Journal of the Eumpean Academy of Dermatologg
`v. 27, no. 3 (Mar. 2013)
`General Collection
`W1 JOQZQ
`2013-03-1211:39:52
`
`Iournal of the European Academy of Dermatology and Venereology
`
`Volume 27 Number 3 March 2013
`
`wmv.jeadv.com
`
`
`
`l
`
`l
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`'.I
`1
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`T1'flatment of Dermatophyte
`Toenail Onychomycosis
`
`Cellulite’s Etiology
`lllfl'lood Mycosis Fungoides
`
`Sporotrichosis
`
`Pemphigus vulgaris
`
`‘ 2011 [m
`2.980
`
`Pact Factor:
`
`PROPERTY or THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`WI LEY
`Blackwell
`
`EADV“
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`EUROPEAN ACADEMY OF DERMATOLOGY AND VENERIEOLDGY lwmvcaduurgl
`ISSN mamaswmex-aow (Dunne)
`
`Page 1 of 15
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`Acrux V. Kaken
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`IPR2017-00190
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`Kaken Exhibit 2052
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`
`
`JEADV
`
`AIMS 8: SCOPE
`
`The journal oflhe European ACIIdEZJ'Hy oflkrmnialogy (incl Venereolugy (IEADV) publishes articles of general and practical interest in
`the field oidermatology and venereology including clinical and basic science topics, as well as research with practical implications. It
`does so through editorials. review and practice articles, original papers of general interest. short repmts» ICUCTS ‘0 The edilor, Features
`and EADV announcements.
`
`JEADV Editorial Board
`Jeffrey D. BERNIIARD (US)
`111011135 iilliltlill (DIE)
`Lassa II. liIiAA'I-I'IEN (Cl I)
`Ieffrey CALLEN (US)
`Francisco CAMACHU MARTINEZ. (1&3)
`Stephano CIIIMI‘INTI (I'i‘)
`lioni Ii. [ELIEWSKI (US)
`Dan [:URSIL'A (RU)
`lean [acques 6110 it (Flt)
`Aditya Kutnar GUP'I'A (CA)
`Rudolf HAPPLE (DIE)
`]-.1n-.1[[IE]{COGOVA (CZ)
`Andreas: D. KA’I‘SAMBAS (GR)
`Stephen 1. KA'I'Z (US)
`l’eter Kurl KOHL (DE)
`Jean-Marie LACI'ir’tI’ELLli (lili)
`Mark LiiliWDHL (US)
`[meph L. PACE (MT)
`Lawrence C. PARISH (U3)
`Gerald E. PIIERARU (HIE)
`Frank C‘ POWELL (IE)
`'l‘humas RUZICKA (DIE)
`Beriholtl liZANY (DI-Z)
`Robert A. SCI lWAlt’l‘Z (us)
`H. Peter BUYER (AU)
`Georg S'I‘INCI. (AT)
`Kristian TIIIiS'l‘RUIL[’EDERSEN (UK)
`Ronni WOLF (IL)
`
`Board of Directors
`Agustin ALOMAI'Z (I13)
`Sihe] ALPER ('I'R)
`lnsettc ANDRE ([iL‘.)
