CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2065 - 1/13
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`JOURNAL OF THE AMERICAN ACADEMY OF
`
`2007
`
`VOLUME 56
`
`NUMBER6
`
`Copyright© 2007 by tbe American Academy of Dermatology, Inc.
`
`CONTINUING MEDICAL EDUCATION
`
`Obesity and the skin: Skin physiology and skin manifestations of obesity
`Gil Yosipovitch, MD, Amy DeVore, MD, and Aerlyn Dawn, MD, MBA Winston-Salenz,
`North Carolina
`
`CME examination
`
`Answers to CME examination (Identification No. 807-106), June 2007 issue of
`the Journal of the American Academy of Dermatology
`
`I REPORTS I
`
`Results of patch testing to a corticosteroid series: A retrospective review
`of 1188 patients during 6 years at Mayo Clinic
`Mark D. P. Davis, MD, Rokea A. el-Azhaty, MD, and Sara A. Farmer, BA
`Rocheste1~ Minnesota
`
`Patients' perceptions of the usefulness and outcome of patch testing
`Leigh Ann Scalf, MD, Joseph Genebriera, MD, Mark D.P. Davis, MD, Sara A. Farmer,
`BA, and James A. Yiannias, MD Rocheste1~ Minnesota, and Scottsdale, Arizona
`
`A survey of skin disease and skin-related issues in Arab Americans
`Dina El-Essawi, MD, Joseph L. Musial, PhD, Adnan Hammad, PhD, and Hemy
`W. Lim, MD Detroit and DEjarborn, .Michigan
`
`901
`
`917
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`920
`
`921
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`928
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`933
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`GALDERMA
`
`Complimentary subscriptions. to the Journal of the American Academy of Dermatology
`are available to dermatology residents, fellows, and osteopathic dermatology
`residents in the United States and Canada as an educational service by Galderma.
`
`Continued on page 6A
`
`DERMJI(® Complimentary subscriptions to the Journal of the American ·Academy of Dermatology
`
`are provided to the Society of Dermatology Physician Assistants and are supported
`by Dermik Laboratories, a business of sanofi-aventis U.S. LLC.
`
`Journal of the American Academy of Dermatology (ISSN: 0190-9622), is published monthly by Elsevier Inc., 360 Park Avenue South, New York, NY
`10010-1710. Business Office: 1600 John F. Kennedy Blvd., Suite 1800, Philadelphia, PA 19103-2899. Editorial Office: 11830 Westline Industrial
`Drive, St. Louis, MO 63146-3318. Customer Service Office: 6277 Sea Harbor Drive, Orlando, FL 32887-4800. Periodicals postage paid at
`New York, NY and additional mailing offices.
`POSTMASTER: Send address changes to Journal of the American Academy of Dermatology, Elsevier Periodicals Customer Service, 6277
`Sea Harbor Drive, Orlando, FL 32887-4800.
`
`SA
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2065 - 2/13
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`

`
`Contents
`
`continued
`
`Onychomycosis: Diagnosis and deitnition of cure
`Richard K. Scher, MD, FACP, Amir Tavakkol, PhD, Dip Bact, Bardur Sigurgeirsson, MD,
`PhD, Roderick J. Hay, DM, WarrenS. Joseph, DPM, Antonella Tosti, MD, Philip
`Fleckman, MD, Mahmoud Ghannoum, MSc, PhD, David G. Armstrong, DPM, Btyan C.
