 83.1%).65 Treatment is important because tissue destruction leads to an increased risk of local and systemic infections, bleeding, pain, and scarring.64,65 Conventional therapeutic options include wound care, topical antiseptics and antibiotics, systemic and intralesional corticosteroids, lasers, and vincristine and interferon-α in severe cases.
Our experience from a prospective study, including 21 infants (age 3–17 months), shows that topical timolol maleate is effective in treating indicated cutaneous IHs, both in the proliferative and involution phase (unpublished data) (Figure 2). It may be recommended as a relatively safe and effective treatment for superficial, plaque-like, small IHs without a deep component. The therapeutic course should be between 3 and 6 months, depending on the response. Other types of hemangiomas, including nodular lesions, IHs spreading over a wide area, or segmental hemangiomas could also benefit from topical β-blockers with a longer duration of treatment and consideration for a switch to systemic therapy in case of uncontrolled proliferation or persistent ulcerations.
Oral propranol in the standard dose was shown to reduce the duration of ulceration by a factor of almost 2.5 when compared with matched untreated controls.66 The mean time of healing with propranolol is about 4 weeks and depends on the size and location.66,67 The literature data are enough to recommend propranolol as a treatment of first choice for ulcerating IHs, although there are reports of suboptimal or lack of response regardless of the optimal dosing of administering propranolol.42
The relatively low toxicity and high efficacy suggest that topical timolol, applied several times daily, is a good candidate for first-line treatment for superficial IHs when parents prefer active treatment rather than active nonintervention and for larger IHs when parents opt out of systemic treatment for their children. Treatment of ulcerations Ulceration is the most common complication of IHs and occurs in up to about 16% of all patients,64 mostly during the proliferaSKINmed. 2013;11:341–349
Conclusions Much has been learned about IHs in the past couple of years. Careful studies of tissue morphology and gene expression have unraveled some of the cellular and molecular grounds of these common still puzzling tumors. All these findings, however, are still insufficient to arrange the puzzle. Future studies should answer the great number of pending questions. What is the exact role of the placenta? Is a specific genetic background sufficient for the occurrence of IHs or does it need an external trigger, such as hypoxia? What promotes the switch from proliferation to involution? Are there any predictive factors of growth and behavior that could help determine the best individual treatment? Answering all these questions and understanding the etiopathogenesis could provide new options for targeted treatment and prophylaxis. Knowing the risk
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factors for IHs would help physicians with early monitoring, parent education, and adequate treatment before or at the beginning of the proliferative phase. New treatment modalities have recently been introduced with high rates of success and even higher rates of enthusiasm. All new therapies should be used with caution and assessed in comparison to standards of care in terms of benefits and risks. Clinical trials are necessary to evaluate the safety and efficacy of topical treatments, β-blockers vs systemic corticosteroids, propranolol vs acebutalol, and systemic therapies vs lasers and surgery. References 1 Hassanein AH, Mulliken JB, Fishman SJ, Greene AK. Evaluation of terminology for vascular anomalies in current literature. Plast Reconstr Surg. 2011;127:347–351.
16 Pittman KM, Losken HW, Kleinman ME, et al. No evidence for maternal-fetal microchimerism in infantile hemangioma: a molecular genetic investigation. J Invest Dermatol. 2006;126:2533–2538. 17 Régnier S, Dupin N, Le Danff C, et al. Endothelial cells in infantile haemangiomas originate from the child and not from the mother (a fluorescence in situ hybridization-based study). Br J Dermatol. 2007;157:158–160. 18 Boscolo E, Bischoff J. Vasculogenesis in infantile hemangioma. Angiogenesis. 2009;12:197–207. 19 Khan ZA, Boscolo E, Picard A, et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest. 2008;118:2592–2599. 20 Yu Y, Flint AF, Mulliken JB, et al. Endothelial progenitor cells in infantile hemangioma. Blood. 2004;103:1373–1375.
2 Hochman M, Adams DM, Reeves TD. Current knowledge and management of vascular anomalies: I. Hemangiomas. Arch Facial Plast Surg. 2011;13:145–151.
21 Kleinman ME, Greives MR, Churgin SS, et al. Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma. Arterioscler Thromb Vasc Biol. 2007;27:2664–2670.
3 Waner M, North PE, Scherer KA, et al. The nonrandom distribution of facial hemangiomas. Arch Dermatol. 2003;139:869– 875.
22 Yu Y, Fuhr J, Boye E, et al. Mesenchymal stem cells and adipogenesis in hemangioma involution. Stem Cells. 2006;24:1605–1612.
4 Bauland CG, Lüning TH, Smit JM, et al. Untreated hemangiomas: growth pattern and residual lesions. Plast Reconstr Surg. 2011;127:1643–1648.
23 Itinteang T, Tan ST, Brasch H, Day DJ. Primitive mesodermal cells with a neural crest stem cell phenotype predominate proliferating infantile haemangioma. J Clin Pathol. 2010;63:771–776.
5 Chang LC, Haggstrom AN, Drolet BA, et al. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics. 2008;122:360–367. 6 Suh K-Y, Frieden IJ. Infantile hemangiomas with minimal or arrested growth: a retrospective case series. Arch Dermatol. 2010;146:971–976. 7 Brandling-Bennett HA, Metry DW, Baselga E, et al. Infantile hemangiomas with unusually prolonged growth phase: a case series. Arch Dermatol. 2008;144:1632–1637. 8 Maguiness SM, Hoffman WY, McCalmont TH, Frieden IJ. Early white discoloration of infantile hemangioma: a sign of impending ulceration. Arch Dermatol. 2010;146:1235–1239. 9 Wright DR, Russi DC, Mancini AJ, et al. The nasal crease sign in segmental facial hemangioma–an early sign of cartilage destruction. Pediatr Dermatol. 2007;24:241–245.
24 Itinteang T, Vishvanath A, Day DJ, Tan ST. Mesenchymal stem cells in infantile haemangioma. J Clin Pathol. 2011;64:232– 236. 25 Jinnin M, Medici D, Park L, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008;14:1236–1246. 26 Boye E, Olsen BR. Signaling mechanisms in infantile hemangioma. Curr Opin Hematol. 2009;16:202–208. 27 Jinnin M, Ishihara T, Boye E, Olsen BR. Recent progress in studies of infantile hemangioma. J Dermatol. 2010;37:939–955. 28 Colonna V, Resta L, Napoli A, Bonifazi E. Placental hypoxia and neonatal haemangioma: clinical and histological observations. Br J Dermatol. 2010;162:208–209.
10 North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137:559–570.
29 Drolet BA, Swanson EA, Frieden IJ; Hemangioma Investigator Group. Infantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants. J Pediatr. 2008;153:712–715, 715.e1.
11 Barnés CM, Huang S, Kaipainen A, et al. Evidence by molecular profiling for a placental origin of infantile hemangioma. Proc Natl Acad Sci USA. 2005;102:19097–19102.
30 Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol. 2010;163:269–274.
12 Bauland CG, Smit JM, Bartelink LR, et al. Hemangioma in the newborn: increased incidence after chorionic villus sampling. Prenat Diagn. 2010;30:913–917.
31 North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol. 2000;31:11–22.
13 Holmes LB. Chorionic villus sampling and hemangiomas. J Craniofac Surg. 2009;20 suppl 1:675–677. 14 Ritter MR, Butschek RA, Friedlander M, Friedlander SF. Pathogenesis of infantile haemangioma: new molecular and cellular insights. Expert Rev Mol Med. 2007;9:1–19.
32 Herbert A, Ng H, Jessup W, et al. Hypoxia regulates the production and activity of glucose transporter-1 and indoleamine 2,3-dioxygenase in monocyte-derived endothelial-like cells: possible relevance to infantile haemangioma pathogenesis. Br J Dermatol. 2011;164:308–315.
15 López Gutiérrez JC, Avila LF, Sosa G, Patron M. Placental anomalies in children with infantile hemangioma. Pediatr Dermatol. 2007;24:353–355.
33 Drolet BA, Frieden IJ. Characteristics of infantile hemangiomas as clues to pathogenesis: does hypoxia connect the dots? Arch Dermatol. 2010;146:1295–1299.
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34 Maguiness SM, Frieden IJ. Current management of infantile hemangiomas. Semin Cutan Med Surg. 2010;29:106–114. 35 AK, Greene. Systemic corticosteroid is effective and safe treatment for problematic infantile hemangioma. Pediatr Dermatol. 2010;27:322–323.
51 O’Loughlin A, O’Donnell B, Watson R. Mature infantile haemangiomas role for propranolol. J Eur Acad Dermatol Venereol. 2010;25:1363–1364. 52 Love JN, Sikka N. Are 1-2 tablets dangerous? Beta-blocker exposure in toddlers. J Emerg Med. 2004;26:309–314.
36 Greenberger S, Boscolo E, Adini I, et al. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med. 2010;362:1005–1013.
53 Blatt J, Morrell DS, Buck S, et al. β-Blockers for infantile hemangiomas: a single-institution experience. Clin Pediatr (Phila). 2011;50:757–763.
37 Greenberger S, Adini I, Boscolo E, et al. Targeting NF-κB in infantile hemangioma-derived stem cells reduces VEGF-A expression. Angiogenesis. 2010;13:327–335.
54 Lawley LP, Siegfried E, Todd JL. Propranolol treatment for hemangioma of infancy: risks and recommendations. Pediatr Dermatol. 2009;26:610–614.
38 Sans V, de la Roque ED, Berge J, et al. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics. 2009;124:e423–e431.
55 de Graaf M, M P J Breur J, Raphaël MF, et al. Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants. J Am Acad Dermatol. 2011;65:320–327.
39 Pope E, Krafchik BR, Macarthur C, et al. Oral versus high-dose pulse corticosteroids for problematic infantile hemangiomas: a randomized, controlled trial. Pediatrics. 2007;119:e1239–e1247. 40 Lomenick JP, Reifschneider KL, Lucky AW, et al. Prevalence of adrenal insufficiency following systemic glucocorticoid therapy in infants with hemangiomas. Arch Dermatol. 2009;145:262–266. 41 Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–2651. 42 Manunza F, Syed S, Laguda B, et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants. Br J Dermatol. 2010;162:466–468. 43 Peridis S, Pilgrim G, Athanasopoulos I, Parpounas K. A meta-analysis on the effectiveness of propranolol for the treatment of infantile airway haemangiomas. Int J Pediatr Otorhinolaryngol. 2011;75:455–460. 44 Claerhout I, Buijsrogge M, Delbeke P, et al. The use of propranolol in the treatment of periocular infantile haemangiomas: a review. Br J Ophthalmol. 2010;95:1199– 1202. 45 Fay A, Nguyen J, Jakobiec FA, et al. Propranolol for isolated orbital infantile hemangioma. Arch Ophthalmol. 2010;128:256–258. 46 Denoyelle F, Leboulanger N, Enjolras O, et al. Role of Propranolol in the therapeutic strategy of infantile laryngotracheal hemangioma. Int J Pediatr Otorhinolaryngol. 2009;73:1168–1172.
56 Holland KE, Frieden IJ, Frommelt PC, et al. Hypoglycemia in children taking propranolol for the treatment of infantile hemangioma. Arch Dermatol. 2010;146:775–778. 57 Bonifazi E, Acquafredda A, Milano A, et al. Severe hypoglycemia during successful treatment of diffuse hemangiomatosis with propranolol. Pediatr Dermatol. 2010;27:195– 196. 58 Cushing SL, Boucek RJ, Manning SC, et al. Initial experience with a multidisciplinary strategy for initiation of propranolol therapy for infantile hemangiomas. Otolaryngol Head Neck Surg. 2011;144:78–84. 59 Blanchet C, Nicollas R, Bigorre M, et al. Management of infantile subglottic hemangioma: acebutolol or propranolol? Int J Pediatr Otorhinolaryngol. 2010;74:959–961. 60 Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol. 2010;146:564– 565. 61 Khunger N, Pahwa M. Dramatic response to topical timolol lotion of a large hemifacial infantile haemangioma associated with PHACE syndrome. Br J Dermatol. 2011;164:886–888. 62 Zimmerman TJ, Kooner KS, Morgan KS. Safety and efficacy of timolol in pediatric glaucoma. Surv Ophthalmol. 1983;28:262–264. 63 Volotinen M, Hakkola J, Pelkonen O, et al. Metabolism of ophthalmic timolol: new aspects of an old drug. Basic Clin Pharmacol Toxicol. 2011;108:297–303.