`Christina AN'l‘ONlOU (Git)
`Petr ARIENIEERGLIR (CZ)
`Ionathan BARKER (GB)
`i‘L‘tL‘I' “LOCI-I (CH)
`Michael ISOFI’A (M'l')
`Maryse IlItANDIiNBURGI-LR (LU)
`Magnus BRUZIi (SE)
`Maliitltt BYLAI'I'E (LT)
`l’iergiacomo CALZAVARA-I’IN‘I‘ON (IT)
`Pavel CHIERNYSHDV (UA)
`Florence CORE: lltli'l' (FR)
`ltodica coscmmaa (1:0)
`America FICUEIIIEDO (P'I')
`l-lerherl HONIGSMANN (AT)
`Iilllll KAZANDIIEVA (HG)
`Lajos [(EMIENY (HU)
`Ktilii KINGO (EE)
`Alcxey KUlir‘tNOV (RU)
`
`JEADV Advisory Board
`Robert IiAItAN (FR)
`Ulrike BLUMII-PEYTAVI (DIE)
`Michael BOFFA (M'l‘)
`Luca G. HOIULMKHH (CI-I)
`Sarah BRENNER (IL)
`'I'humas DIEI‘GIiN (DIE)
`James FERGUSON (GB)
`Ramon GRIMAL'I' (ES)
`Roderick Iames i-iAY (C B)
`Karl llOLUlmR (at)
`Demetris IOANNIDI‘IS (GR)
`[can KANI'I'AKIS (17R)
`Gertruud KRIEKI'II.5 (NL)
`Michael LAND'I'I-iALIER (DE)
`’l‘homas LUGIJR (DE)
`Hans ML-‘ltK (DH)
`ILA. Martini) NIEUMANN (NL)
`Carlo [’AUI. (Flt)
`Huberl I’EIIAMBERGER (A'i')
`Francoise I’OOT (BE)
`Albert—Adrien ItAMliLI-j'l' (CII)
`Johannes RING (DE)
`largen StiltU1’(l)K)
`Iirwin 'i'SCI IACI I LER (AT)
`Giovanna ZAMBRUNO (1’1")
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`Board of Directors (cont)
`Iulicn I.1\MBIER'1'(BLE)
`Claus LU'I'ZUVV-I'IULM (NU)
`Branka MARINOVIU (11R)
`Pauline MARRI‘EN (Ill)
`Ljiljana MIEDIENICA (RS)
`Martino NIIUMANN (NL)
`Juraj PEG (SK)
`Ramon 1’ UJOI. (ES)
`T'JPIU IlAN'i'ANIiN (Iii)
`Mich.th REUSCII (DE)
`Martin REJL'KEN (DI-2)
`Franco IIONCHOIE'I'II'I (I’I')
`Silvestrx ItUIilNS (LV)
`Sedef SAHIN (TR)
`Carmen SALAVAS'I'RU (R0)
`Dillliil'IS SO'i'IRIADIS (UK)
`Iacck SZEPIIYI'UWSKI (I’L)
`Kristin 'I‘HOIUSDO‘I'TIR (IS)
`Georgina: VA K15 (CY)
`Catherine VAN MON'i'IIIiANS (NL)
`
`JEADV EDITORIAL BOARD
`
`Editor-in-Chiet
`lean-Paul OR'I'ONNEE (FR)
`Ilépital L’Archet 2 — Dermatologie
`BP 307“)
`06202 Nice Cedex 3 - France
`E—muil: <1rtt)|1|1e@ttnice.fr
`
`ASSistant Editors
`Lorenzo (IiiltltONl (AT)
`'l‘hierry I’ASSI‘illUN (FR)
`
`Editoriai Stat!
`Marys: (ILAPI’IHR
`Ii- mail: marysexlappierEnu niceJ'r
`
`Statistical Adviser
`Alan KELLY (IE)
`
`Founding Editors
`'I'orello LO'f'l‘l (l'l‘)
`Derek FREEDMAN (IE)
`
`Honorary Editors
`Otto BRAUN—t-IALCO (ma)
`lean CIVA'i‘TF. (FR)
`Iohn HARRIS (G13)
`Stefania JABLONSKA (PL)
`I'En‘liiianu i-’ANCONESI (IT)
`
`EADV LEADERSHIP
`
`Executive Committee
`Inna HERCOGOVA (CZ)
`I‘resident
`Erwin 'I‘SCHACHLIER (AT)
`President-elect
`Frank POWELL (iii)
`Past President
`Carle I‘AUL (FR)
`Secretary-General
`lorgen RONNl-ZVIG (N0)
`'l‘rcasurer
`
`Ljiljana MEDENICA (RS)
`Representative of the Board
`Martin ROCKL-LN (on)
`Representative of the Board
`
`Page 2 of 15
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`HEADV
`
`CONTENTS
`
`March 2013 Volume 27, Issue 3
`
`
`
`REVIEW ARTICLES
`
`Terbinafine in the treatment ofdermatophyte toenail onychomycosis: a metaianalysis of efficacy for
`continuous and intermittent regimens
`AK. Gupta, M. Paquet, F. Simpson, A. Tavakkol
`
`Cellulite’s aetiology: a review
`M. tie In Case Aimcido, C. Suarez Serrano, I. Robotic Roldan, 1.]. Iii-ne‘nez Rejnno
`
`
`
`ORIGINAL ARTICLES
`
`Vitiligo patients from India (Mulnbai) show differences in clinical, demographic and autoantibody
`profiles compared to patients in western cunntries
`V. Pmdhmi, M. Patwordhan, V. Timkkor, V. Khorkor. U. Khopkm‘, K. Ghosh, AP. Weetmnn,
`DJ. Gawkrodger, EH. Kerri}!