`Markinson, DPM, and Boni E. Elewski, MD New York, New York; East Hanove1;
`New jersey; Reykjavik, Iceland; Belfast, Ireland; Coatesville, Pennsylvania;
`Bologna, Italy; Seattle, \-Vashington; Cleveland, Ohio; North Chicago, Illinois;
`and Birmingham, Alabanza
`
`Distribution of toenail dystrophy predicts histologic diagnosis
`of onychomycosis
`Hobart W. Walling, MD, PhD, and Patrick J. Sniezek, MD Iowa City, Iowa
`
`A literally blinded trial of palpation in dermatologic diagnosis
`Neil H: Cox, MD, BSc(Hons), FRCP(Lond & Edin) Carlisle, United Kingdom
`
`Outbreak of lepidopterism at a Boy Scout camp
`John T. Redel, MD, MPH, FACP, Ronald E. Voorhees, MD, MPH, and
`Thomas J. Torok, MD, MPH Atlanta, Georgia, and Santa Fe, New Nfexico
`
`Differential expression of decorin in localized scleroderma following
`ultraviolet-At irradiation
`Thilo Gambichler, MD, Marina Slnygan, MD, Nordwig S. Tomi, MD,
`Peter Altmeyer, MD, and Alexander Kreuter, MD Bochum, Germany
`
`High-dose intravenous immunoglobulins for the treatment of
`autoimmune mucocutaneous blistering diseases: Evaluation
`of its use in 19 cases
`Sonia Segura, MD, Pilar Iranzo, MD, Isabel Martinez-de Pablo, MD, Jose Manuel
`Mascaro, Jr, MD, Merce Alsina, MD, Josep Herrero, MD, and Carmen Herrero, MD
`Barcelona, Spain
`
`Descriptive epidemiology of dermatofibrosarcoma protuberans in the United
`States, 1973 to 2002
`Vincent D. Criscione, AB, and Martin A. Weinstock, MD, PhD Providence, Rhode Island
`
`Prevalence of stratified epithelium-specific antinuclear antibodies in 138
`patients with lichen planus
`Aurora Parodi, MD, Emanuele Cozzani, MD, PhD, Cesare Massone, MD, Alfredo
`Rebora, MD, Luigi Priano, MD, Giovanni Ghigliotti, MD, Paolo Balbi, MD, Franco
`Rongioletti, MD, Claudia Micalizzi, MD, Rossella Cestari, MD, Giuseppe Varaldo, MD,
`Gianfranco Barabino, MD, Giuseppe Cannata, MD, Francesco Drago, MD, Vittorio
`Moreno, MD, Luciano Schiazza, MD, Gianfranco Muzio, MD, Enrico Scaparro, MD,
`Bruno Alibrandi, MD, Roberto Bandelloni, MD, Marina Ciaccio, MD, Giovanni
`Desirello, MD, Pier Mario Isola, MD, Stefano Ottoboni, MD, Paolo Rampini, MD,
`Giuseppe Santoro, MD, Stefania Sorbara, MD, and Giovanni Virno, MD Genoa,
`Savona, La Spezia, Imperia, Chiavari, Alassio, and Ventimiglia, Italy
`
`Treatment of pruritus with topically applied opiate receptor antagonist
`PaulL. Bigliardi, MD, Bolger Stammer, MSc, Gerhard Jost, MD, Theo Rufli, MD,
`Stanislaw Biichner, MD, and Mei Bigliardi-Qi, PhD Lausanne, Basel, and Egerkingen,
`Switzerland; and Nfunich, Germany
`
`939
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`945
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`949
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`952
`
`956
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`960
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`968
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`974
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`979
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`6A
`
`}UNE 2007
`
`Continued on page 1 OA
`
`JAM AcAD DERMATOL
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2065 - 3/13
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`

`
`Contents
`
`continued
`
`DERMATOLOGIC SURGERY
`
`Intralesional methotrexate treatment for keratoacanthoma tumors:
`A retrospective study and review of the literature
`Nicole M. Annest, MD, MS, Marta]. VanBeek, MD, MPH, Christopher]. Arpey, MD, and
`Duane C. Whitaker, MD La jolla, California; Iowa Ci~Jl, Iowa; and Tuscan, Arizona
`
`I DERMATOPATHOLOGY I
`
`Prolonged urticaria with purpura: The spectrum of clinical and
`histopathologic features in a prospective series of 22 patients exhibiting
`the clinical features of urticarial vasculitis
`Joyce Siong See Lee, MMed (Int Med), MRCP(UK), FAMS, Teck Hiong Loh, MBBS,
`MRCP(UK), FAMS, Swee Chong Seow, MBBS, MRCP(UK), and Suat Hoon Tan,
`MMed (Int Med), DipRCPath (DMT), FAMS Singapore
`
`Mast cell distribution, activation, and phenotype in xanthoma
`Masaaki Matsumoto, MD, PhD, Sawa Kunimitsu, AD, Kana Wada, AD, Mitsunori Ikeda,
`MD, PhD, Akira Keyama, MD, PhD, and Hajime Kodama, MD, PhD Kocbi, japan
`
`Cutaneous lupus erythematosus simulating squamous neoplasia:
`The clinicopathologic conundrum and histopathologic pitfalls
`Daniel C. Zedek, MD, Elton T. Smith, Jr, MD, Michael G. Hitchcock, MBChB, Steven R.