47 Theletsane T, Redfern A, Raynham O, et al. Life-threatening infantile haemangioma: a dramatic response to propranolol. J Eur Acad Dermatol Venereol. 2009;23:1465–1466.
64 Chamlin SL, Haggstrom AN, Drolet BA, et al. Multicenter prospective study of ulcerated hemangiomas. J Pediatr. 2007;151:684–689.
48 Muthamilselvan S, Vinoth PN, Vilvanathan V, et al. Hepatic haemangioma of infancy: role of propranolol. Ann Trop Paediatr. 2010;30:335–338.
65 Hermans DJ, Boezeman JB, Van de Kerkhof PC, et al. Differences between ulcerated and non-ulcerated hemangiomas, a retrospective study of 465 cases. Eur J Dermatol. 2009;19:152–156.
49 Sarialioglu F, Erbay A, Demir S. Response of infantile hepatic hemangioma to propranolol resistant to high-dose methylprednisolone and interferon-α therapy. Pediatr Blood Cancer. 2010;15:1433–1434. 50 Mazereeuw-Hautier J, Hoeger PH, Benlahrech S, et al. Efficacy of Propranolol in hepatic infantile hemangiomas with diffuse neonatal hemangiomatosis. J Pediatr. 2010;157:340–342.
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66 Hermans DJ, van Beynum IM, Schultze Kool LJ, et al. Propranolol, a very promising treatment for ulceration in infantile hemangiomas: a study of 20 cases with matched historical controls. J Am Acad Dermatol. 2011;64:833–838. 67 Naouri M, Schill T, Maruani A, et al. Successful treatment of ulcerated haemangioma with propranolol. J Eur Acad Dermatol Venereol. 2010;24:1109–1112.
What’s New in Infantile Hemangiomas
Edward L. Keyes Resident Contest for Outstanding Case Reports To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 10th World Congress of the International Academy of Cosmetic Dermatology in Rio de Janeiro, Brazil, July 18-20, 2014. We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The author whose abstract receives the highest score during the review process will be awarded a scholarship by the IACD to present the full paper at the 10th World Congress of the International Academy of Cosmetic Dermatology in Rio de Janeiro, Brazil, July 18-20, 2014. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Abstracts should be submitted via email to vrosic@medicine.bsd.uchicago. edu before noon, CDT, March 15, 2014 via e-mail and should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thought-out, and complete presentation. The winner(s) will publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. All applicants will receive e-mail notice of the Resident Case Report Review Committeeâ&#x20AC;&#x2122;s decision by May 1, 2014. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Associate Professor Ambulatory Practice Medical Director University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu
Official publication of IACD
November/December 2013
Volume 11 • Issue 6
Perils of Dermatopathology W. Clark Lambert, MD, PhD, Section Editor
Location, Location, Location: Proper Site Selection and Use of Direct Immunofluorescence Testing Basil Patel, BS;1 Cindy Wassef, BS;1 Divya Sharma, BS;1 Kiran Mian, BS;2 W. Clark Lambert MD, PhD3 There is a story of a drunkard searching under a street lamp for his house key, which he had dropped some distance away. Asked why he didn’t look where he had dropped it, he replied, “It’s lighter here.”—Coined the “principle of the drunkard’s search” by Abraham Kaplan in The Conduct of Inquiry (1964)
D
irect immunofluorescence (DIF) is a technique that detects the presence of immunoglobulins and complement components. By using antibodies tagged with a fluorophore such as fluorescein isothiocyanate (FITC) and a fluorescence microscope, their deposition in specific locations as they bind to the target antigens may be observed.1 A differential diagnosis can be made based on the primary location of antibody deposition, the primary deposited antibody type, any secondary antibody types or deposition locations, and the pattern of deposition.2 In this fashion, DIF is commonly used as a diagnostic tool for various autoimmune blistering diseases such as pemphigus and dermatitis herpetiformis, as well as for vasculitis and subtypes of lupus erythematosus.2 False Negatives To minimize false negatives obtained from DIF, care must be taken to retrieve the biopsy specimen from the appropriate anatomic site. For autoimmune blistering diseases, including bullous pemphigoid, pemphigus, linear IgA disease, dermatitis herpetiformis, and epidermolysis bullosa acquisita, the biopsy should be of perilesional unaffected skin.2,3,4 The immune deposits at the lesion itself may be degraded and thus the test more likely to result in a false negative, so lesional biopsies for the purpose of DIF when these diseases are under consideration should be avoided.2 In addition, treatment history should be taken into account. For instance, a patient with dermatitis herpetiformis who has recently been on
a gluten-free diet is more likely to have a negative DIF test result than a patient on a normal diet.5 Immune deposits on vessel walls signaling the presence of vasculitis can be visualized by DIF. For suspected cases of leukocytoclastic vasculitis, a lesion, rather than perilesional tissue, should be biopsied.2 A lesion that has been present no longer than 24 hours should be selected; otherwise, degradation of the immune deposits on the vessel walls may have occurred, resulting in a higher chance of a false-negative result.2 If possible, the lesion should be from a site other than the lower aspects of the legs. Vessel wall immune deposition can be seen on biopsies from these areas in patients unaffected by leukocytoclastic vasculitis; retrieving a biopsy specimen from a different location can reduce the number of falsepositive results.2 Lupus Band Test The lupus band test, which looks for deposition of IgG and IgM at the dermoepidermal junction in DIF, has a high sensitivity for systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE). Lesional skin should be biopsied for the lupus band test in both DLE and SLE.2,6 For suspected cases of DLE, biopsies are most often positive when taken from older, untreated lesions.2 In addition, there is regional variation in the proportion of positive results obtained from DIF of DLE lesions; lesions from the head, neck, and upper extremities are more likely to be positive
From Rutgers University – New Jersey Medical School, Newark, NJ;1 Rowan University – School of Osteopathic Medicine, Stratford, NJ;2 and the Departments of Dermatology and Pathology, Rutgers University – New Jersey Medical School, Newark, NJ3 Address for Correspondence: W. Clark Lambert, MD, PhD, Professor and Director, Dermatopathology, Professor and Associate Head, Dermatology, Rutgers University – New Jersey Medical School, Medical Science Building, Room C520, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu
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Figure 1. Dermatopathology specimen of a bullous pemphigoid lesion. A subepidermal bulla is observed with eosinophils in the dermis. (Hematoxylin and eosin, original magnification ×67.)
Figure 2. Indirect immunofluorescence study of patient’s serum in a case of bullous pemphigoid. The substrate is monkey esophagus. (Immunofluorescence, original magnification ×240.)
than lesions from the trunk.2,7 The lupus band test may also be useful in distinguishing DLE from SLE, since the test is often positive in both involved and uninvolved skin in patients with SLE, whereas it is only positive in involved skin in DLE.8 Sun-exposed uninvolved skin is most likely to return a positive result in SLE, although some experts report that using sun-protected uninvolved skin is also a sensitive, specific measure for SLE.2,6,7
Table. Biopsy Site Selection for Direct Immunofluorescence Testing
Other Recommendations DIF is also useful, in concert with a number of specialized neuropathological stains, in diagnosing dermatomyositis (DM) and/ or myositis. These tests are usually interpreted by subspecialists in neuropathology. Here again, however, the site of the biopsy is critical. Surgeons, when asked to obtain a muscle biopsy without further direction, usually obtain a biopsy of the gastrocnemius muscle, which is virtually never involved in DM, so that all biopsy results tend to be negative. It is far better to obtain a muscle biopsy from the pelvic girdle, especially one of a muscle fiber that has been identified by other means, such as electromyography, to be involved. All immunofluorescence biopsies should be labeled with pertinent information; in the case of DIF, details such as lesional vs perilesional vs uninvolved skin, age of the lesion, anatomic region, and SKINmed. 2013;11:351–353
Suspected Disease
Biopsy Location and Notes
Autoimmune blistering diseases (pemphigoid, pemphigus, linear IgA disease, dermatitis herpetiformis, epidermolysis bullosa acquisita)
Unaffected perilesional skin
Leukocytoclastic vasculitis
Lesion (preferably a new lesion not located on the lower legs)
Discoid lupus erythematosus Systemic lupus erythematosus
Lesion (preferably older, untreated lesion from neck or upper extremity) Uninvolved skin (distinguishes systemic lupus erythematosus from discoid lupus erythematosus); also positive in lesional biopsies
level of sun exposure may be important and should be mentioned accordingly. Recent treatment affects the test results and should be noted as well.
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Conclusions The results of DIF should always be considered in conjunction with other laboratory findings and the overall clinical picture. Other related tests that may be used in concert with DIF are routine histopathology (Figure 1) and indirect immunofluorescence testing. The latter is performed by examining a sample of the patient’s serum, which is layered over a frozen section of an animal substrate, such as monkey esophagus, selected so as to minimize reactivity caused by xenoantigen recognition. This is followed by application of anti-human immunoglobulin or other immune substrate, such as complement, following which the same procedure is used as for DIF (Figure 2). If properly executed and read by a pathologist with the proper expertise, the routine dermatopathology test is the most accurate of these tests, but DIF and indirect immunofluorescence may be very helpful when dermatopathology does not provide a clear diagnosis. References 1 Mohan KH, Sathish P, Raghavendra R, Sripathi H, Prabhu S. Techniques of immunofluorescence and their significance. Indian J Dermatol Venereol Leprol. 2008;74:415–419.
2 Mutasim DF, Adams BB. Immunofluorescence in dermatology. J Am Acad Dermatol. 2001;45:803–824. 3 Zone JJ, Meyer LJ, Petersen MJ. Deposition of granular IgA relative to clinical lesions in dermatitis herpetiformis. Arch Dermatol. 1996;132:912–918. 4 Antsey A, Venning V, Wojnarowska F, Bhogal B, Black MM. Determination of the optimum site for diagnostic biopsy for direct immunofluorescence in bullous pemphigoid. Clin Exp Dermatol. 1990;15:438–441. 5 Alonso-Llamazares J, Gibson LE, Rogers RS. Clinical, pathologic, and immunopathologic features of dermatitis herpetiformis: review of the Mayo Clinic experience. Int J Dermatol. 2007;46:910–919. 6 Monroe E. Lupus band test. Arch Dermatol. 1977;113:830– 834. 7 Weigand DA. Lupus band test: anatomic regional variations in discoid lupus erythematosus. J Am Acad Dermatol. 1986;14:426–428. 8 Reich A, Marcinow K, Bialynicki-Birula R. The lupus band test in systemic lupus erythematosus patients. Ther Clin Risk Manag. 2011;7:27–32.
Historical Diagnosis and treatment Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic Skin Clinic by, Dr S. I. Rainforth.
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November/December 2013
Volume 11 • Issue 6
Photo Capsule
Inverse Lichen Planus Michael D. Lee, MD; Laurel R. Schwartz, MD
A
61-year-old woman presented to the emergency department with a pruritic eruption of 1-weeks’ duration. Erythema was present in her axillae, on her neck, and at the inframammary areas (Figure 1). On physical examination, there were violaceous, shiny, polygonal papules coalescing into plaques in the affected regions (Figure 2). A punch biopsy from the right shoulder area revealed a bandlike infiltrate of lymphocytes, obscuring the dermoepidermal junction, and associated with an epidermis altered by jagged epidermal hyperplasia, foci of hypergranulosis, compact orthokeratosis, and presence of necrotic keratinocytes (Figure 3). This is consistent with a diagnosis of lichen planus in an “inverse” distribution.
The patient was treated with prednisone 20 mg a day for 7 days, then 10 mg a day for 7 days and triamcinolone .1% cream applied twice a day for 1 week with minimal benefit. She is currently undergoing narrowband UV-B treatment as an outpatient. Lichen planus (LP) is a pruritic, papular eruption characterized by its violaceous color and polygonal shape. It is most commonly found on the flexor surfaces of the upper extremities, on the genitalia, and on the mucous membranes. We herein report a classic case of LP in an inverse distribution. A literature search with the search term “inverse lichen planus” was not fruitful. A MEDLINE/PubMed search produced 2 articles, one discussing the entity of inverse lichen planus pigmentosus1 and one historic article2 discussing annular inverse LP in
Figure 1. Inverse distribution of lichen planus.