`
`Efficacy, safety and tolerability of topical terbinafine nail solution in patients with niild-to-Inoderate
`toenail onychomycosis: results from three randomized studies using double—blind vehicle-controlled
`and open—label active-controlled designs
`BE. Elewski. MA. Glimmoum. P. Mayser, AK. Gupta, H.-C. Korting, R], Si-Jouey, DR. Baker, PA. Rich,
`M. Ling, S. Huger, B. Damoj, I. Nyimdy, K. Thongnveln. M. Notter, A. Pnrnei'x-Spake, B. Signrgeirssmi
`
`Childhood mycosis fungoides: a report of 20 cases from Turkey
`KJ). Yazgmwglu, Z. Topkm'ei, N. Bnyrrkbnbmii, C. Baylml
`Facial sebum affects the development of acne. especially the distribution of inflammatory acne
`C. W. Choi, LW. Choi. ICC. Park. S. W. Your:
`
`Comparative study of treatment efficacy and the incidence of post—inflammatory liyperpigmentation
`with different degrees of irradiation using,F two different quality—switched lasers for removing solar
`lentigines on Asian skin
`K. Negishi, H. Akita, S. Tamika, Y. Yokoyomo, S. Waknmntsn, K. Matstmaga
`
`Report of 457 sporotrichosis cases from Jilin province, northeast China, a serious endemic region
`Y. Song, 51-5. Li. 3,-X. Zhong. Y.—Y. Lin. L. Yon. S.-S. Him
`
`Association of psoriasis with the VEGF gene polymorphism in the northern Polish population
`M. Zabloma. M. Sobjanek, B. Nedoszytku, M. Lange, D. Kozicka, j. Glen, Ii Roszkiewirz
`
`A randomized two-sided placebo-controlled study on the efficacy and safety of atmospheric
`nonthermol argon plasma for pruritus
`I. Heirtlm. G. lsbary, W. Stole, F. Zemmi, M. Loridthrder, G. Morflll, T. Shimizu, IL. memermami,
`S. Karrcr
`
`The effects of systemic isotretinoin and antibiotic therapy on the microbial Horas in patients with acne
`vulgaris
`RY. Bfl§flk, HS. Germ. i. Giirses. AG. Ozscven
`
`Clinical significance of serum retinol binding protein—4 levels in patients with systemic sclerosis
`T. Toymtm, Y. Asmw, T. Tnkalmshi, N. Aozasn, K. Akmimta. S. Node. T. Tanignchi, Y. {chin-mm,
`H. Sumida. Z. 'i’amaki, Y. Masai, Y. Ttldfl, M. Sugaya. 3. Sato, T. Kaa‘ono
`
`267
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`273
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`279
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`287
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`301
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`307
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`313
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`319
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`324
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`332
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`337
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`This materialwas copied
`at the NLM and maybe
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`Page 3 of 15
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`JEADV
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`COVER iLLUSTRATION
`
`Il’ml’l‘oC'i’tcs aligned in epidermal basal
`[Case 12) (llll X400}
`
`IJYL‘I'. purpura in the papillary dermis
`
`Page 4 of 15
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`

`) HA I) V
`m
`
`345 Rcsveratrate protects human skin from damage due to repetitive ultraviolet irradiation
`l: W“, LI-L 1”" Y"N' th’fi Xs'G» X“, Yr]. Lao, B. Wang: 1.2.5. Chen. X.-H. Goo, H-D. Chen, M. Matsui.