`Feldman, MD, Brent]. Shelton, PhD, and Wain L. White, MD Cbapel Hill, Winston(cid:173)
`Salem, and Greensboro, N011b Carolina; Roanoke, Virginia; and Lexington, Kentucky
`
`Folliculosebaceous smooth muscle hamartoma
`Payam Saadat, MD, Arvin Doostan, MD, and Manjunath S. Vadmal, MD
`Los Angeles, California
`
`PERIODIC SYNOPSIS
`
`Parasitic infestations
`Christine C. Jacobson, MD, and Elizabeth A. Abel, MD Stanford, California
`
`I REVIEWS I
`
`Fomite transmission in head lice
`Craig N. Burkha1t, MD, MSBS, and Craig G. Burkhart, MD, MPH
`Chapel Hill, N011b Carolina, and Toledo, Obio
`
`Contact dermatitis in athletes
`Brett Kockentiet, MD, MS, and Brian B. Adams, MD, MPH
`Richmond, Virginia, and Cincinnati, Ohio
`
`I DIALOGUES IN DERMATOLOGY I
`
`Oral contraceptives for the treatment of acne vulgaris
`Warren R. Heymann, MD Dialogues Editor (based on the dialogue "Oral contraceptives
`in dermatology" between Drs Julie C. Harper and Jacqueline Junkins-Hopkins)
`
`989
`
`994
`
`1006
`
`1013
`
`1021
`
`1026
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`1044
`
`1048
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`1056
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`lOA
`
`}UNE 2007
`
`Continued on page 14A
`
`JAM ACAD OERMATOL
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2065 - 4/13
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`

`
`Contents
`
`continued
`
`COMMENTARY
`
`Of spiders and zebras: Publication of inadequately documented loxoscelism
`case reports
`Richard S. Vetter, MS, and David L. Swanson, MD Riverside, California,
`and Scottsdale, Arizona
`
`LETTERS: NOTES & COMMENTS
`
`Bazex syndrome or dermatomyositis?
`Robert I. Rudolph, MD, FACP Wyomissing, Pennsylvania
`
`Current strategies to address the ongoing shortage of academic
`dermatologists
`Jashin]. Wu, MD Irvine, California
`
`Head-to-head studies of botulinum toxin A in aesthetic medicine:
`Which evidence is good enough?
`Berthold Rzany, MD, ScM, and Alexander Nast, MD Berlin, Gennany
`
`The merits of adding toluidine blue-stained slides in Mohs surgery in the
`treatment of a microcystic adnexal carcinoma
`Steven Q. Wang, MD, Leonard H. Goldberg, MD, FRCP, and Alexandra Nemeth, HTL
`New York, New York, and Houston, Texas
`
`I LETTERS: CASE LETTERS I
`
`Is apoptosis involved in the development of balloon cell nevus?
`Suggestion from a case report
`Yun ]eon Kim, MD, You Chan Kim, MD, and Hee Young Kang, MD Suwon, Korea
`
`Symptomatic response of erythropoietic protoporphyria to
`iron supplementation
`S. Alexander Holme, MRCP, Charles L. Thomas, MRCP, Sharon D. Whatley, PhD,
`Douglas P. Bentley, FRCP, Alexander V. Anstey, FRCP, and Michael N. Badminton,
`MRCPath Card~ff, United Kingdonz
`
`Squamous cell carcinoma over tattoos
`Gerard Pitarch, MD, Teresa Martfnez-Mench6n, MD, Antonio Martfnez-Aparicio, MD,
`PhD, Jose Lufs Sanchez-Carazo, MD, PhD, Dionfs Mui1oz, MD, and Jose Miguel Fortea,
`MD, PhD Castello, Spain
`
`I MEDIA REVIEWS I
`
`My skin's on f'.tre: Living with psoriasis (DVD). Directed by Fred Finkelstein
`Reviewed by Lauren Alberta-Wszolek, MD, Leah Belazarian, MD, Laura Capaldi,
`MD, Keri Clifford, MD, Dori Goldberg, MD, and Mayra Lorenzo, MD, PhD
`Worceste1~ Nfassachusetts
`
`1063
`
`1065
`
`1065
`
`1066
`
`1067
`
`1069
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`1070
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`1072
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`1074
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`14A
`
`jUNE 2007
`
`Continued on page 18A
`
`JAM ACAD DERMATOL
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2065 - 5/13
`
`

`
`, Contents
`
`continued
`
`Patch testing and prick testing: A practical guide. Jean-Marie Lachapelle
`and Howard I. Maibach; Management of positive patch test reactions.
`J. E. Wahlberg, P. Elsner, L. Kanerva, H. I. Maibach, editors; Irritant dermatitis.