From the Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA Address for Correspondence: Michael D. Lee, MD, Jefferson Medical College of Thomas Jefferson University, Department of Dermatology and Cutaneous Biology, Philadelphia, PA 19107 • E-mail: mdlee@mdlee.com
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Figure 2. Planar, polygonal, pruritic, purple papules of lichen planus.
Figure 3. Lichen planus in our patient (hematoxylin and eosin stain, original magnification, ×4).
patients from subtropical countries. Our patient does not clinically resemble previously published cases.
References
LP is a disease with classic morphology and the diagnosis of inverse LP appears to have been rendered when LP affects certain locations; however, there does not appear to be significant literature specifically addressing the entity of inverse LP.
1 Pock L, Jelínková L, Drlík L, et al. Lichen planus pigmentosus-inversus. J Eur Acad Dermatol Venereol. 2001;15:452–454. 2 Dostrovsky A, Sagher F. Lichen planus in subtropical countries; study of an annular type with inverse localization (uncovered surfaces of the skin). Arch Dermatol Syphilol. 1949;59:308–328.
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Volume 11 • Issue 6
New to the Clinic Noah Scheinfeld, MD, JD, Section Editor
New Drugs to Treat Hereditary Angioedema Noah Scheinfeld, MD, JD
H
ereditary angioedema (HAE) is a rare (prevalence ~1:10,000–50,000) genetic autosomal-dominant disease. HAE presents as painful and potentially fatal episodic attacks of cutaneous and submucosal edema. Pathophysiology HAE results from functional deficiency of the C1 inhibitor (C1INH). C1-INH is a serine proteinase inhibitor that suppresses production of plasma kallikrein, which generates bradykinin. Thus, C1-INH is a regulator of the complement, fibrinolytic, kinin (contact), and coagulation systems. Coagulation and fibrinolytic systems are activated in HAE patients with an acute angioedema attack. In patients with HAE, the low plasma concentration of functional C1-INH results in overactivation of the kinin cascade and local release of bradykinin. Bradykinin causes the pain, vascular permeability changes, and edema associated with HAE. Clinical Manifestations Patients with HAE experience recurrent and unpredictable angioedema that lasts for 3 to 5 days and typically involves the arms, legs, gastrointestinal tract, genitalia, face, oropharynx, and larynx. Laryngeal edema can be fatal, while its gastrointestinal attacks mimic a surgical abdomen. HAE is a significant physical and psychological burden in patients. Traditional Agents Before the development of the newer agents, HAE was treated with tranexamic acid, which is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin by binding to specific sites of both plasminogen and plasmin. Fibrin is a protein that forms the framework of blood clots. It has roughly 8 times the antifibrinolytic activity of an older analogue, ε-aminocaproic acid.
Antiandrogen therapy also treats HAE. C1-INH, derived from pooled human plasma, has been available for decades in Europe. Attenuated (17α-alkylated) androgens, such as danazol and stanozolol, increase hepatic production of C1-INH and have been used for HAE prophylaxis. Their adverse effects include weight gain, virilization, acne, menstrual irregularities, hepatotoxicity, and lipid abnormalities. Newer Agents Seven drugs have been approved for treatment of HAE worldwide, including.1,2 The agents being reviewed include (1) the plasma-derived C1-INH cinryze was approved in October 2008 by the US Food & Drug Administration (FDA) for prophylaxis of HAE attacks; (2) berinert was FDA approved in October 2009 for the treatment of acute attacks; (3) the kallikrein inhibitor-ecallantide, kalbitor, was FDA approved in November 2009; and (4) icatibant (firazyr), a peptidomimetic drug consisting of 10 amino acids, which is a selective and specific antagonist of bradykinin β2-receptor, was FDA approved in August 2011 for the treatment of acute attacks of HAE. These agents are discussed in brief individually. General Comments on Replacement Therapy In a randomized controlled trial, replacement therapy with C1INH significantly shortened the time to onset of symptom relief in HAE attacks compared with placebo, and similar improvements were consistently reported in observational and descriptive studies accompanied by improvements in patient quality of life. C1-INH has been shown to be effective for patients receiving home therapy and short- and long-term prophylaxis. Drug-to-drug trials of a C1-INH with anabolic androgens for prophylactic treatment of HAE are not available. Both are effective in preventing HAE attacks and decreasing their severity, but breakthrough attacks may occur despite treatment with either
From the Department of Dermatology, Weill Cornell Medical College, New York, NY Address for Correspondence: Noah Scheinfeld, MD, JD, Assistant Clinical Professor of Dermatology at Weil Cornell Medical College, 150 West 55th Street, New York, NY 10021 • E-mail: NSS32@columbia.edu
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product. Androgens cost much less and can be taken orally, but have many side effects and are contraindicated for use in pregnant women and in children.
and 4 hours of infusion of C1-INH NF concentrate, regardless of the site (ie, gastrointestinal, cutaneous, laryngeal, or genitourinary) of the defining symptom.
Berinert
When administered prior to a procedure, open-label intravenous C1-INH NF concentrate 1000 U reduced the incidence of angioedema attacks during and after a variety of dental, surgical, or interventional diagnostic procedures in pediatric and adult patients with HAE. Routine preventive treatment with intravenous C1-INH NF concentrate 1000 U every 3 or 4 days reduced the number of angioedema attacks. In a randomized, double-blind, crossover trial in pediatric and adult patients with HAE, the mean normalized number of attacks per 12-week period was significantly lower during routine prevention with C1INH NF concentrate than with placebo.
Replacement therapy with Berinert (CSL Behring, Marburg, Germany), an intravenous pasteurized C1-INH concentrate derived from human plasma, is a recommended treatment for rapid resolution of acute attacks of HAE caused by C1-INH deficiency.3 The International Multicentre Prospective Angioedema C1-INH Trial 2 (I.M.P.A.C.T.2) was an open-label extension study of I.M.P.A.C.T.1 designed to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary) analyzed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety, and antiâ&#x20AC;&#x201C;C1-INH antibodies. Self-administered home therapy with C1-INH concentrate significantly improved HAE from baseline according to Dermatology Life Quality Index and Short-Form 36-Item Health Survey scores. Dosing for Berinert is 20 U/kg given intravenously. Patients taking intravenous C1-INH HAE tolerated Berinert without any viral transmission.4 Possible side effects of Berinert include nausea, headache, hypersensitivity reactions, abdominal pain, anaphylaxis, and thrombosis, if overdosed. Berinert has a half-life of 21 hours. For a 70-kg patient, the cost of one dose (20 U/kg) of Berinert is $6210. Cinryze Cinryze (ViroPharma Biologics, Inc, Exton, PA), a C1-INH, is given intravenously every 3 or 4 days. Intravenous nanofiltered human C1-INH (C1-INH NF) concentrate (Cinryze) is used as a direct replacement of deficient levels of plasma C1-INH in patients with HAE.4 In the European Union, C1-INH NF concentrate 1000 U is indicated in the treatment, pre-procedural prevention, and routine prevention of angioedema attacks in adults and adolescents with HAE. Intravenous C1-INH NF concentrate 1000 U effectively relieved angioedema attacks in patients with HAE. In a randomized, double-blind trial in pediatric and adult patients, the median time to onset of unequivocal relief from an attack was significantly shorter with C1-INH NF concentrate than with placebo. In an open-label trial, both unequivocal relief and clinical relief were shown in the majority of attacks within 1 SKINmed. 2013;11:357â&#x20AC;&#x201C;359
Routine prevention with C1-INH NF concentrate reduced the median monthly attack rate from baseline in an open-label trial. Intravenous C1-INH NF concentrate was well tolerated in clinical trials in patients with HAE. No cases of viral transmission were reported. Possible side effects associated with Cinryze include sinusitis, dermatitis, upper respiratory tract wheezing, breathing difficulty, chest tightness, turning blue (lips and gums), tachycardia, facial swelling, fainting, dermatitis, and hives, in addition to anaphylaxis, headache, hypersensitivity reactions, anaphylaxis, and thrombosis if over-dosed. Cinryze increases the risk of injection as (1) it suppresses the endotoxic activity of a wide range of lipopolysaccharides and interacts with live gram-negative bacteria, (2) suppresses vascular endothelial activation by inhibiting vascular cell adhesion molecule-1 action, and (3) reduces neutrophil activation in patients with sepsis. Berinert likely has similar immunosuppresive affects. Generally, susceptibility to Staphylococcus aureus nasal carriage is associated with the C1INH V480M polymorphism. The cost of one dose (1000 U) of cinryze is $5040.76. Ecallantide (Kalbitor) Kalbitor (Dyax Corp, Burlington, MA) a recombinant plasma protein kallikrein inhibitor, is given subcutaneously and has a half-life of 2 hours. The cost of one dose of Kalbitor given intravenously (30 mg, administered in three 10-mg injections) is $9540. A single, 30-mg dose of ecallantide was effective for most HAE attacks (88.0%). Patients with peripheral attacks of HAE are more likely to require a second dose of ecallantide after 4 hours. Treatment with ecallantide within 6 hours of symptom onset leads to more rapid and sustained improvement of symptoms. Trials that have tested ecallantide include EDEMA2,
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New Drugs to Treat Hereditary Angioedema
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EDEMA4, and DX-88/19. Up to 4% of patients showed anaphylaxis, which has led to a black box warning in the United States. The FDA approval of Kalbitor was based on the results of two placebo-controlled phase 3 clinical studies, EDEMA3 and EDEMA4. In both trials, the effects of Kalbitor were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS).
EDEMA3 In a 72-patient pivotal study of drug vs placebo, Kalbitor demonstrated a greater decrease from baseline in the MSCS than placebo and a greater TOS than patients treated with placebo; these results were statistically significant. In addition, at 24 hours, more patients in the placebo group (36%) required additional intervention vs 14% in the Kalbitor-treated group (14%).
EDEMA4 In another study of 96 patients, the primary endpoint was change from baseline in MSCS score at 4 hours, and the TOS at 4 hours was a key secondary endpoint. Patients treated with Kalbitor demonstrated a greater decrease from baseline in the MSCS and a greater TOS (P=.003) than placebo; these results were statistically significant. At 24 hours, patients treated with Kalbitor also demonstrated a greater decrease from baseline in MSCS than placebo (–1.5 vs –1.1) and a greater TOS (89 vs 55, P=.03). More patients in the placebo group (50%) vs in the treated group (33%) at 24 hours needed additional intervention.
ma Subcutaneous Treatment [FAST-1] and FAST-3) and with tranexamic acid in the FAST-2 trial. Patients receiving Icatibant in FAST-1 did not experience a significant improvement in median time to clinically significant relief of the index symptom, whereas patients receiving icatibant in FAST-3 experienced a significant improvement in median time to at least 50% reduction in symptom severity. When Icatibant was compared with tranexamic acid in FAST-2, the median time to clinically significant relief of the index symptom was shorter for patients receiving Icatibant (P<.001).8 How it compares with the other 2 drugs approved for treatment of HAE remains to be determined.3 A single dose of Icatabant costs $2427.86. Patients who do not respond to the first dose can receive a second dose and, if necessary, a third, at 6-hour intervals. Conclusions Physicians now have a variety of more effective options to treat HAE, whether for acute attacks (Icatibant, a bradykinin β2antagonist) or Kalbitor (a recombinant plasma protein kallikrein inhibitor). This is true for prophylaxis with the plasma products Cinryze or Berinert. These drugs will save lives. How they play out for angioedmema due to angiotensin-converting enzyme inhibitors and the exact dosing schedules in all patients, obese and thin, with few or many breakouts remains a matter of research. References
Icatibant (Firazyr) (Shire) Icatibant, a C1-INH (really a bradykinin β2-antagonist), is approved for prophylaxis and given intravenously every 3 or 4 days. Icatibant use for acute attacks is supported by strong clinical data. Side effects include nausea, fatigue, diarrhea, pyrexia, headache, hypersensitivity reactions (up to 3.9% of patients), injection reactions, and nasophaynrgitis. In a double-blind randomized trial, clinically significant relief of acute HAE symptoms occurred earlier with Icatibant than with tranexamic acid (2 hours vs 12 hours). In another trial, icatibant was found to have a nonsignificant benefit (2.5 hours vs 4.6 hours) compared with placebo.7 In three phase 3 clinical trials icatibant was found to be a safe and effective option for the treatment of acute HAE. Icatibant was compared with placebo in 2 clinical trials (For Angioede-
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1 Medical Letter. In brief: icatibant (Firazyr) for hereditary angioedema. Med Lett Drugs Ther. 2011;53:96. 2 Three new drugs for hereditary angioedema. Med Lett Drugs Ther. 2010;52:66. 3 Bork K. Human pasteurized C1-inhibitor concentrate for the treatment of hereditary angioedema due to C1-inhibitor deficiency. Expert Rev Clin Immunol. 2011;7:723–733. 4 Keating GM. Human C1-esterase inhibitor concentrate (Berinert). BioDrugs. 2009;23:399–406 5 Craig TJ, Bewtra AK, Bahna SL, et al. C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks—final results of the I.M.P.A.C.T.2 study. Allergy. 2011;66:1604–1611. 6 MacGinnitie AJ, Campion M, Stolz LE, Pullman WE. Ecallantide for treatment of acute hereditary angioedema attacks: analysis of efficacy by patient characteristics. Allergy Asthma Proc. 2012;33:178–85. 7 Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010;363:532–541. 8 Cole SW, Lundquist LM. Icatibant for the treatment of hereditary angioedema. Ann Pharmacother. 2013;47:49– 55.