`.-H. Li
`
`351 Estimation of tissue osteopontin levels before and after different traditional therapeutic modalities in
`psorialic patients
`NH. El-El'slti, D. Kadry, ILA. Hcgazy, L_ Rushed
`
`356 A PatCh “Sting and “055"50n5itiVitY Study of carbamazepine-induced severe cutaneous adverse drug
`reactions
`
`Y.—'l‘_ Lin. Y."C. Chang, R.C.~Y. Hui, (2—H. Yang. H.—C. Ho. S.-I. Hung, W.-H. Chang
`
`365 Status of oxidativc stress on iesional skin surface of plantar warts
`O. Arimn. P. Ozturk, lil}. Kurzttns, V. Unsai
`
`370
`
`Self—declared sensitive skin in China: a community—based study in three top luetmpulises
`F. X34. S. Yam. M. Wu. F. Li. Q. Sim. W. Lai. X. Sheri. N. Rahhali, C.
`'l‘aieb, I. X1!
`
`376 Mucocutaneous manifestations of HIV-infected patients in the era of HAAR‘I‘ in Guangxi 21mm”;
`Autonomous Region, China
`1. Han, W.H. Lam. Z.H. Meng, K. Huang, Y. Mao, W. Zhu, S. Lian
`
`W S
`
`HORT REPORTS
`
`333 Determinants of social anxiety and social avoidance in psoriasis outpatients
`G. Schneider, G. Hellfi. I. Huckmmm
`
`387 The influence of systemic therapy on the serum levels of IL-6 and IL78 in pemphigus
`vulgaris
`H‘ Mormz‘m" F' Bab‘mfim‘f‘lgh‘ll M- Akbflrzadeha N- Rem-2‘!) AA. Amirzargur, M. Daneshpazhooh,
`A. fulfill, Z Halloji
`
`
`
`LETTERS TO THE EDITOR
`
`391 Classification of acne scars is difficult even for acne experts
`AY— Finlay: V- Torres- 3- Kai's: V- Berton; B. Dram, CL. ooh, H. Gollriiclc, of: behalf ofthc Global
`Alliance
`
`393 Mucocutaneous teiangiectasia — it’s the tip of the iceberg
`B.C, Bdckle, M. Shoukier, S. Know-1.8, NT. Sepp
`
`395
`
`Increased levels ofCOX—Z and oral lichen planus
`RD. Pigatto. F. Spadarl, GP. Bombeccori, G. Guzzi
`
`395 Reply to increased levels of COX-2 and oral lichen planus by PD. Pigatto, F. Spaderi, G.P. Bombeccari,
`G. Guzzi by Danielsson er al.
`K. Danielsson, M. Ebrahimi, KB. Wahlin, K. Nyltmder, L. Boldrtip
`
`
`397 Forthcoming events
`
`
`
`398 Announcement
`
`Page 5 of 15
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`

`

`JEADV
`
`ONLINE ARTICLES
`
`The following articles are available exclusively online as part of this volume
`and issue at: www.jeadv.com
`
`
`e263
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`e271
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`e276
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`e282
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`6289
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`0320
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`e328
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`6333
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`e338
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`e345
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`e357
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`e363
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`ORIGINAL ARTICLES
`
`2012 European guideline for the management of anogenital warts
`C.IN. Lacey, SC. Woodhaii, A. Wikstrom, J. Ross
`
`Biomarkers of oxidative stress in epidermis of Tunisian pemphigus foliaceus patients
`0. Abide, B. Garguuri, R. Ben Monsoon M. Mseddi-Djemal', A. Masmoudi. M. Ber: Aycd, M. Abdeimoaia,
`H. Tar-kt, S. Lasseued, H. Masmoudi
`
`Quality of life in alopecia areata: a disease-specific questionnaire
`G. Pabbmcini, L. Panarielio, V. De Vita, C. Vinccnzi, (2. Laura, D. Nappo, Ii. Ayala, A. Tom
`
`Differences between objective efficacy and perceived efficacy in patients with palmar hyperhidrosis
`treated with either botuliaum toxin or endoscopic thoracic sympatheetomy
`MA. Alvarez, I. Ritano, F]. Gomez, E. Cases, C. Bnamoml'e, A. Salvatferm, LC. Moreno
`
`Lipoprotcin-associated phosPholipase A, level in patients with Behcet’s disease