`Ai-Lean Chew and Howard I. Maibach, editors; and Condensed handbook
`of occupational dermatology. L. Kanerva, P. Elsner, J. E. Wahlberg,
`H. I. Maibach, editors
`Reviewed by Lionel Bercovitch, MD Providence, Rbode Island
`
`A review of VisualRx Version 4.0
`Reviewed by Noah Scheinfeld, MD New York, New York
`
`EBLUEPRINTS
`
`Available at www.eblue.org
`
`World Wide Web resources of open access, educational dermatology clinical
`image quizzes and databases
`Evangelia Papadavid, MD, and Matthew E. Falagas, MD, MSc, DSc Atbens, Greec~, and
`Boston, Massacbusetts
`
`ANNOUNCEMENTS
`
`American Board of Dermatology examination dates
`
`Change of address
`
`Eczema herpeticum patients needed for referral
`
`International Board Certification in Dermatopathology
`
`Registration of clinical trials
`
`4th International Workshop for the Study of Itch
`
`1074
`
`1076
`
`e81
`
`920
`
`1062
`
`978
`
`973
`
`948
`
`951
`
`1064
`
`1081
`
`1094
`
`What's new online?
`
`READER SERVICES
`
`Index to volume 56
`
`Author index
`
`Subject index
`
`Information for authors
`
`Information for readers
`
`Instructions for Category I CME credit
`
`Dermatology calendar
`
`Statement on advertising in the journal
`
`18A
`
`}UNE 2007
`
`www.eblue.org and
`January 2007, 27A, 28A, 29A, 30A, and 31A
`
`26A
`
`30A
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`57 A
`
`30A
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`Continued on page 22A
`
`JAM ACAD DERMATOL
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2065 - 6/13
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`

`
`Contents
`
`continued
`
`BLUE NOTES
`
`Iotaderma #161
`Robert I. Rudolph, MD, FACP
`
`Reviewers for volumes 54 and 55
`
`1058
`
`1059
`
`Full text access to Journal of the American Academy of Dermatology Online is now
`available for Academy members and all print subscribers. To activate your online
`subscription, please visit Journal of the American Academy of Dermatology Online by
`pointing your browser to http:/ /www.eblue.org.
`
`Early online publication: Articles in press
`
`The Journal of the American Academy of Dermatology posts in-press articles online before they appear in the print edition
`of the Journal. These Articles in Press are available from both the JAAD Web site (www.eblue.org) and ScienceDirect
`(www.sciencedirect.com). To access Articles in Press, simply click the Articles in Press link. Each article will have an
`online publication date (the date it first appeared online) and a Digital Object Identifier (DOl). These articles are fully
`citable following the example below.
`
`Adebamowo CA, Spiegelman D, Danby FW, Frazier AL, Willett WC, Holmes MD. High school dietary daily intake
`and teenage acne. JAm Acad Dermatol cloi:10.1016/j.jaacl.2004.08.007 .. Published online October 29, 2004.
`
`Because the DOl for each article will not change once Articles in Press appear in the print version of the Journal, both
`the DOl citation and the print citation will remain valid.
`
`Please visit www.eblue.org to view these Articles in Press.
`
`22A
`
`JuNE 2007
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`JAM AcAo DERMATOL
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`
`I
`Onychomycosis: Diagnosis and definition of cure
`
`Richard K. Scher, MD, FACP,a Amir Tavakkol, PhD, Dip Bact,b Bardur Sigurgeirsson, MD, PhD,c
`Roderick]. Hay, DM,d Warren S. Joseph, DPM,e Antonella Tosti, MD/
`Philip Fleckman, MD,g Mahmoud Ghannoum, MSc, PhD, 11 David G. Armstrong, DPM/
`Bryan C. Markinson, DPM,i and Boni E. Elewski, MDk
`New York, New York; East Hanover, New jersey; Reykjavik, Iceland; Belfast, Ireland;
`Coatesville, Pennsylvania; Bologna, Italy; Seattle, Washington; Cleveland, Ohio;
`North Chicago, Illinois; and Birmingham, Alabama
`
`Until now, there has been no agreement on criteria defining resolution of onychomycosis. Most published
`reports use clinical and mycological cure, which comprises a completely normal-appearing nail plate,
`and negative nail culture and microscopy results, as the end point for defining success of therapeutic
`intervention. Reported here is the definition of onychomycosis, which delineates both primaty and
`secondaty criteria for diagnosis of onychomycosis and identifies clinical and laborat01y parameters to
`define a resolved fungal nail infection. Onychomycosis cure is defined by the absence of clinical signs or
`the presence of negative nail culture and/ or microscopy results with one or more of the following minor
`clinical signs: (1) minimal distal subungual hyperkeratosis; and (2) nail-plate thickening. Clinical signs
`indicative of persistent onychomycosis at the end of the observation period include (1) white/yellow or
`orange/brown streaks or patches in or beneath the nail plate; and (2) lateral onycholysis with subungual debris.