New Drugs to Treat Hereditary Angioedema
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Soft Tissue Augmentation – Oral Commisures Soft Tissue Augmentation – Lips Soft Tissue Augmentation – Volume Enhancement Editors: Michael H. Gold, MD Lawrence Charles Parish, MD Wm. Philip Werschler, MD
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COMING ALSO IN 2014 TAAG TOXINS
November/December 2013
Volume 11 • Issue 6
COSMETIC SCIENCE Howard A. Epstein, PhD, Section Editor
Will Epigenetics Change Our Approach to Treating Skin Conditions? Howard A. Epstein, PhD
E
pigenetics is the study of heritable changes in gene expression or cellular appearance caused by mechanisms other than changes in the underlying DNA sequence. The cost and time to conduct epigenetic studies continues to decrease, resulting in the publication of numerous papers focused on skin hydration, barrier repair, renewal of the extracellular matrix pigmentation, antioxidant capacity, and certain skin cancers. The effect of epigenetic-stimulating agents may be found in cosmetics, foods, and drugs and are manifested as biological markers that can be detected in the laboratory. Epigenetics play a role in cellular metabolism, wound healing, inflammation, antioxidant synthesis, DNA repair, cancer, and aging. It is an area of active research in the cosmetics industry, and references in published papers suggest that “epigenic therapy” will revise skin care treatments with additional strategies aimed at improving the appearance of skin. Epigenetics—Molecular Component Principles of Epigenetics: Can Skin Conditions be Treated as a Metabolic/ Immunological Disorder?
It is becoming increasingly evident that cell signaling modifies gene expression of critical genes associated with physiologic and pathologic processes. The expression of these genes can be influenced by external or internal environmental factors and lifestyle patterns of individuals. Recent publications in the field of epigenetics suggest that a variety of skin conditions may be improved if treated as a metabolic disorder. Emerging evidence indicates that impaired cellular energy metabolism is the key defining characteristic of nearly all cancers regardless of cellular tissue origin.1 This hypothesis may apply to less serious skin conditions as well. Radiation, chemicals, viruses, and chronic inflammation are associated with a variety of skin conditions including malignancies and the clinical manifestations of aging. Often, a specific cause for skin pathologies may not be evident;
however, there is agreement that oxidative stress and inflammation are a common factor reported in the literature. Prolonged exposure to environmental factors generates excessive expression of proinflammatory genes, leading to alteration of expression and function of other regulating genes with resulting epigenetic loss of expression of antioxidant molecules.2 Chronic inflammation can be significantly reduced by avoiding exposure to conditions that provoke tissue inflammation, such as smoking, alcohol, carcinogenic chemicals, ionizing radiation, and obesity. Part of the associated injury to body tissue includes damage to the mitochrondria. In addition, the metabolism of ketone bodies protects the mitochrondria from inflammation and damaging reactive oxygen species (ROS). Ketone body metabolism is thought to decrease superoxide production and promote destruction of hydrogen peroxide. The reduction of free radicals through ketone body metabolism reduces tissue inflammation provoked by ROS and enhances energy efficiency of mitochrondria. Ketone bodies contain the active groups of respiratory enzymes (iron salts, riboflavin, nicotinamide, and panthothenic acid), when combined with diet energy restriction, may offer a potential approach for treating appropriate skin conditions.1 Stress, Overnutrition, and Inflammation Metabolic and immune pathways have evolved to be closely linked and interdependent. Many hormones, cytokines, signaling proteins, transcription factors, and bioactive lipids can function in both metabolic and immune roles, cross-regulating both systems in the body.4–6 Approximately 20 years ago, tumor necrosis factor α expression was identified as a molecular link between inflammation and obesity. This inflammatory cytokine was found to be overexpressed in adipose tissue in rodent models
From EMD Chemicals, Philadelphia, PA Address for Correspondence: Howard A. Epstein, PhD, EMD Chemicals, Cosmetic Actives, Performance Materials DivisionNAFTA Region, Philadelphia, PA • E-mail: howard.epstein@emdmillipore.com
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of obesity.7,8 Since that time, lipids have been shown to participate in the regulation of inflammation and metabolism. Elevated plasma lipid levels are characteristic of obesity, infection, and other inflammatory states. The overlapping biology and function of macrophages and adipocytes in the association of inflammation and metabolism is another link.6 Epigenetics:Nrf2 at the Crossroads of Cell Communication The Nrf2 signaling pathway is emerging as a critical and principal factor in the protection against cancer, neurodegeneration, and inflammation. It represses multiple proinflammatory genes including the regulation of more than 200 genes, crucial for the metabolism of drugs and toxins and signaling for protection against oxidative stress and inflammation. The ability of Nrf2 to downregulate inflammation has made it a pathway of research interest for modulating immunity, wound healing, and the treatment of neoplasm(s).8,9
viding therapeutic benefits. Potential molecular pathways have even been identified for phytonutrients.13 Conclusions One can envision the skin care expert of the future providing epigenetic-guided lifestyle counseling to patients and consumers interested in state-of-the-art skin care. This would include guidance on diet, protection from environmental pollutants, and appropriate precautions against excessive sun exposure. Epigenetic studies have also revealed that many plant-based foods, including broccoli plus flavonoids in fruits and vegetable, provide health benefits for skin via epigenetic mechanisms. References
Clinical Implications An assortment of drugs targeted for specific enzymes involved in the epigenetic regulation of gene expression are currently being investigated. The ultimate approach is to attack epigenetic targets using chemotherapy and chemoprevention of cancer and other diseases.10 The DNA of older individuals commonly has deviations from the expected methylation pattern that can lead to less stringent control of gene expression, resulting in increased potential for genomic instability. Such genomic instability can result in the initiation of tumorigenesis and sustain a malignant state of cancer cells.10 One goal of epigenetic therapy is to restore a normal DNA methylation pattern and prevent cells from further methylation patterns that would inhibit cells from normal function. Epigenetic clinical studies using histone deactylase inhibitors have been conducted to evaluate melanoma and T-cell cutaneous lymphoma, showing partial results employing butyric acid in a melanoma study10 and providing complete remission using a cyclic peptide in the T-cell lymphoma study.10 Another application involves lesional skin in psoriasis that is accompanied by changes in DNA methylation. The changes revert back to baseline with treatment, suggesting alternative clinical options for treatment in the future.11 Other potential applications for epigenetic testing and therapy may be for vitamin deficiency–related conditions in the elderly. Data obtained from epigenetic studies indicate that nutritional and topical skin care interventions would be effective for maintenance of health and treatment of skin diseases. Phytochemicals associated with human nutrition are prime candidates for proSKINmed. 2013;11:362–363
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1 Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab (London). 2010;7:1–22. 2 Singh RK, Sudhakar A, Lokeshwar BL. From normal cells to malignancy: Distinct role of pro-inflammatory factors and cellular redox mechanisms. J Cancer Sci Ther. 2011;3:70–75. 3 Choi SW, Friso S. Epigenetics: a new bridge between nutrition and health. Adv Nutrition. 2010;1:8–16. 4 Rijken F, Bruijnzeeel-Koomen CA. Photoaged skin: the role of neutrophils, preventative measures, and potential pharmacological targets. Clin Pharmacol Ther. 2011; 89:120–124. 5 Komine M, Rao LS, Kaneko T, et al. Inflammatory versus proliferative process in epidermis. J Biol Chem. 2000;275:32077–32088. 6 Wellen KE. Hotamisligil, Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111–1119. 7 Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor α inhibits signaling from the insulin receptor. Proc Natl Accad Sci. 1994;91:4854–4858. 8 McCusker MM, Grant-Kels JM. Healing fats of the skin: the structural and immunologic roles of the ω-6 and ω-3 fatty acids. Clin Dermatol. 2010;28:440–451. 9 Lewis KN, Mele J, Hayes JD, Buffenstein R. Nrf2, a guardian of healthspan and gatekeeper of species longevity. Integrative Compar Bio. 2010;50:829–843. 10 Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nature Rev Drug Disc. 2006; 5:37–50. 11 Grommiger E, Weber B, Heil O, et al. Aging and chronic sun exposure cause distinct epigenetic changes in human skin. Genetics. 2010;27:E1000971. http://www. ncbi.nlm.nih.gov/pmc/articles/PMC2877750/pdf/ pgen.1000971.pdf. Accessed August 21, 2013. 12 Gudjonsson JE, Krueger G. A role for epigenetics in psoriasis: methylated cytosine-guanine sites differentiate lesional from nonlesional skin and from normal skin. J Invest Dermatol. 2012;12:506–508. 13 McNaughton SA, Marks GC, Green AC. Role of dietary factors in the development of basal cell cancer and squamous cell cancer of the skin. Cancer Epidemiol Biomarkers Prev. 2005;14:1596–1607.
Will Epigenetics Change Our Approach?