`A. Orem, S. Yayli, DA. Arica, B. Akcaa. 14'. B. Yiicesmi, S. Balmdz‘r
`
`Evaluation of tourists' UV exposure in Paris
`E. Mahé. MP. Corréa. S. GodiaeBeekmana, M. Haeflelin, F. Iéguu, P. Suing, A. Benuchct
`
`Efficacy and safety ofacitretin in three fixed doses of 25, 35 and 50 mg in adult patients with severe
`plaque type psoriasis: a randomized, double blind, parallel group, (lose ranging study
`3. Dogm, A. Iain, AJ. Kanwar
`
`A simple scoring system for the diagnosis of palino-plantar pigmented skin lesions by digital
`dermoscopy analysis
`P. Rubegni, G. Cevertini, N. Nomi, G. Argenziano, T. Snider, M. .tinrmai, P. Quagiino, R. Bonn,
`R. HofirrnnneWeernhof, M. Fimfani
`
`Correlation among metallothionein expression, intratumoural macrophage infiltration and the risk of
`metastasis in human cutaneous malignant melanoma
`E. Emri, K. Egcrvari. T. Vnrvoigyi, D. Rezso, E. Mike, B. Dezso, I. Veres, G. Makes, G. Emrf, E. Remeayfk
`
`Effect of skin pH for wrinkle formation on Asian: Korean, Vietnamese and Singaporean
`KC. lung, 8.}. Kirn,].C. Che, KD. Sula. G.W. Nam
`
`Effect of physician dress style on patient confidence
`A. Mormmi, I. Leger. B. Giraadeau, M. Naomi, Ii. Le dere. M. Samiraf, M. Deluge
`
`Hereditary angioedema: first report of the Brazilian registry and challenges
`AS. Grumach. 5.0.1-3. Valle, E. Toledo, D. {it} Memes Vascancelos, M.M.S. Villain, H. Monsoon 1A. Pinto,
`RA. Campos. AT. France, 011 beiiay‘ofgroup interested rm HAE (GINHA)
`
`Freckles and solar lentigines have different risk factors in Caucasian women
`K. Ezzea'iae, E. Manger. I. Latreifi'e, R. Mid, D. Mahry. F. Grnber. P. Galaa, 8. Hercberg, If.
`
`'i‘schachler, C. Gail-101
`
`Ilirhombic flap, a modified biiobcd flap, for repair ofnasal defect
`AM. Skarfa
`
`Randomized, double-blind, placebo—controlled study of safety and efficacy of miltefosine in
`antihistamine—resistant chronic spontaneous urticaria
`M. Magerl, M. Rather, T. Bieber, T. lifedermaaa, I. anth, R. Dominicus, N. Hicrzzelmmm, T. Jakob,
`V. Mnhier, G. Popp. K. Schc‘ikef, R. Schliagcnsiepea, I. Schmitt, F. Siebeahaar, }.C. Simon. P. Sraubach.
`B. Wadi, C. Weidaer, M. Maurer
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`Page 6 of 15
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`6435
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`The relationship between oxidative stress. smoking and the clinical severity of psoriasis
`S. Era-ire, A. Marin. DJ). Demirseren. 5. Kiiic. S. isikoght. O. Bret
`
`Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a
`phase II, multicenter, randomized, double-blind, Placebo-controlled, parallel-group, dosercomparison
`study
`KA. Popp. R. Katya-man, D. Thaci, C. Ir‘u, D. Sitti-ierim-rd, P. Roimne
`
`Efficacy and safety of systemic methotrexate vs. acitrctin in psoriasis patients with significant
`palmopiantar involvement: a prospective, randomized study
`A.B. Janagond. A]. Kanwar. S. Handn
`
`IL—13: a marker of Chromium contact allergy
`I..I:'.A.M. Martins. V.M.S. Reis
`
`i’retherapeutic laboratory findings, extent of metastasis and choice of treatment as prognostic
`markers in ocular melanolna— a single centre experience
`N. Schicher, G. Edeihcmser. K. Han-mmkaya, K. Schindler, A. Gieiss, H. Pehnmbcrgcr. C. Hustler
`
`Efficacy and safety of diphenylcyclopropenone among Chinese patients with steroid resistant and
`extensive alopecia areata
`MM. Lnk, LS. Chin. KC. Lee, C.T.S. Chan, V. W.Y. Lee. M. Chang, KK. Lian-z, H. C. Lee
`
`
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`SHORT REPORTS
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`Nevns oligemicus: a case series
`A. Barriiia. A. Flérez, C. Posrida, C. De in Torre