`Although nail appearance will usually continue to improve after cessation of therapy, the nails may have
`a persistent abnormal appearance even in cases where treatment has been effective. (]Am Acad Dermatol
`2007;56:939-44.)
`
`0 nychomycosis is estimated to affect ap(cid:173)
`
`proximately 2% to 13% of the population
`of North America and Europe. 1
`7 Both
`-
`physician and patient expectations of treatment
`
`outcome are influenced by the widely vatying per(cid:173)
`ceptions of what constitutes cure of onychomycosis.
`Yet, physicians often do not discuss with their
`patients the likely end result of therapy.
`
`From the Department of Dermatology, Columbia University, New
`Yorka; Dermatology Clinical Research, Novartis Pharmaceuticals
`Corporation, East Hanoverb; Department of Dermatology, Uni(cid:173)
`versity of Iceland, Reykjavikc; Queens University Belfastd; Ve(cid:173)
`terans Administration Medical Center, Coatesvillee; Department
`of Dermatology, University of Bolognaf; Department of Medi(cid:173)
`cine (Dermatology), University of Washington School of Med(cid:173)
`icine, Seattle9; Department of Dermatology, Case Western
`Reserve University, Clevelandh; Dr William M. Scholl College
`of Podiatric Medicine at Rosalind Franklin University of Medi(cid:173)
`cine and Science, Green Oaks, North Chicagoi; Department of
`Orthopedic Surgery, Mount Sinai Medical Center, New Yor!<i;
`and Department of Dermatology, University of Alabama,
`Birmingham.k
`Supported by Novartis Pharmaceuticals Corporation.
`Disclosure: This report is based on a consensus conference
`sponsored by Novartis Pharmaceuticals Corporation. Technical
`assistance from CPE Communications is appreciated. All con(cid:173)
`tributors have received honoraria from Novartis Pharmaceuti(cid:173)
`cals Corporation for their participation
`in
`the consensus
`conference meeting that formed the basis for this article.
`Dr Tavakkol is Director of Dermatology Clinical Research at
`Novartis Pharmaceuticals Corporation. All authors received
`honoraria from Novartis and are consultants/advisors, speakers,
`and investigators for Novartis. Dr Scher is a consultant, and
`investigator, and received honoraria and grants from Barrier.
`He is also an advisory board member, consultant, and received
`honoraria from Stiefel. Dr Sigurgeirsson is an investigator,
`consultant, and speaker for Galderma and has received grants,
`
`honoraria, and salary from this company. He is also an advisory
`board member, investigator, and consultant for Stiefel and has
`received grants and honoraria from this company. Dr Hay is
`an advisory board member receiving honoraria from Barrier.
`Dr Tosti is an advisory board member receiving honoraria
`from both Stiefel and Galderma. Dr Ghannoum is an investigator
`and speaker receiving grants and honoraria from Pfizer;
`and investigator and speaker receiving grants and honoraria
`from Enzon; an investigator and consultant receiving grants
`and honoraria from Schering-Piough; and investigator and
`speaker receiving grants and honoraria from Merck; an inves(cid:173)
`tigator receiving grants and honoraria from Vicuron; and a
`consultant receiving honoraria from NexMed. Dr Armstrong is
`an advisory board member and investigator for Lilly. He is also
`an advisory board member of, investigator for, and receives
`honoraria from Pfizer. Dr Markinson is a speaker, consultant,
`and advisory board member receiving honoraria and stock
`options for Bradley Pharmaceuticals and is an advisory board
`member receiving honoraria from Stiefel. Dr Elewski is an
`advisory board member receiving honoraria from Anacor and
`Stiefel and an investigator for Barrier and Novartis.
`Accepted for publication December 21, 2006.
`Reprint requests: Boni E. Elewski, MD, Department of Dermatology,
`University of Alabama, 700 18 St S, Suite 414, Birmingham,
`AL 35233. E-mail: beelewski@aol.com.
`Published online February 20, 2007.
`0190-9622/$32.00
`© 2007 by the American Academy of Dermatology, Inc.
`doi:1 0.1 016/j.jaad.2006.12.019
`
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`
`940 Seber et a!