November/December 2013
Volume 11 • Issue 6
CASE STUDY Vesna Petronic-Rosic, MD, MSc, Section Editor
From Mole to Scar: The Unintended Consequence of Treatment With an Over-the-Counter Mole Removal Cream Tara Bronsnick, BA;1 A. Yasmine Kirkorian, MD;1 Irfan Khan, BA;2 Allison Cole;3 Babar K. Rao, MD1
A 26-year-old man presented with a scar at the site of a pigmented lesion treated with DermaTend (Solace Interntational, Inc., Reno, NV), an over-the-counter mole removal cream. According to the patient, the pigmented lesion had been present since childhood, was asymptomatic, and had not changed in appearance. It remained cosmetically displeasing to him. In an effort to remove the lesion, he had applied DermaTend on a daily basis for several weeks, at which point he noticed a scar at the site of treatment. (SKINmed. 2013;11:364–366)
O
n examination, there was an 8-mm, medium to dark brown papule with a central, pink, atrophic area on the patient’s back, consistent with a traumatized nevus or an atypical pigmented lesion. Dermatoscopy revealed an irregular reticuloglobular network at the periphery, pigment alteration, and a scar-like area in the middle. A shave removal of the entire lesion was performed to rule out melanoma. Histopathologic evaluation revealed a broad scar, above which were single melanocytes and poorly nested melanocytes located at and above the dermoepidermal junction with a few similar nests of melanocytes within the fibrotic dermis. On either side of this area, there was a compound nevus with congenital features (Figure). The patient did not have a prior biopsy at this site. Given the clinical history, the lesion was thought to be a benign melanocytic nevus with architectural disarray secondary to previous trauma. Discussion Patients seeking removal of nevi for cosmetic purposes may pursue alternative treatments given the scarring and cost associated with surgical removal, which is not covered by insurance companies.1,2 Over-the-counter mole removal creams, which are easily purchased online and are not subject to regulation by the Food and Drug Administration (FDA), claim to provide a safe, natural “scar-free,” “do-
it-yourself” solution for patients.2,3 This case is the first report of scar formation secondary to treatment with DermaTend, which is advertised as a safe and inexpensive alternative to surgery that is effective for the removal of moles and skin tags.4 Ingredients include Sanguinaria canadensis, glycerin, zinc chloride, germall plus, and water.4 Sanguinaria canadensis (bloodroot) and zinc chloride are both escharotic agents, which are corrosive, caustic agents that cause skin to slough off and die.5,6 There are several similar reports of scars and keloids after treatment of warts with Wart & Mole Vanish (Pristine Enterprises, Inc, Los Angeles, CA).1–3,7 In these cases, patients are replacing one cosmetic issue with another, while introducing additional problems outlined below. Given the risk of melanoma, pigmented lesions should be appropriately evaluated by a dermatologist and examined histopathologically, if removed. The need for microscopic evaluation of pigmented lesions precludes the use of destructive methods, including these creams, cryotherapy, electrodessication, and laser surgery for removal.1,2 Additionally, these compounds are not proven to be safe or effective, may have unknown effects on skin cells, and may disguise or encourage malignant transformation.1–3,7 If the clinical history was unknown in this case, the pathology would be consistent with a nevus with prior biopsy
From the Department of Dermatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ;1 the American University of Antigua College of Medicine, Antigua;2 and Rutgers University, New Brunswick, NJ3 Address for Correspondence: Tara Bronsnick, I World’s Fair Drive, Somerset, NJ, 07052 • E-mail: tarabronsnick@gmail.com
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or destructive treatment (ie, cryotherapy), and the management and clinical outcome of the patient would be different. Finally, self-treatment of skin lesions with over-the-counter products may be associated with delayed diagnosis and treatment of cancerous lesions and consequent morbidity and mortality. In one case, a 52-year-old man had treated a black papule on his chest with bloodroot salve and was diagnosed with malignant melanoma at the same site 6 months later.5 In another investigation, 4 patients with basal cell carcinoma treated with similar escharotic agents, including zinc chloride and bloodroot, demonstrated severe scarring and residual, recurrent and metastatic disease.6 It is likely that the incidence of adverse effects is higher than reported as these products are widely available to patients without a prescription.7 Physicians, therefore, must be aware of commercially available over-the-counter mole removal creams (Table). These creams contain various active ingredients, including Chelidonium majus, which contains the alkaloid sanguinarine that is extracted from several plants including bloodroot,3 and extracts of cashew plant (Anacardium occidentale), which contains highly sclerosing phenanthridine alkaloids.7 Price per unit varies from $29.95 to $79.95. More than 5000 H-Moles products have been sold.8 Other producers report that thousands of patients have used these products since the early 2000s.4 Given availability of these products and the issues addressed above, physicians should be aware of and advise patients of the pitfalls and adverse effects associated with their use. Conclusions Over-the-counter mole removal creams are used by patients to eliminate cosmetically displeasing nevi or other growths. Physicians should be aware of the available products and their associ-
Figure. Histopathologic evaluation revealed a broad scar, above which were single melanocytes and poorly nested melanocytes located at and above the dermoepidermal junction with a few similar nests of melanocytes within the fibrotic dermis. On either side of this area, there was a compound nevus with congenital features (H&E, x10).
ated pitfalls and adverse effects, including scar and keloid formation, preclusion of histologic analysis of initial lesion, delayed diagnosis of malignant lesions, and lack of FDA approval and warn their patients accordingly.
Table. Over-the-Counter Mole, Wart, and Skin Tag Removal Creams Available on the Internet Product
Ingredients
Company
DermaTend
Sanguinaria canadensis, glycerin, zinc chloride, germall plus, water
Solace International, Inc
H-Moles
Melaleuca alternifolia, cedrus lycea, Sesamum indicum, Melissa officinalis, Lavandula angustifolia, Boswellia carteri
Healing Natural Oils
ItWorksPaste
Cashew plant (Anacordium occidentale), fig plant (Ficus Carica), greater celandine (Chelidonium majus)
New Skin Naturally
Moles No More
Melaleuca alternifolia (tea tree) oil, thuja, lavandine super, geranium, lelissa, sesame
Forces of Nature
Wart & Mole Vanish
Cashew plant (Anacordium occidentale), fig plant (Ficus Carica), greater celandine (Chelidonium majus)
Pristine Herbal Touch
Nevexen
Water, octyl palmitate, glyceryl stearate, ceteayl alcohol, PEG-100 stearate, caprylic/cpric triglyceride, sodium hydroxide, triethanolamine, Ficus Carica, Anacardum occidentale, citrus limon, Chelidonim Majus, talc
Nevi-Skin
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References 1 Clayton R, Turner R. Cosmetic surgery: who needs surgeons when you’ve got creams? BJD. 2007;156:1383– 1389. 2 Hilton S, Reinerth G, Heise H, et al. Hypopigmented scar formation after application of over-the-counter wart and mole removal cream. Wien Klin Wochenscher. 2011;123:183–185. 3 McAllister JC, Petzold CR, Lio PA. Adverse effects of a mole removal cream. Pediatr Dermatol. 2009;26:628– 629. 4 DermaTend. The Original: Removes Moles & Skin Tags. http://www.dermatend.com/. Accessed July 25 2013.
5 Cieneki JJ, Zaret L. An Internet misadventure: bloodroot salve toxicity. J Altern Complement Med. 2010;16:1125– 1127. 6 McDaniel S, Goldman GD. Consequences of using escharotic agents as primary treatment for nonmelanoma skin cancer. Arch Dermatol. 2002;138:1593–1596. 7 Boada A, Carrascosa JM, Ferrandiz C. Keloid development on skin lesions after the application of a cream purchased over the internet. Actas Dermosifiliogr. 2011;102:71–72. 8 H-Moles: Natural Mole Removal Product. http://www. amoils.com/mole-removal.html. Accessed September 9, 2013.
Wax Moulage
“Dermatits herpetiformis Duhring”, Moulage No. BS20 made by Otto Vogelbacher in Freiburg i.Br. around 1900. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD
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OFFICIAL PUBLICATION
November/December 2013
Volume 11 • Issue 6
CASE STUDY
Dermatographic Fixed-Drug Eruption: Another Cause of Pseudo-Darier’s Sign Michael T. Cosulich, BSE;1 Scott A. Norton, MD, MPH2
A 7-year-old boy from El Salvador presented with several well-demarcated 3- to 4-cm round to oval, grey-brown patches on his shoulder and trunk (Figure a) that appeared simultaneously about 1 year previously. The lesions were red initially and thought by the patient’s mother and primary care physicians to be bruises, but a hematologist’s evaluation was unremarkable. The erythema soon subsided, leaving persistent lightbrown spots on the torso. The patient was otherwise asymptomatic. (SKINmed. 2013;11:368–369)
T
he pigmented lesions were occasionally pruritic and the boy’s mother stated that they became bright red and inflamed when the boy scratched them. This precisely fits the clinical definition of the Darier’s sign of cutaneous mastocytosis and we were able to duplicate this easily in the clinic by stroking the entire surface of the lesions (Figure b). Although cutaneous
mastocytosis was in our differential diagnosis, the unprovoked lesions resembled a fixed-drug eruption. When questioned, the patient’s mother reported that the boy had not taken any prescription medications in several years, but she recalled giving him an over-the-counter cough medicine around the
Figure. (a) Pigmented macule. Fixed light-brown patches in their usual, nonurticarial condition on the anterior torso of a 7-year-old boy. (b) Pseudo-Darier’s sign. Same lesion 20 seconds after being rubbed firmly with a pen. The lesion is an urticarial red, edematous wheal of the sort seen with a positive Darier’s sign.
From Georgetown University School of Medicine,1 and Georgetown University Medical Center and Children’s National Medical Center, Washington, DC2 Address for Correspondence: Scott A. Norton, MD, MPH, Children’s National Medical Center, Dermatology Division, 111 Michigan Avenue, NW, Washington, DC 20010 • E-mail: snorton@cnmc.org
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time that the spots first appeared. The cough syrup was obtained from El Salvador and our investigation showed that it contained trimethoprim/sulfamethoxazole, a well-recognized cause of fixeddrug eruptions.1 Discussion Darier’s sign, the rapid appearance of pressure-induced urticarial plaques at sites of pigmented lesions, is associated with various forms of cutaneous mastocytosis. The term pseudo-Darier’s sign has been applied to clinical findings in nonmastocystosis conditions, such as congenital smooth muscle hamartoma, in which edematous urticaria-like lesions also appear after induced pressure.2
matographism was responsible for a pseudo-Darier’s sign, thus confounding the diagnosis. We therefore made a clinical diagnosis of fixed-drug eruption, probably caused by sulfamethoxazole or, less likely, trimethoprim. No biopsy was performed. The unrelated dermatographic urticaria was explained to the patient and his mother, and they were advised to avoid trimethoprim/sulfamethoxazole and other sulfa-containing medications. Conclusion This case highlights the need to consider underlying dermatographism in patients with a reportedly positive Darier’s sign. References
While a fixed-drug eruption accounted for the pigmented macules, this diagnosis did not explain the observed Darier’s sign; however, when other areas of the patient’s body were scratched, there was similar urtication. This suggested that underlying der-
1 Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37:833–838. 2 Johnson MD, Jacobs AH. Congenital smooth muscle hamartoma. A report of six cases and a review of the literature. Arch Dermatol. 1989;125:820–822.
Historical Diagnosis and treatment: epithelioma
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Dermatographic Fixed-Drug Eruption: Pseudo-Darier’s Sign
July 18 - 20, 2014 SulAmérica Convention Center Rio de Janeiro Brazil
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November/December 2013
Volume 11 • Issue 6
CASE STUDY
Recurrent Infantile Myofibromatosis in a 19-Month-Old Boy Presenting as Ulcerated Plaque Ouafa Hocar, MD;1 Imane Ait Sab, MD;2 Nadia Akhdari, MD;1 Said Amal, MD;1 Mohamed Ouladsiad, MD;3 Badiaa Belaabidia, MD4
A 19-month-old boy presented to our department with ulcerated plaque on the right lumbar region. The lesion was known to have been growing for about 5 months. At another center 9 months prior to presenting to our department, the patient’s parents reported a history of cutaneous nodules from the same lumbar region. Their total excision was performed, and the pathology report stated that it was infantile calcifying fibromatosis or nodular fasciitis. The patient was healthy with a nonsignificant, medical history including no use of medications, no known drug allergies, and no significant family history of disease. (SKINmed. 2013;11:371–373)
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n physical examination, there was a surgical incision scar on the right lumbar region due to the previous surgery, centered by an ulcerated and infiltrated cutaneous plaque (15 mm) with some minimal and superficial slight telangiectasia (Figure 1). There were also small firm, rubbery, flesh-colored satellite cutaneous nodules (7 nodules) whose size ranged from 5 to 12 mm (Figure 1). Magnetic resonance imaging (MRI) was performed, which revealed infiltrative, subcutaneous nodules in the right lumbar region without deep invasion. Pathological re-study of previously excised nodules found alternating areas of 2 distinct cell populations: peripheral smooth muscle-like fascicles consisting of plump spindle-shaped cells with an eosinophilic cytoplasm and central pericyte-like vascular areas consisting of less differentiated rounder cells with areas of calcification (Figure 2A–C). The lesion showed a marked proliferation of cells positive for smooth muscle actin and vimentin but negative for desmin, S-100, and CD 34 (Figure 3). A final diagnosis of myofibromatosis was made. No skeletal or other visceral lesions were evident (results from skeletal and chest xray, abdominal ultrasonography, and electrocardiography were normal). The patient was followed-up for 1 year; however, due to rapid growth of lesions, surgical treatment was performed. The patient’s postoperative course was uneventful and at 3 years of age, he showed no sign of any tumor recurrence.
Figure 1. An ulcerated cutaneous plaque with small firm satellite cutaneous nodules in a patient with recurrent infantile myofibromatosis.