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`Methotrexate for treatment of lichen planus: old drug, new indication
`AJ. Krmwnr, D. De
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`Correlation of photographic images from the Leeds revised acne- grading system with a six-category
`global acne severity scale
`IKE“ Tan. X. iii-tang. E. Jones, L. Bulger
`
`DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function
`variants
`
`AH, Ziyab, W, Kara-mas, J. W. Hoiiowny. H. Zhrmg. S. Ewart. SH. first-rad
`
`Counselling on sun protection, a survey of French paediatricians
`E. Mahe', R. Assathimty, F. Foy—Chrtieirtrd, M. 'l'ayior, S. Bonwcsse, M. Navel, P. Sning, B. Ciievailier,
`n. Beaurhet
`
`French teenagers and artificial tanning
`'i'elta, A. Banach-2.5. I. Vouidoukis, }.—F. Se'i, P. Beniilien, MrL. Sigai. E. Mohé
`
`
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`LETI'EFIS TO THE EDITOR
`
`Ocniocntancous albinism and skin cancer risk
`
`H. C. dc Vijider, H. M. (iii! Vije‘der, H.A.M. Ncommm
`
`Why there is a wide difference in the clinical and mycological results in different onychmnycosis
`clinical studies
`A. Simmer, R. Sci-tar. R. Forhi, R. Megan. R. Daniel
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`Urticaria-like follicular mncinosis: four new cases of a controversial entity
`E. Cinotti. D. Basso. P. Donati, A. Parodi, F. Rorrgioietti
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`
`DOI: 10.1111fj.1468-3{]83.2011.043731 IEADV
`
`ORIGINAL ARTICLE
`
`Efficacy, safety and tolerability of topical terbinafine nail
`solution in patients with mild-to-moderate toenail
`
`onychomycosis: results from three randomized studies
`using double-blind vehicle—controlled and open-label
`active—controlled designs
`
`as. Elewski,” MA. Ghannoum,‘ P. Mayser.§ AK. Gupta.‘- H.-c. ironing,” ad. snouey,ii
`on. Baker.§§ P.A. Rich.“ M. Ling.m s. Hugot.iii B. Damaj.§§§ J. Nyirady.‘-'-' K. Thangaveluffi
`M. Notter.iii A. Parneix-Spake.-
`' B. SigurgeirssonwrT
`TDepartment of Dermatology, University of Alabama at Birmingham School of Medicine. Birmingham. USA
`tCenter for Medical Mycology. Case Western Reserve University. Cleveland and University Hospitals of Cleveland. Cleveland,
`OI l. USA
`ficentor of Dermatology and Andrciogy. Justus Liebig University, Giesscn. Germany
`'Division of Dermatology. Department of Medicine. University of Toronto, Canada
`tiDepar‘tn’icnt of Dermatology and Allergy. Ludwig Maximilian University. Munich. Germany
`t*l—larrisonlourg Foot Clinic. Harrisonburg. VA. USA
`’i’J‘Aliergy. Asthma & Dermatology Research Center. LLC. Lake Dewego. OR. USA
`"Oregon Dermatology and Research Center. Portiand. OH. USA
`“TMedaphase |no.. Newnan. GA, USA
`mNcwanis Pharma AG. Basei. Swrtzerland
`'i'i'iivexivied (USA). Inc., San Diego. cA. USA
`"' Novartis Pharmaceuticals Corp. East Hanover. NJ. USA
`er[Iropartment of Dermatoicgy, University of Icoland. Reytqavik, iceland
`‘Correspondence: B.E. Elewski, E-mail: bee!ewski@aci.com
`
`Abstract
`Background Terbinafine nail solution (we) was developed for the treatment of onychomycosis.
`Objective To assess the efficacy of TNS vs. vehicle and amorolfine 5% nail lacquer.
`Methods Subjects with mild-to-moderate toe onychomycosis {25% to 575% nail-involvement. matrix uninvolved)
`were randomized to receive either TNS or vehicle in two double-blind studies. and to This or amorolfine in an active-
`controlled. open—label study. Primary endpoint was complete cure (no residual clinical
`involvement and negative
`mycology) at week 52. Secondary endpoints were mycological cure (negative mycology defined as negative KOH
`microscopy and negative culture} and clinical effectiveness {emu/o residual—involvement and negative mycology) at
`week 52.