`
`J AM ACAD DERMATOL
`jUNE 2007
`
`Table I. Diagnosis of onychomycosis caused
`by dermatophytes
`
`Clinical
`Primary criteria
`White/yellow or orange/brown patches or streaks
`Secondary criteria*
`Onycholysis
`Subungual hyperkeratosis/debris
`Nail-plate thickening
`Laboratory
`Positive microscopic evidence
`Positive culture of dermatophyte
`
`Table IT. Poor prognostic factors
`
`1. Areas of nail involvement > 50%
`2. Significant lateral disease
`3. Subungual hyperkeratosis > 2 mm
`4. White/yellow or orange/brown streaks in the nail
`(includes dermatophytoma 14
`)
`5. Total dystrophic onychomycosis (with matrix
`involvement)
`6. Nonresponsive organisms (eg, Scytalidium mold)
`7. Patients with immunosuppression
`8. Diminished peripheral circulation
`
`*Tinea pedis often occurs concomitantly with pedal onychomycosis,
`and tinea manuum with infected fingernails.
`
`other nails, in some cases one or more of the other
`toenails will continue to show signs of infection. 13
`
`Fmther, clinicians base their therapeutic decisions
`on results of clinical trials. However, the current
`clinical trial data are often difficult to interpret and
`compare because there have been numerous defini(cid:173)
`tions of "cure" and different measures used to assess
`treatment efficacy. Most published studies use dif(cid:173)
`ferent combinations and definitions of mycological
`cure (often defined as negative potassium hydroxide
`[KOH] microscopy and culture results), clinical cure
`(often defined as a percentage [eg, 80o/o-100o/o] of nail
`plate that is visibly clear of infection), and complete
`cure (mycological plus clinical cure) to define efficacy
`and cure. Large-scale and adequately powered clini(cid:173)
`cal trials using the most stringent efficacy criteria often
`show low rates of therapeutic response and com(cid:173)
`plete cure than seen in clinical practice or published
`studies. The lack of consistency in defining and meas(cid:173)
`uring cure is one reason for the disparity between
`the results of therapy, as recorded in drug trials, and
`experience from clinical practice. For example, in
`an analysis of 26 published clinical studies for oral
`treatment of toenail onychomycosis, a complete cure
`was achieved in only 25o/o to 50o/o of patients receiving
`standard courses oftherapy,8 and complete cure rates
`in the range of 14o/o to 38o/o have been reported
`in the prescribing information of Food and Drug
`10 In clinical
`Administration-approved oral agents. 9
`·
`trials, efficacy assessments are often based on final
`evaluations at 48 to 52 weeks, but a toenail may not
`grow fully for up to 78 weeks. 11
`12 Although one
`'
`would not expect all studies to be the same, variations
`in study designs might also account for some dispar(cid:173)
`ities in cure rate.
`In addition, many clinical studies base treatment
`success on the progress of a single target toenail,
`whereas in clinical practice, patients and physicians
`evaluate the potentially different responses of all
`toenails. Although mycological cure in a target toe(cid:173)
`nail usually corresponds with similar trends in the
`
`DIAGNOSIS OF ONYCHOMYCOSIS
`The criteria for the diagnosis of dermatophyte
`onychomycosis, including both laboratory and clin(cid:173)
`ical features, are summarized in Table I.
`Dependence on culture of an organism alone is
`not sufficient for the diagnosis of infection -a fungus
`isolated from a normal nail does not demonstrate
`infection. The reverse is also true-an abnormal nail
`without mycological confirmation is insufficient to
`make an accurate diagnosis of onychomycosis. The
`accurate diagnosis can be made only when both
`positive laboratmy and clinical criteria are present.
`Tinea pedis and tinea manuum offer clinical clues
`of infection because they often occur concomitantly
`with pedal onychomycosis. Certain nail changes may
`be nonspecific. Onycholysis, for example, may result
`from trauma but could also be seen in psoriasis, as is
`subungual hyperkeratosis. Nail-plate thickening is
`also relatively nonspecific because it may be associ(cid:173)
`ated with trauma, onychog1yphosis, lichen planus,
`and psoriasis. Other nail anomalies that are generally
`unrelated to onychomycosis include longitudinal or
`transverse ridging, pits, onychoschizia, and d1yness
`of the nail plate. Surface leukonychia may be seen in
`some forms of onychomycosis, including white su(cid:173)
`perficial onychomycosis and proximal white subun(cid:173)
`gual onychomycosis, but is othe1wise nonspecific.