Discussion Diagnosis of infantile myofibromatosis (IM) is histologically and clinically difficult and relies on a clear anatomoclinical confrontation. The clinical aspects are varied. The case presented here represents a unique form of myofibromatosis occurring on the right lumbar region with local recurrence as an ulcerated cutaneous plaque. Myofibroma (unifocal) and myofibromatosis (multifocal) are rare spindle cell neoplasms composed of myofibroblasts cells with
From the Departments of Dermatology,1 Pediatrics,2 Pediatric Surgery,3 and Anatomopathology,4 Mohammed theVIth University Hospital, Cadi Ayyad University, School of Medicine, Marrakesh, Morocco Address for Correspondence: Ouafa Hocar, MD, Department of Dermatology, School of Medicine, Cady Ayyad University, Marrakesh, Morocco • Email: ouafahocar@yahoo.com
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A
C
Figure 2. Myofibroblastic cells found in a loose stroma on histopathological examination. The cells are fusiform in shape, regular, and do not show nuclear atypia.
characteristics intermediate between smooth muscle, fibroblastic, and undifferentiated cells. Lesions often undergo spontaneous remission, which may be mediated by massive apoptosis.4 Clinically these lesions show a predilection for the head and neck, followed by the trunk and extremities. IM may occur in two distinct forms5: solitary type and multicentric type. The solitary type is defined by the presence of one nodule in the skin, muscle, bone, or subcutaneous tissue. The multicentric type can be divided into two subtypes: one involves the subcutaneous tissue only, while the other involves the subcutaneous tissue, musculoskeletal system, and viscera.4,5 Multicentric IM grows principally during the immediate prenatal period and is usually present at birth; however, the solitary form presents later in infancy or in adulthood.6 The condition is approximately twice as common in men as in women.6 More than 50% of patients with solitary lesions and more than 90% with multiple lesions have lesions present at birth SKINmed. 2013;11:371â&#x20AC;&#x201C;373
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Figure 3. Immunohistochemical results showing strong expression for smooth muscle actin (original magnification Ă&#x2014;200). Recurrent Infantile Myofibromatosis in a 19-Month-Old Boy
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CASE STUDY
or soon after.3 The etiology of IM is unknown; however, a hereditary condition may contribute to its occurrence, since some patients who have ≥2 siblings with IM have been reported.7 In a recent publication, researchers8 hypothesized whether maternal mesenchymal stem cells transferred during pregnancy could participate or entirely constitute tumoral tissue in the fetus. They studied samples of tumoral tissue from 4 newborn patients with solitary or multiple cutaneous IM. Few maternal cells and a dense male XY infiltration were detected in all patients; therefore, they demonstrated that tumor cells did not derive from maternal chimeric cells. Maternal estrogen has been shown to influence the development of IM, with spontaneous tumoral regression documented after birth, when the estrogen exposure disappears.9,10 The tumor usually presents two distinct components.1,2 Peripherally, fusiform cells are regrouped in small fascicles or packets with slender elements suggestive of fibroblasts as well as larger cells resembling smooth muscle.6 Their nuclei are elongated or oval and the cytoplasm is eosinophilic. The surrounding matrix is rich in collagen. Finally, mitoses are rare. Centrally, the cells are less differentiated and round and there are areas of necrosis, calcifications, or sheets of hyalinization. Vascularization with capillary channels may be quite dense and evoke a diagnosis of a hemangiopericytoma.11 IM must be distinguished from other proliferations12 and, in particular, hemangiopericytoma, in which there is no peripheral cellular component. Desmoid fibromatosis, which is more aggressive and invasive, does not show hyalinization or a central hemangiopericytoma-like appearance, and fibrosarcoma, which is very cellular, has marked atypia and mitoses. Other differential diagnoses to be considered are leiomyoma, leiomyosarcoma, fibrous histiocytoma, and nodular fasciitis. The diagnosis is confirmed by immunohistochemistry, where markers for smooth muscle actin and vimentin are positive, while those for S100 protein and desmin are negative.
Because these lesions may not be easily discernible and most spontaneously resolve, the condition is underdiagnosed and underreported. Conclusions IM must be considered in any child who presents with either solitary or multiple tumors, particularly those occurring in the neonatal period, especially in the presence of firm or rubbery subcutaneous nodules, often with a telangiectatic dusky red to purple surface or an ulcerated plaque as our case. If IM is suspected, a biopsy of the tumor must be performed to confirm the diagnosis. Laboratory and radiologic examination and a complete clinical evaluation should be performed to establish the extent of involvement and prognosis. Therapeutic options are numerous, ranging from active nonintervention to surgical excision, and decisions are generally based on the degree of vital organ involvement. Considering the regressive nature of this condition, however, the nonintervention approach may be treatment of choice for solitary or multiple cutaneous IM without visceral involvement. References
The natural history of IM lesions appear to evolve in 3 stages. Numerous publications have reported a first phase of tumor growth, either in the form of an increase in the nodular volume6 or an increase in the number of lesions in multiple IM.2 After a second phase where the lesions are stable, quite a high proportion of tumors show spontaneous regression (30% of multiple IM in Chung’s series).2 The prognosis for IM depends on the degree of visceral involvement. Since spontaneous tumoral regression is usual, therapeutic abstention and patient observation are recommended in cases of limited involvement. Surgery, chemotherapy, or radiotherapy are reserved for patients with multiple visceral localizations, particularly in the lung and gastrointestinal tract, which may have a worse prognosis and potentially fatal outcome.5,6 In our case, a follow-up was performed giving possibility to spontaneous regression, but due to fast progression of lesions, surgical excision was done. SKINmed. 2013;11:371–373
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1 Stout AP. Juvenile fibromatosis. Cancer. 1954;7:953978. 2 Chung EB, Enzinger FM. Infantile myofibromatosis. Cancer. 1981;48:1807-1818. 3 Schrodt BJ, Callen JP. A case of congenital multiple myofibromatosis developing in an infant. Pediatrics. 1999;104:113-115. 4 Fukasawa Y, Ishikura H, Takada A, et al. Massive apoptosis in infantile myofibromatosis. A putative mechanism of tumor regression. Am J Pathol. 1994;144:480485. 5 Fraitag S, Hénin D. Myofibromatose infantile cutanée isolée. Ann Pathol. 2004;24:427-431. 6 Stanford D, Rogers M. Dermatological presentations of infantile myofibromatosis: a review of 27 cases. Australas J Dermatol. 2000;41:156-161. 7 Arcavgeli F, Calista D. Congenital myofibromatosis in two siblings. Eur J Dermatol. 2006;16:181-183. 8 Yousefi P, Khosrotehrani K, Oster M, et al. Neonatal cases of infantile myofibromatosis do not derive from maternal cells transferred during pregnancy. Br J Dermatol. 2009;160:1356-1357. 9 Gopal M, Chahal G, Al-Rifai Z, et al. Infantile myofibromatosis. Pediatr Surg Int. 2008;24:287-291. 10 Schurr P, Moulsdale W. Infantile myofibroma: a case report and review of the literature. Adv Neonatal Care. 2008;8:3-20. 11 Maradeix S, Cribier B. Myofibromes et myofibromatose. Ann Dermatol Venereol. 2005;132:271-275. 12 Speight PM, Dayan D, Fletcher CD. Adult and infantile myofibromatosis: a report of three cases affecting the oral cavity. J Oral Pathol Med. 1991;20:380384.
Recurrent Infantile Myofibromatosis in a 19-Month-Old Boy
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CASE STUDY
HIV/AIDS Kaposi Sarcoma: The Indian Perspective Virendra N. Sehgal, MD; Prashant Verma, MD; Sonal Sharma, MD
A 58-year-old, nonalcoholic, nonsmoker, official in private enterprise presented with a confirmed case of human immunodeficiency virus/ acquired immune deficiency syndrome (HIV/AIDS) and an itchy, violaceous skin eruption over the lower part of the left leg. He noticed a change in the color and texture of the skin for the first time 2 years ago. Ever since that time, the eruptions had insidiously progressed. He was started on highly active antiretroviral therapy (HAART), comprising 600 mg of zidovudine, 300 mg of lamivudine, and 600 mg of efavirenz for the past year. Despite the therapy, the lesions continued to progress. He claimed to be very compliant with therapy. In addition, he developed pulmonary tuberculosis during the course of the disease. Accordingly, he was treated with a daily schedule1 of antitubercular therapy, comprising 450 mg of rifampicin, 300 mg of isoniazid, 1500 mg of pyrazinamide, and 800 mg of ethambutol for 9 months. He experienced a significant loss of weight and appetite. The patient was a divorcee but refused to divulge any details of his married life after a considerate and focused discussion by a trained counselor on HIV/AIDS. He emphatically denied any extramarital sexual contact, blood transfusion, and surgery in the past. Ultimately, the patient’s disease status was defined by HIV viral load (<20 copy/mL) after obtaining informed consent. (SKINmed. 2013;11:375–377)
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esults from complete hemography, total and differential leukocyte count, and liver and renal function tests were normal.
Skin surface examination was marked by the presence of a violaceous raised plaque (15 cm × 10 cm across). It had an irregular configuration with a few satellite papules and/or nodules. The surface of the lesions was punctuated by grayish white scales. The lesions were located on the anterolateral aspect of the left leg (Figure 1) and the big and adjoining toe. There was no edema or regional lymph node enlargement. The oral, genital, ocular, and nasal mucosae were unremarkable. Hair and nails appeared normal. Serial sections prepared from the biopsy of the representative lesion showed infiltration of the entire dermis with vascular spaces and spindle cells. The infiltration extended to subcutaneous adipose tissue. There were scarce mitotic figures and lack of nuclear or cytological pleomorphism. Numerous vascular channels filled with red cells were also seen dissecting the collagen bundles. Many foci of hemosiderin-laden macrophages were present (Figure 2). The patient was prescribed 5% topical imiquimod for the lesions to be applied 3 times a week for 4 months. There was minimal improvement of lesions and the drug was discontinued.
Figure 1. Human immunodeficiency virus/acquired immune deficiency syndrome–Kaposi sarcoma depicting a violaceous, scaly, well-demarcated plaque with satellite papules and nodules.
Discussion Since the identification of AIDS-Kaposi sarcoma (KS) in the United States in 1981,2 the entity has been conceived as a salient skin marker of HIV/AIDS. It has been reported in 30% to
From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati-Delhi, Department of Dermatology and STD and Department of Pathology, University College of Medical Sciences, and associated Guru Teg Bahadur Hospital, Shahdara Delhi, India Address for Correspondence: Virendra N Sehgal MD, Dermato Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033 India • E-mail: drsehgal@ndf.vsnl.net.in
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Figure 2. Section shows diffuse cellular infiltration of dermis with spindle cells and vascular channels (hematoxylin-eosin stain, original magnification ×100). Inset shows a higher-power view of channels containing numerous red cells (hematoxylin-eosin stain, original magnification ×400).
It is difficult to understand an epidemiologic cause among Indians, because the information on the entity is limited; yet, the age range was found to be 19 to 50 years, in contrast to its peak incidence in 40 to 70 years of age in United States and Europe, with a wide range up to 89 years.13 The female:male ratio was 1:9, a similar rate to that reported elsewhere,14 and wherein heterosexual patients were more prominently affected. In India, tuberculosis is one of the most frequently encountered opportunistic infections. Two of the 10 earlier reported HIV/ AIDS-KS cases had associated pulmonary tuberculosis.5,11
Table. HIV/AIDS Kaposi Sarcoma Pattern in the Indian Context Authors
Age, y
Sex
Regions
Risk Behavior
Site
CD4+ Count
Shroff et al3
35
Woman
Western India (Mumbai)
Heterosexual
Chin, palate, forearm, and legs
220 cells/mm3
Kumarasamy et al4
19
Man
South India (Chennai)
Intravenous drug user
–
–
Singh et al5
50
Man
Western India (Mumbai)
Heterosexual/blood transfusion
Trunk
–
Chandan et al6
39
Man
Western India (Mumbai)
Heterosexual
Soft palate, trunk and extremities
247 cells/mm3
Krishna and Reddy7
35
Man
Southern India (Hyderabad)
–
Right upper limb
–
Shenoy and et al8
45
Man
Western India (Mumbai)
Heterosexual
Trunk and extremities
Low
Bhagat et al9
30
Man
Western India (Vadodara)
Heterosexual
Trunk, upper and lower extremities
–
Dongre and Montaldo10
40
Man
Western India (Mumbai)
–
Soft palates, hands, thighs, and legs
179 cells/mm3
Kharkar et al11
38
Man
Western India (Mumbai)
Heterosexual
Soft palate, right and left lower extremities, and left sole
–
Vaishnani et al12
26
Man
Western India (Gujarat)
Heterosexual
Face (right upper and lower eyelids, upper lip), trunk, and proximal part of both extremeties
186 cells/mm3
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There appears to be a low prevalence of human herpes virus-8 (HHV-8) infections in India and elsewhere in Asia.15 Additional studies are needed to confirm this finding, especially in men who have sex with men. The west coast areas of India, in particular, have had many centuries of immigration and trade interaction with east and central Africa, where half or more of adults are infected with HHV-8 and KS.16 In Africa, HHV-8 prevalence is high, particularly in poorer households without access to clean water; however, HHV-8 has not spread in India or other areas of Asia despite a large population living in poor socioeconomic conditions with a lack of access to clean water. HAART is the mainstay for HIV/AIDS-KS in India. It is provided free of cost by the National AIDS Control Organisation (NACO) at the antiretroviral treatment clinics.17 A variety of adjunct treatment modalities such as topical alitretinoin18 and injectable liposomal anthracyclines (doxorubicin and daunorubicin) are currently used across the globe for HIV/AIDS-related KS. These drugs are approved for use by the US Food and Drug Administration; however, they are costly and not currently available in India. Imiquimod is available, however, which is an immune response modifier that is able to induce interferon-α secretion in situ. Topical 5% imiquimod has been successfully used in localized cutaneous cases of classic KS in an open-label trial comprising 17 HIV-negative patients.19 The current case, however, failed to respond after 4 months of therapy, besides HAART for 1 year. One case with KS involving both hands and feet and oral mucosa accompanied by lymphedema was treated with intravenous paclitaxel, 90 mg/m2 of body surface area, over 3 hours 3 times per month. Significant improvement was observed after 6 cycles of therapy10; however, due to its toxic potential, it is considered second-line therapy. In another patient with extensive mucocutaneous KS, intralesional injection of vincrystine resulted in total flattening of skin lesions; furthermore, a good therapeutic response to sublingual administration of 200 IU of interferon-α, was achieved in palatal, gingival, chin, forearm, and right leg lesions within 2 weeks.3 Cryotherapy, intralesional vinblastine, interferon-α, laser, and radiation therapy are other viable treatment options.20 References 1 Sehgal VN, Sardana K, Sharma S. Inadequacy of clinical and/or laboratorycriteria for the diagnosis of lupus vulgaris, re-infection cutaneous tuberculosis: fallout/ implication of 6 weeks of anti-tubular therapy as a precise diagnostic supplement to complete the scheduled regimen. J Dermatolog Treat. 2008;19:164-167. 2 Friedman-Kien AE. Disseminated Kaposi’s sarcoma syndrome in young homosexual men. J Am Acad Dermatol. 1981;5:468-471.