`
`Results Complete cure was not different between TNS vs. vehicle and amorolfine. Mycological cure was higher
`with TNS vs. vehicle. as was clinical effectiveness with TNS vs. vehicle. and This and amorolfine were not different
`for secondary efficacy endpoints. Patients achieving mycologicai cure had a better clinical outcome. and efficacy
`was improved in subjects with milder disease. Post has analysis suggests that nail
`thickness is an important
`prognostic factor. Moreover, mycological cure may require ES months of treatment regimen while complete cure and
`clinical effectiveness may be achievable only after 10 months. A simuiation study suggests that longer treatment
`duration would have resulted in higher complete cure with TNS vs. vehicle. Study treatments were well—tolerated.
`Conclusion Primary efficacy objectives Were not met in the studies reported herein. Possible reasons for failure to
`achieve significant outeo mes include insufficient length of treatment; stringency of primary endpoint and severity of
`nail involvement of study population.
`Received: 29 May 2011: Accepted: 10 November 2011
`
`Conflict of interest
`
`H.C. Korting has previously collaborated with Novartis in the development of topicals containing terbinafine. and
`with Gaiderma concerning amorolfin-containing preparations. Drs'. P. Mayser,
`Fi. Shouey, A. Gupta and B.
`
`IEADV 20H}. 2?. 287—294
`
`Journal of the European Academy of Dermatology and Venoreology o 2th European Academy of Dermatology and Venereoiogy
`
`(o 2011 The Authors
`
`Page 8 of 15
`
`

`

`Elewski et at.
`285
`WW
`
`Sigurgeirsson have no conflict of interests. 3. Hugot, M. Notter. K. Thangavelu. A. Parneix-Spake and J. Nyirady are
`employees of Novartis. Drs' ELE. Eiewski, P. Rich and M. Ling have received research grant fund from Novartis for
`the perlorming of the study. Dr B. Damaj
`is an employee of NexMed {USA},
`Inc. Dr D. Baker was a principal
`investigator at one of the research sites. Dr M. Ghannoum has accepted as a consultant
`for Novartis
`Pharmaceuticals.
`
`Funding sources
`Novartis Pharma AG. Basel, Switzerland.
`
`Introduction
`
`the most common cause of nail dystrophy,
`Onychomycosis is
`affecting 12—13% of the general p0ptllt‘ttl0n.1_7 and 25% of the
`geriatric and diabetic populationfi'm The disease can be painful or
`cause functional disability, psychosocial problems and compro,
`mised quality oflife.'0'12
`Topical treatments are generally reserved for mild cases of ony—
`cltomycosis as they are less effective than systemic oral therapy
`due to reasons including poor penetration,
`less depot effect and
`1055 depot area.13 However, systemic therapy is not recommended
`in some patients due to the risk of possible drug—drug interactions
`and patient co-inm'biclities.'4'15 Because of the slow growth rate of
`toenails, treatment of tee onychornycosis is more challenging than
`finger onychomycosis and it may take up to 18 menths of therapy
`to achieve clearancem'zu Although topical agents like amorolfine
`5% (marketed in Europe) and ciclcpirox 8% (available in Europe
`and US) formulated as lacquers have improved drug delivery to
`nails,2| cure rates are lower than with systemic therapy and
`re-infection or relapse often occurs, as is the case with oral antir
`Fungal thciczip}r.H'""22‘23
`Terbinafinc, a synthetic allylarninc is a well-established broad—
`spcctrum anti—fungal drug.z'l with unique cliniml efficacy combined
`with good toleral'rilit’y.W‘25 Based on the reservoir effect observed
`with a film-forming solution of terbinafine 1%25'27 (allowing for a
`single-application treatment of inrerdigital
`tinea pedis), a nail
`solution [topical
`tcrbinaftoe HCl nail solution (TNSH was
`developed. This formulation demonstrated mycological and clinical
`efficacy in in Vim}23 models of onyChomycosis and was superior to
`ciclopirox 8% nail lacquer in a Phase II study.29 This article presents
`results from three large clinical studies [two vehicle—controlled
`(2301 dz 2302) and one active comparator-controlled study
`[2303]} which assessed efficacy and safety of This used for 24
`weeks and 48 weeks in patients with mild—to~modcratc toenail
`onychomycosis.