`These factors make diagnosis of onychomycosis on
`clinical grounds alone difficult and correlation with
`mycological evidence critical. It should be noted that a
`variety of clinical signs present at the initial clinical
`evaluation indicate a poor overall prognosis for ulti(cid:173)
`mate cure. These factors are listed in Table II. 14
`15
`•
`Definitive laboratmy criteria include positive
`microscopic evidence of septate hyphae and/ or
`arthroconidia (KOH preparation, Calcofluor white,
`Sigma-Aldrich, St Louis, Mo), periodic acid-Schiff,
`and/or biopsy, and positive fungal culture findings
`for dermatophytes (Tricbophyton, Epidennophyton,
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`Seber eta! 941
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`Table m. Proposed definitions of cure when assessing patients with onychomycosis in clinical trials
`
`Criteria for cure:
`A) 1 OOo/o Absence of clinical signs of onychomycosis (mycology not required)
`OR
`B) Negative mycological laboratory results with one or more of following clinical signs
`i) Distal subungual hyperkeratosis or onycholysis leaving less than 1 Oo/o of nail plate affected
`ii) Nail-plate thickening that does not improve with treatment because of comorbid condition
`
`Criteria for noncure:
`A) Presence of positive mycological results
`OR
`B) Any one of the 4 clinical signs, even in the presence of negative mycological results
`i) Residual major changes (> 1 Oo/o) of the nail plate compatible with dermatophyte infection
`ii) White/yellow or orange brown/patches or streaks in or beneath the nail
`iii) Lateral onycholysis with debris in an otherwise clear nail plate
`iv) Hyperkeratoses on the lateral nail plate/nailfold edge (Fig 1, 0)
`
`or Microsponl1n species) or certain nondermato(cid:173)
`phyte nail pathogens (eg, Scytalidiu1n dinzidiatznn
`and S hyalinum). Candida albicans can occasionally
`be a pathogen in fingernail disease, but clinical
`correlation is critical. Other nondermatophyte nail
`pathogens
`(certain
`species of Acremonium,
`Alternaria, Aspergillus, Fusarium, Onychocola, and
`Scopulariopsis) must be isolated from sequential
`specimens to prove origin, and correlation with
`direct microscopy and clinical changes is required.
`Mycology test results should be used to confirm the
`clinical diagnosis and it should be noted that absence
`of a proof is not a proof of absence.
`Successful eradication of the fungus may leave
`the nail abnormal and the residual changes may be
`totally unrelated to infection (eg, onychoschizia) or a
`result of damage to the nail unit from long-standing
`disease (eg, onycholysis).
`If onychomycosis is suggested based on clinical
`observation, diagnostic laboratmy tests should be
`performed. If these produce negative findings, they
`should be repeated. Clinical manifestations of other
`nail disorders-such as psoriasis, neosplasms, and
`lichen planus-may mimic those of onychomycosis
`but can be diagnosed by nail-unit biopsy. 16
`18
`-
`
`PRACTICAL CONSIDERATIONS FOR
`ASSESSING CURE
`Although the goal of patients seeking treatment
`is almost always a normal-appearing nail, it has been
`suggested that cure of all 10 toenails is a desired
`clinical outcome, but the latter may be unattainable.
`It is important that patients understand the distinc(cid:173)
`tion between cure of their nail infection and gross
`appearance of the affected (now treated) nail, be(cid:173)
`cause some residual change is likely after chronic
`infection. Assessment of cure should not rely entirely
`on visual appearance, and patients and physicians
`
`need to have realistic expectations of successful
`treatment outcome.
`Mycological cure signifies that the fungal infection
`has been successfully treated and has resolved, but it
`will not necessarily result in a 100% normal nail. 19
`Both intrinsic and extrinsic factors may influence the
`appearance of the nail. Trauma to the nail unit,
`particularly the bed and plate, may precede the
`development of onychomycosis and even a return to
`mycological negativity will not necessarily produce
`a normal-appearing nail. In severe cases of onycho(cid:173)
`mycosis, up to 10% of the nail surface is likely to
`remain abnormal in appearance even when mycol(cid:173)
`ogy indicates a cure of fungal infection. 20
`
`CLINICAL SIGNS ACCEPTABLE IN CURED
`CASES AT THE END OF THE
`OBSERVATION PERIOD
`Several minor clinical signs that, when combined
`with negative mycology laboratmy results, may be
`present in a patient who has been successfully cured
`are summarized in Table III. Although repeated
`if clinical
`mycological testing is not necessaty,
`suggestion of infection is strong, a second sample
`should be taken to confirm the negative mycological
`results. The presence of minor clinical signs (Table
`III) and positive mycologicallaboratmy results indi(cid:173)
`cates that the nail is not cured, and further treatment
`and/or appropriate follow-up may be indicated. In
`contrast, in the absence of clinical signs of onycho(cid:173)
`mycosis, mycology laboratmy assessments (eg, ei(cid:173)
`ther KOH or cultures) are not required to validate
`cure, although some physicians consider mycologi(cid:173)
`cal confirmation optimal practice.