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3 Shroff HJ, Dashatwar DR, Deshpande RP, et al. AIDSassociated Kaposi’s sarcoma in an Indian female. J Assoc Physicians India. 1993;41:241-242. 4 Kumarasamy N, Solomon S, Yesudian PK, et al. First report of Kaposi’s sarcoma in an AIDS patient from Madras, India. Ind J Dermatol. 1996;41:23-25. 5 Singh VR, Singh S, Pandey SS. Numerous giant mollusca contagiosa and kaposi’s sarcomas with HIV disease. Indian J Dermatol Venereol Leprol. 1996;62:173-174. 6 Chandan K, Madnani N, Desai D, et al. AIDS-associated Kaposi’s sarcoma in a heterosexual male--a case report. Dermatol Online J. 2002;8:19. 7 Krishna AG, Reddy GVR. Kaposi’s sarcoma in a follow-up patient of malignant schwannoma after seroconversion. Indian Journal Surg. 2004;2:110-112. 8 Shenoy VV, Joshi SR, Duberkar D, et al. Kaposi’s sarcoma with thrombocytopenia in a heterosexual Asian Indian male. J Assoc Physicians India. 2005;53:486-488. 9 Bhagat U, Sharma A, Marfatia YS. Violaceous papulonodular lesions in an AIDS case. Indian J Sex Transm Dis. 2008;29:51-53. 10 Dongre A, Montaldo C. Kaposi’s sarcoma in an HIV-positive person successfully treated with paclitaxel. Indian J Dermatol Venereol Leprol. 2009;75: 290-292. 11 Kharkar V, Gutte RM, Khopkar U, et al. Kaposi’s sarcoma: a presenting manifestation of HIV infection in an Indian. Indian J Dermatol Venereol Leprol. 2009;75:391-393. 12 Vaishnani JB, Bosamiya SS, Momin AM. Kaposi’s sarcoma: a presenting sign of HIV. Indian J Dermatol Venereol Leprol. 2010;76:215. 13 Hermans P, Lundgren J, Sommereijns B, et al. Epidemiology of AIDS-related Kaposi’s sarcoma in Europe over 10 years. AIDS in Europe Study Group. AIDS. 1996;10:911-917. 14 Piette WW. The incidence of second malignancies in subsets of Kaposi’s sarcoma. J Am Acad Dermatol. 1987;16:855-861. 15 Chatlynne LG, Ablashi DV. Seroepidemiology of Kaposi’s sarcoma-associated herpesvirus (KSHV). Semin Cancer Biol. 1999;9:175-185. 16 Biggar RJ, Chaturvedi AK, Bhatia K, et al. Cancer risk in persons with HIV/AIDS in India: a review and future directions for research. Infect Agent Cancer. 2009;4:4. 17 National Guidelines for Implementation of Antiretroviral Therapy (ART) (Draft), NACO-National AIDS Control Organization; New Delhi, August 9, 2004:151. 18 “Panretin (Alitretinoin) drug information.” RxList. November 21, 2000. http://www.rxlist.com/panretin-drug. htm. Accessed January 14, 2009. 19 Célestin Schartz NE, Chevret S, Paz C, et al. Imiquimod 5% cream for treatment of HIV-negative Kaposi’s sarcoma skin lesions: A phase I to II, open-label trial in 17 patients. J Am Acad Dermatol. 2008;58:585-591. 20 Krown SE, Lee JY, Lin L, et al. Interferon-alpha2b with protease inhibitor-based antiretroviral therapy in patients with AIDS-associated Kaposi sarcoma: an AIDS malignancy consortium phase I trial. J Acquir Immune Defic Syndr. 2006;41:149-153.
HIV/AIDS Kaposi Sarcoma: The Indian Perspective
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November/December 2013
Volume 11 • Issue 6
CASE STUDY
Borderline Tuberculoid Leprosy Mimicking Mycosis Fungoides Elva Dalia Rodríguez-Acosta, MD;1 Lilly Esquivel-Pedraza, MD;1 Marcela Saeb-Lima, MD;2 Roberto Arenas-Guzmán, MD;3 Julio Granados-Arriola, MD;4 Judith Domínguez-Cherit, MD1
A 65-year-old unemployed man, originally from Michoacán and currently living in Toluca, state of Mexico, presented for medical consultation for disseminated dermatosis in all body segments. The condition was limited to the head and neck, was bilateral and symmetrical, and was characterized by infiltrated and confluent erythematous-edematous plates of diverse diameter covering 90% of the upper and lower extremities (Figure 1). The ailment had 2 years’ evolution and a progressive course. The patient was diagnosed in private practice as having atopic dermatitis. After exacerbation of symptoms, he was treated with deflazacort and hydroxychloroquine with no improvement. Results from lesion biopsies revealed sarcoidal granulomas and the patient was therefore referred to the dermatology department at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán for further study and treatment with the presumptive diagnosis of mycosis fungoides vs sarcoidosis. (SKINmed. 2013;11:379–381)
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pon admission he reported involuntary weight loss and unmeasured fever. Further evaluation revealed dysesthesia of the palms and soles.
During oral examination, chronic, exfoliative, erythematous plaques and nodules affecting the skin and vermillion borders of the lips were observed. Intraoral, red papules in the left area of the floor of the mouth were detected, as well as erythema predominantly affecting the hard and soft palate (Figure 2). Mild fissures and furred tongue were also noted. The clinical appearance of oral lesions was more consistent with a process of lymphoproliferative etiology. No palpable lymph nodes were found in the head or neck or presence of other signs. Laboratory studies revealed a fasting glucose level of 14.2 mmol/L (256 mg/dL), and results from chest x-rays were normal. Biopsy of normal skin and dermis showed diffuse granulomatous infiltrate mainly by macrophages, foamy histiocytes, and scarce lymphocytes forming sarcoidal granulomas without neurotropism. Considering the dysesthesia precedent, staining for Mycobacteria was performed (Fite-Faraco and auramine-rhodamine stains) with positive results (Figure 3). Skin lymph (skin and left earlobe) and nasal mucosa bacilloscopy were analyzed, as well as
immunoreactions to lepromine type A, with all results being positive. At the DNA level, alleles of the HLA-DR locus were examined by the specific allele oligonucleotide technique; results were HLA-DR4 and HLA-DR1. Borderline tuberculoid leprosy was diagnosed and treatment for multibacillary liprosy was initiated with the standard World Health Organization (WHO) scheme consisting of dapsone, clofamizine, and rifampicin. As the disease evolved, new lesions appeared on the face, neck, trunk, and oral mucosa, as well as madarosis and anhydrosis of the palms, which decreased by 20% 1 month after onset of treatment. No epidemiologic precedent of contact with leprosy could be found, and the patient’s first-degree family members showed no data suggestive of the disease on examination. Discussion Leprosy is a chronic infectious disease of slow progress caused by Mycbacterium leprae. It mainly affects the skin and peripheral nerves and constitutes a mutilating and stigmatizing ailment. The incubation period is long, and although the disease is highly infectious, pathogenicity and virulence are low.1-4
From the Department of Dermatology1 and Pathology,2 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; the Department of Dermatology, Hospital General Manuel Gea González;3 and the Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán,4 Mexico Address for Correspondence: Elva Dalia Rodriguez-Acosta, MD, Vasco de Quiroga No.15, Belisario Domínguez Secc. XVI, Tlalpan, Mexico City. Mexico • E-mail: daliarodriguezacosta@gmail.com
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Figure 3. Sarcoidal granulomatous dermatitis without neurotropism (hematoxylin eosin staining, original magnification ×40) (a and b). Multiple bacilli (Fite-Faraco and Auramina Rodamina staining) (original magnification ×40) (c and d).
A case of borderline tuberculoid leprosy is reported because of its diagnostic difficulty. Initially, the clinical picture was highly suggestive of T-cell skin lymphoma, which is a disease considered in the differential diagnosis of leprosy. Since the patient was a native of an endemic region of leprosy, this disease was considered. It should be mentioned that a large number of leprosy cases are misdiagnosed, leading to progression and dissemination of the disease and to the inappropriate use of steroids, which worsen the disease.7–9
Figure 1. Disseminated dermatosis in all body segments, bilateral and symmetrical, characterized by infiltrated and confluent erythematous-edematous plates of diverse diameter.
The WHO recommend multidrug therapy with the combination of 3 drugs (rifampicin, clofazimine, and dapsone) for multibacillar patients and the combination of 2 drugs (rifampicin and dapsone) for paucibacillar patients as first-line treatment.10 Combined treatment with several drugs effectively removes the bacillus in the smallest possible time, and also prevents the appearance of microbial resistance.11
Figure 2. Exfoliative erythematous plaques and nodules affecting skin and vermillion borders of the lips (a). Generalized erythema affecting the hard and soft palate (b).
Its geographic distribution has varied with time. In Mexico, its prevalence has decreased 95% in the past 16 years, the number of cases falling from 16,694 in 1990 to 820 in 2005; however, the disease is endemic in the state of Michoacán.5 Leprosy is a priority public health problem since it is the second cause of neuropathy after diabetes mellitus.6 SKINmed. 2013;11:379–381
Among the symptoms of the present case, the most conspicuous were the erythematous-edematous infiltrated plates, which later showed significant flattening. These led to the tentative clinical inference of mycosis fungoides; however, the histopathological study showed sarcoidal granulomas. The presence of dysestesia fostered the suspicion of a mycobacterial infection. According to the clinical characteristics, bacteriological index, and histopathological findings, the final diagnosis was borderline tuberculoid leprosy.
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Finally, it is of much interest that the HLA-DRB1*04 allele shows the highest gene frequency among the Mexican population (of mestizo and Amerindian origin);12 on the other hand, the HLADRB1*01 allele has a gene frequency of 0.05 in the normal Mexican population, but is significantly increased among leprosy cases, particularly of the lepromatous kind.13 During ambulatory follow-up, the patient showed progressive improvement of the number of lesions and degree of infiltration, as well as discreet recovery of sensitivity, which allowed him to continue with his habitual lifestyle.