`
`Methods
`
`controlled study, subjects received either TNS or amorolline 5% nail
`lacquer for 48 weeks followed by a treatment free period oft! weeks.
`The total duration of each study was 52 weeks. Subjects were
`randomized using a validated automated system in equal ratios.
`The studies were conducted in accordance with the ethical prin—
`ciples specified in the Declaration of Helsinki and in compliance
`with the requirements of local regulatory committees and all sub-
`jects provided written informed consent.
`
`Subjects
`
`Subjects aged 12—75 years with mild—to-moderate toe onychoiny-
`cosis of the great toenail due to dermatophytcs were included.
`Mild-to—moderatc toe onychomycosis was defined as a toenail
`involvement of 225% to 575% without spikes and without matrix
`(lunula) involvement, and nail infection was confirmed by positive
`KOH microscopy and culture of a dermatophyte. The subjects
`who had nail abnormalities, obscuring appearance of infection-free
`normal nail (including traumatic or onychogrypltotic nail) or in
`whom the target toenail had <2 mm unaffected nail plate length
`beyond the proximal fold were excluded. Also excluded were those
`with severe plantar tinea pedis requiring systemic therapy, mixed
`infections (dermatophyte and nonrdcrmatophyte), tlcrmatophye
`toma (thick masses of fungal hyphae between the nail plate and
`nail bed),30 those receiving systemic or topical anti—fungal therapy
`within 6 months or 3 months, respectively, and those who used
`any commercial topical nail medication within 1 month. Subjects
`with severe diabetic foot neuropathy, malignancy, and sensitivity
`to the study medication were also excluded.
`
`Treatment
`
`'l'crbinafinc nail solution or vehicle were supplied in identical
`packaging and were to he applied daily to all affected toenails with
`no surgical dcbrideincnt, chemical avulsion, excessive grinding or
`filing of diseased nails. Amorclfinc 5% nail lacquer was supplied
`as commercially available and was used as per label, twice weekly
`and with filling of the nails, as desu'ihcd in the package insert.
`
`Study design
`In the vehicle-controlled studies, subjects received either 'I'NS or
`vehicle for 24 weeks or 48 weeks followed bya treatment free period
`of 28 weeks or 4 weeks respectively.
`in the active comparator-
`
`Efficacy and safety assessments
`The primary efficacy measure was the proportion ofsubjects achiev—
`ing complete cure (no residual clinical involvement and negative
`KOH and culture) of the target teenail at week 52. The secondary
`
`}EADV 20l3. 2?, 287—294
`
`it} 201 1 The Authors
`Joumal of the European Academy 01 Dermatology and Venereology to 201 1 European Academy 0! Dermatology and Venereology
`
`Page 9 of 15
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`289
`
`Terblnafine nail solution for toenail onyohomyoosis
`
`efficacy endpoints were rates of mycologieal cure (negative KOH
`microscopy and negative culture for dermatophyte), clinical effec-
`tiveness (510% residual involvement of the target toenail. negative
`culture and negative KOH microscopy) and clinical cure (no resid—
`ual involvement of the target toenail) at week 52. In addition, the
`proportion of subjects achieving a negative Culture and 250%
`decrease in per cent involvement ofthe target toenail was analyzed.
`The safety assessments included monitoring and recording of all
`adverse events until week 52.
`
`Suseeptibility testing
`'l‘erbinafine susceptibility, expressed as minimum inhibitory con-
`centration (MIC) and minimum fungicidal concentration (MFC),
`for all strains isolated at baseline was assessed using the method
`developed under auspices of the Clinical and Laboratory Standards
`Institute (CLSI).3 "32
`
`Statistical analyses
`Data from the two vehicle-controlled studies were Combined for
`
`analysis. The intent—to-treat (I’l‘I‘) population included all subjects
`who were randomized and dispensed study drug and the safety pop-
`ulation included all subjects who received at least one dose of study
`drug. For the combined analysis of the efficacy, a normal inverse
`
`combination rest was performed that c