`Certain clinical signs may require diagnostic my(cid:173)
`cology laboratmy tests to confirm cure. Distal ony(cid:173)
`cholysis that has improved from baseline but affects
`more than 10% of the nail might be a clinical concern.
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`942 Scher et a!
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`J AM ACAD DERJ\IATOL
`jUNE 2007
`
`Fig 1. Examples of pretreatment and posttreatment of onychomycosis. A, Patient (36-year-old
`man) who recently experienced subtle change of big toenail. There is mild distal onycholysis
`with bilateral edge involvement. In this case, it was impossible to make diagnosis of
`onychomycosis without laborato1y confirmation. Microscopy produced positive results and
`Trichophyton rubrwn was cultured from lateral edge. B, Patient (34-year-old man) with
`onychomycosis of distal subungual type with approximately 30% distal involvement. There is
`onycholysis with mild distal hyperkeratosis and nail-plate fragility. Microscopy revealed
`positive findings and T rubrum was cultured. C, Patient (29-year-old man) with distal lateral
`subungual onychomycosis (DLSO). Nail is 90% involved. Nail plate is thickened and subungal
`hyperkeratosis is apparent. This nail has several negative prognostic factors and is likely to be
`difficult to treat. On first sample, microscopy revealed positive findings, but culture produced
`negative results. However, T rubrwn was grown on culture when second, more proximal
`sample was obtained. D, Patient ( 46-year-old woman) treated with standard course of oral
`antifungal. At baseline, nail had 50% area involvement and matrix was affected. Photograph
`was taken 18 months after treatment was initiated. Patient was satisfied and, on examination,
`only slight distal onycholysis and scaling/hyperkeratosis of lateral nailfolds was noted. When
`edge was trimmed, veq little subungual debris could be found. Material was sent for culture;
`the microscopy revealed positive findings and T rubrum was cultured. E, Patient (64-year-old
`man) with severe onychomycosis before treatment was initiated. Nail displays several negative
`prognostic signs. Whole nail plate is involved; nail is thick; dermatophytoma is seen at left
`lateral edge; and there is severe hyperkeratosis at lateral edge. F, Patient was treated with
`standard course of oral antifungal. T rubnun could be cultured from nail up to 3 months after
`treatment was initiated and microscopy revealed positive findings for up to 1 year. Both culture
`and microscopy results remained negative at 18 and 24 months. Clinically, there is slight
`discoloration at distal edge of nail and minimal onycholysis is noted. These signs are minor and
`are compatible with cure because both microscopy and culture results were negative. G, Before
`treatment was initiated, 100% of nail plate was involved. Patient (37-year-old woman) was
`treated with standard course of oral therapy. T rubrum was cultured and microscopy revealed
`positive findings up to 6 months after treatment was initiated. Both parameters remained
`negative thereafter at 9, 12, 18, and 24 months. Clinical status improved continuously during
`and after treatment. Photograph shows nail at 12 months. Distal onycholysis can be seen, and
`considerable hyperkeratosis was noted when distal nail plate was removed. These signs are
`compatible with cure only in light of negative microscopy and culture results. Hyperkeratosis
`was not apparent at 18 and 24 months, but mild distal onycholysis could still be seen.
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`I AM ACAD DER/v\ATOL
`VOLUME 56, NUMBER 6
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`Seber et a I 943
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`Lateral nail plate/nailfold edge hyperkeratosis may
`also warrant additional tests.
`
`RECURRENCE OF ONYCHOMYCOSIS
`Recurrence (relapse or reinfection) of onychomy(cid:173)
`cosis is not uncommon, with reported rates ranging
`from 10% to 53%. 21
`23 Recurrence often implies that,
`-
`although the clinical signs have resolved, either
`mycological cure was not achieved with the initial
`treatment or a new infection has developed during or
`immediately after the treatment period. Thus, ensur(cid:173)
`ing that mycological cure is achieved is important in
`questionable cases, so that reLapse may be avoided.
`Positive mycologicallaborat01y findings (KOH, pe(cid:173)
`riodic acid-Schiff, or culture) are not consistent wi