Conclusions In places of endemic leprosy, physicians need to be specifically trained to identify chronic granulomatous diseases, which are characterized by diverse clinical presentations. The present case emphasizes the importance of considering other entities in the differential diagnosis of patients with clinical data suggestive of leprosy, as well as the importance of skin biopsies to piece together and confirm the entity. Since leprosy has a long period of incubation and may be masked by a wide variety of clinical manifestations, its diagnosis may be severely delayed. References 1 Ramos-e-Silva M, Rebello P.F. Leprosy. Recognition and treatment. Am J Clin Dermatol. 2001;2:203–211. 2 World Health Organization. A guide to leprosy control. 2nd ed. Geneva: WHO; 1988:6–8.
3 Goulart IM, Goulart LR. Leprosy: diagnostic and control challenges for a worldwide disease. Arch Dermatol Res. 2008;300:269–290. 4 Matsuo C, Talhari C, Nogueira L, et al. Borderline lepromatous leprosy. An Bras Dermatol. 2010;85:921–922. 5 Terencio de las Aguas J. Consideraciones histórico – epidemiológicas de la Lepra en América. Med Cutan Iber Lat Am. 2006;34:179–194. 6 Ferreira-Guerrero EE, Velásquez-Monrroy O, Torres Reynoso N, Tapia Conyer R. Manual para la vigilancia epidemiológica de la lepra. Secretaría de Salud. 1993. 7 Heng YK, Chiam YT, Giam YC, Chong WS. Lepromatous leprosy in erythema nodosum leprosum reaction mimicking Sweet’s syndrome. Int J Dermatol. 2011;50:1124– 1125. 8 Rongioletti F, Cerroni L, Massone C, et al. Different histologic patterns of cutaneous granulomas in systemic lymphoma. J Am Acad Dermatol. 2004;51:600–605. 9 Sampaio L, Silva L, Terroso G, et al. Hansen’s disease mimicking a systemic vasculitis. Acta Reumatol Port. 2011;36:61–64. 10 Rodrigues LC, Lockwood DN. Leprosy now: epidemiology, progress, challenges, and research gaps. Lancet Infect Dis. 2011;11:464–470. 11 Surveillance of drug resistance in leprosy: 2010. Wkly Epidemiol Rec. 2011;3;86:237. 12 Vargas-Alarcón G, Granados J, Rodríguez-Pérez JM, et al. Distribution of HLA class II alleles and haplotypes in Mexican Mestizo population: comparison with other populations. Immunol Invest. 2010;39:268–283. 13 Barquera R, Zúñiga J, Hernández-Díaz R, et al. HLA class I and clas II haplotypes in admixed families from several regions of México. Mol Immunol. 2008;45:1171– 1178.
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SKINmed. 2013;11:379–381
381
Borderline Tuberculoid Leprosy Mimicking Mycosis Fungoides
November/December 2013
Volume 11 • Issue 6
Book Review Jennifer L. Parish, MD, Section Editor
Dermatology at a Glance By Mahbub M. U. Chowdhury, Ruwani P. Katugampola, and Andrew Y. Finlay 112 pages. Oxford, England; Wiley-Blackwell; 2013 $39.95
In a largely European tradition, key figures of 20th-century dermatology, as well as other historical highlights and cultural aspects of skin disease, are at the beginning of Dermatology at a Glance. A substantial amount of text is dedicated to discussing the burden of skin disease, appropriately so, as the impact of skin disease on quality of life has increasingly become a significant consideration when choosing treatment options. The chapter on surgical basics very nicely explains various procedures used in dermatology and the basic instructions on how to perform them. There are some useful common sense warnings, such as not to start a procedure unless the patient is 100% sure he or she wishes to proceed. Similarly, it warns the reader not to skimp on the history just because the disease is visible. Although most of the photos are decent, quite a few illustrating common diseases are not entirely representative. The list of abbreviations erroneously lists XP as xeroderma pigmentosa and faithfully repeats the error throughout (the correct name is xeroderma pigmentosum). Some chapters, though, such as atopic dermatitis and blistering skin diseases, are amazingly comprehensive and impressively summarize all the salient points from etiology to diagnosis and management. The authors present some rather interesting chapter concepts such as “the red face.” This approach to differential diagnosis, rather than individual diagnosis, may be useful, particularly for practitioners who are not familiar with the greater than 2000 skin diseases. Interestingly, it considers Bowen’s disease, as well as lentigo maligna, premalignant, even though the paragraph named Bowen’s disease defines it as intraepidermal squamous cell carcinoma! These are widely accepted to be in situ malignancies, confined to
the epidermis. Regarding them as premalignant seems archaic and obsolete. The recommendation to avoid punch biopsies in the diagnosis of basal cell carcinoma, as they may introduce tumor deeper into the dermis, is likewise not supported by the scientific literature. Lastly, in the clinical picture quiz at the end of the book, it states that seborrheic keratoses have no malignant potential, which is not entirely true, as there have been reports of both melanoma and nonmelanoma skin cancers arising in association with a seborrheic keratosis. This is misleading and may cause general practitioners or medical students, not invested in dermatology, to ignore changes in lesions they suspect to be seborrheic keratoses. The companion Web site basically contains the same images as does the book, albeit in a slightly larger format; however, there is a useful word document: “Dermatology: further online reading,” which has direct links for free open-access journals, dermatology image Web sites, and Web sites for clinical guidelines. It also very nicely lists sources for researching guidelines (www.euroderm.org) or systematic reviews (http:///skin.cochrane.org), as well as the best resources for dermatology on the Web. This is invaluable for students and practitioners in the current day, where information is most readily sought through the World Wide Web. Overall, this textbook is more about the approach to the patient than the approach to the diagnosis. In this sense, it can be used for a quick algorithmic evaluation of what someone not familiar with skin diseases encounters in practice, with quick short tips on management. I would recommend double-checking any major decisions that rely on this text in a well-referenced scientific source.
Reviewed by Vesna Petronic-Rosic, MD, MSc, Associate Professor of Dermatology, University of Chicago Pritzker School of Medicine, Chicago, IL • E-mail: vrosic@medicine.bsd.uchicago.edu
SKINmed. 2013;11:383
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28/03/12 12:1 9:5 24/12/11 19/01/12 2:0
IMPORTANT INFORMATION ABOUT ®
Mirvaso
(Brimonidine) Topical Gel, 0.33%* *Each gram of gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base BRIEF SUMMARY This summary contains important information about MIRVASO (Mer-VAY-Soe) Gel. It is not meant to take the place of the full Prescribing Information. Read this information carefully before you prescribe MIRVASO Gel. For full Prescribing Information and Patient Information please see package insert. WHAT IS MIRVASO GEL? MIRVASO (brimonidine) Topical Gel, 0.33% is a prescription medicine that is used on the skin (topical) to treat facial redness due to rosacea that does not go away (persistent). WHO IS MIRVASO GEL FOR? MIRVASO Gel is for use in adults ages 18 years and older. WHAT WARNINGS AND PRECAUTIONS SHOULD I BE AWARE OF? MIRVASO Gel should be used with caution in patients that: • • • • • • • • •
have depression have heart or blood vessel problems have dizziness or blood pressure problems have problems with blood circulation or have had a stroke have dry mouth or Sjögren’s Syndrome have skin tightening or Scleroderma have Raynaud’s phenomenon have irritated skin or open sores are pregnant or plan to become pregnant. It is not known if MIRVASO Gel will harm an unborn baby. • are breastfeeding. It is not known if MIRVASO Gel passes into breast milk. You and your female patient should decide if she will use MIRVASO Gel or breastfeed. She should not do both. Ask your patient about all the medicines they take, including prescription and over-the-counter medicines, skin products, vitamins and herbal supplements. Using MIRVASO Gel with certain other medicines may affect each other and can cause serious side effects. Keep MIRVASO Gel out of the reach of children. If anyone, especially a child, accidentally swallows MIRVASO Gel, they may have serious side effects and need to be treated in a hospital. Get medical help right away if you, your patient, a child, or anyone else swallows MIRVASO Gel and has any of these symptoms:
MIRVASO Gel can lower blood pressure in people with certain heart or blood vessel problems. See “What warnings and precautions should I be aware of?” These are not all of the possible side effects of MIRVASO Gel. Remind your patients to call you for medical advice about side effects. You are also encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. HOW SHOULD MIRVASO GEL BE APPLIED? • Remind your patients to use MIRVASO Gel exactly as you instruct them. They should not use more MIRVASO Gel than prescribed. • Patients should not apply MIRVASO Gel to irritated skin or open wounds. • Important: MIRVASO Gel is for use on the face only. Patients should not use MIRVASO Gel in their eyes, mouth, or vagina. They should also avoid contact with the lips and eyes. • Instruct your patients to see the detailed Instructions for Use that come with MIRVASO Gel for information about how to apply MIRVASO Gel correctly. GENERAL INFORMATION ABOUT THE SAFE AND EFFECTIVE USE OF MIRVASO GEL Remind your patients not to use MIRVASO Gel for a condition for which it was not prescribed and to not give MIRVASO Gel to other people, even if they have the same symptoms. It may harm them. WHAT ARE THE INGREDIENTS IN MIRVASO GEL? Active Ingredient: brimonidine tartrate Inactive Ingredients: carbomer homopolymer type B, glycerin, methylparaben, phenoxyethanol, propylene glycol, purified water, sodium hydroxide, titanium dioxide. WHERE SHOULD I GO FOR MORE INFORMATION ABOUT MIRVASO GEL? • Go to www.mirvaso.com or call 1-866-735-4137 GALDERMA LABORATORIES, L.P. Fort Worth, Texas 76177 USA Revised: August, 2013 HCP
• Lack of energy, trouble breathing or stops breathing, a slow heart beat, confusion, sweating, restlessness, muscle spasms or twitching. WHAT ARE THE POSSIBLE SIDE EFFECTS OF MIRVASO GEL? The most common side effects of using MIRVASO Gel include: • redness, flushing, burning sensation of the skin, skin irritation Skin redness and flushing may happen about 3 to 4 hours after applying MIRVASO Gel. Ask your patients to tell you if they get skin redness and flushing that is uncomfortable. Mirvaso and Galderma are registered trademarks. ©2013 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway Fort Worth, TX 76177 MIR-164B Printed in USA 08/13 Mirvaso Brief Summary HCP R3.indd 1
References: 1. Fowler J Jr, Jackson JM, Moore A, et al; Brimonidine Phase III Study Group. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12(6):650-656. 2. Mirvaso [package insert]. Galderma Laboratories, L.P. Fort Worth, TX; 2013.
9/4/13 11:51 AM
Help your patients with facial erythema of rosacea experience...
Not an actual patient. Individual results may vary. Results are simulated to show a 2-grade improvement of erythema. At hour 12 on day 29, 22% of subjects using Mirvaso Gel experienced a 2-grade improvement of erythema compared with 9% of subjects using the vehicle gel.*
RAPID AND SUSTAINED ERYTHEMA REDUCTION BROUGHT TO YOU BY ® M I R V A S O ( b r i m o n i d i n e ) T O P I C A L G E L , 0 . 3 3 %† • The first and only FDA-approved topical treatment specifically developed and indicated for the facial erythema of rosacea1 • Fast results that last up to 12 hours1 • The most commonly reported adverse events in controlled clinical studies included erythema (4%), flushing (2%), skin-burning sensation (2%), and contact dermatitis (1%)2 Important Safety Information Indication: Mirvaso® (brimonidine) topical gel, 0.33% is an alpha-2 adrenergic agonist indicated for the topical treatment of persistent (nontransient) facial erythema of rosacea in adults 18 years of age or older. Adverse Events: In clinical trials, the most common adverse reactions (≥1%) included erythema, flushing, skin-burning sensation, and contact dermatitis. Warnings/Precautions: Mirvaso Gel should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. Alpha-2 adrenergic agents can lower blood pressure. Mirvaso Gel should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease. Serious adverse reactions following accidental ingestion of Mirvaso Gel by children have been reported. Keep Mirvaso Gel out of the reach of children. Not for oral, ophthalmic, or intravaginal use. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see brief summary of full Prescribing Information on the following page.
See for yourself. Visit www.mirvaso.com/hcp. *Phase 3 clinical studies of 553 subjects 18 and older. Subjects were randomized 1:1 to either Mirvaso Gel or vehicle for 29 days. Subjects and clinicians were asked to grade the improvement they saw at 30 minutes and hours 3, 6, 9, and 12 following application. † Each gram of gel contains 5 mg of brimonidine tartrate equivalent to 3.3 mg of brimonidine free base.