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`British Journal of Dermatology
`
`The British Journal of Dermatology is owned by and is the official organ of the British Association of Dermatologists.
`
`EDITORS
`..R D.EEDY
`
`“~;'paI‘fH1BHl of Dermatology. Craigavon Area Hospital Group Trust, Cruiyavon, BT63 SQQ
`DR R.A.C.GRAHAlVl—BR(JWN
`i'cester Royal Infirmary, Department of Dermatology, Leicester LE1 S WW
`
`WESTON LIBRAR
`
`MAY 0 5 2004
`
`*'-ICTION EDITORS
`
`DA LCOULSON, Burnley
`,
`: G.DUNNlLL, Bristol
`DR J.S.C.ENGLISII, Nottingham
`’OF. R.W.GROVES. London
`DR /\.M.II.HF.AGERTY, Solihull
`!' “ C.l\/LLAWRENCE, Newcastle
`DR C.MOSS. Birmingham
`G.M.MURPHY, Dublin, Ireland
`l‘1kOF. N.O.NESTLE, Zurich, Switzerland
`DB D.N.SLATF.R. Sheffield
`t_. H.TSAO, Boston, U.S.A.
`
`I‘ “ITORIAL ADVISORY BOARD
`
`U.K.
`i‘..OF. ].N.W.N.BARKER, London
`DR S.M.BREA’l'H.\lACH, London
`i
`.()F. R.D.R.CAMP, Leicester
`DR i\.H.COX, Carlisle
`E LOP. J.F‘ERGUSON, Dundee
`PROF. D.R.GARROD, Manchester
`T
`R.A.C.GRAHAM—BROWl\', Leicester
`PROF. C.E.M.GRIFFITHS. Manchester
`l7"’\OF. I.M.l.F1lGl-l, London
`PROF. ].A.l\/ICGRATH, London
`PROF. C.S.l\/IIJNRO, Glasgow
`LR A.D.ORMEROD, Aberdeen
`PROF. NJREYNOLDS, Newcastle upon Tyne
`. LOP. l—I.C.WILLIAMS. Nottingham
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`'ORLDVVIDE
`PROF. M.AMAGAI. Tokyo. Japan
`"ROE. W.M.H.EAGLSTEIN, Miami, U.S.A.
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`J5l120 CLINICAL SCIENCE CENTER
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`EDITORIAL MANAGER
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`MR LCAULFIELD
`BAD Office, London
`EDITORIAL C0—ORl)lNA'l‘OR
`MR J.IBIT(JYE
`BAD Office, London
`
`. R.L.EDELSON. New Haven, U.S.A.
`. L.A.Gt)LDSMl'1‘H, Chapel Hill. U,S.A.
`. J.M.HA_\IIFIN, Oregon, U.S.A.
`. S.I.KATZ,
`ll/Iaryland, U.S.A.
`. B.KRAPCHIK. Toronto, Canada
`. R.MARKS, Melbourne, Australia
`. Y.MlYACHl. Kyoto, Japan
`. N. PROSE, Durham, U.S./1.
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`. A.TAlEB, Bordeaux, France
`. G.'l‘0DD. Cape Town, South Africa
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`. K.WOLFF, Vienna, Austria
`. XUE-JITN ZHU, Beijing. China
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`the Netherlands
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`“he British Journal ofDermatology publishes papers on all aspects of the biology
`and pathology of the skin. Originally the Journal, founded in 1888. was
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`
`British Iournal of Dermatology
`Volume 150, Number 4, April 2004
`
`CONTENTS
`
`Snippets
`
`Research Snippets
`Clinical Snippets LOWELL A.coLDsMiTH
`
`Editorial
`
`A new editor in changing times D.I.EEDY
`
`Topical review
`
`Fumaric acid esters, their place in the treatment of psoriasis A.Dl0Rl\/IEROD AND
`U.MROWI]3TZ
`
`Original articles
`
`Cutaneous Biology
`
`Refined localization of dyschromatosis syinmetrica hereditaria gene to a 94-CM region
`at 1q2l—22 and a literature review of 136 cases reported in China k'.E’.HF., C.T).l-IE. Y.CUI,
`S.YANG.H.H.XU,M.LLW.'1'.YUAN,M.GAO,Y.H.LIANG.C.R.LI.S,l.XU,I.].CHEN,H.DiC1-IEN.
`W.HUANG AND X.].ZHANG
`
`Inhibition of nuclear factor kappa B activation and inducible nitric oxide synthase
`transcription by prolonged exposure to high glucose in the human keratinocyte cell line
`HaCaT K.i\’A1<Ai, Y.KUBO'l'A AND PLKOSAKA
`’
`A novel mutation of keratin 9 in a large Chinese family with epidermolytic
`palmoplantar keratoderma X-H.HE. X-N/AHANLI. W.MAO. H.P.cHEN, L—RiXU. H.CHEN. X-L.HE
`AND Y—P,LE
`
`Mutational analysis of the ATPZAZ gene in two Darier disease families with
`intrafamilial variability T.0N()ZLJKA. D,s.~\wAMiiRA, K.YOKOTA AND ILSHIMIZC
`Ultraviolet B induces hyperproliferation and modification of epidermal differentiation in
`normal human skin grafted on to nude mice SDEL BINO, C.VlULiX, P.ROSSIO—PASQIlIER,
`A.1oMARD, M.Dl:'MARCHE7,, D.ASSEI.Il\IEAU AND F.BERNERD
`
`Psoriasis genomics: analysis of proinllammatory (type 1) gene expression in large
`plaque (Western) and small plaque (Asian) psoriasis vulgaris w.LEw, E.LEE AND
`J.G.KRUECiF.R
`
`Clinical and Laboratory Irivestigations
`
`Baseline staging in cutaneous malignant melanoma ].HAFNER, M.HESS scaM1D. W.KF.MPF,
`G.BURG. W.KU1\'ZI, C.MEULI-SIMMEl\. l’.NF.FF, V.MEYER, D.MIHIC, E.GARZOLIi K-P.]UNGIU$.
`B.SEIFERT,R.DUMlV1l3R AND ILSTEINERT
`
`Improvement of malignant/benign ratio in excised melanocyiic lesions in the
`‘dermoscopy era’: a retrospective study 1997—2[)01 P.CARLI, v.DE GIORGL s.ci<ocF.Tri.
`F.MANNONE, D.MASSI,
`./LCHIARUGI AND s.mANNoTTi
`
`H
`
`|
`
`0007-O963(200404)150:04;1—X
`
`CoverPhotograph
`
`Masson-Fontana melanin staining of biology samples from the
`dorsal aspects of the hand, from a hyperpigrnented inacule.
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`
`CONTENTS ll
`
`The circulating lymphocyte profiles in patients with discoid lupus erythematosus and
`systemic lupus erythematosus suggest a pathogenetic relationship c.H.P.wouTERs,
`c.DIEcsi\ANr.1.L.csm=PENs, [LDEGREEF AND E.A.M.STEVENS
`
`Onychomycosis: the development of a clinical diagnostic aid for toenail disease. Part I.
`J:‘.stablisl1ing discriminating historical and clinical features c.I..Fi.ETci-IER, R.].IlAY AND
`N.C.SMF.ETON
`
`Melanomas detected with the aid of total cutaneous photography N.E.FEl'l‘. s.w.Dus7.A
`AND A.A.MAR(}l-l(JOB
`
`Dermatological Surgery and Lasers
`
`Permanent repigmentation of piebaldisni by erbium:YAG laser and autologous cultured
`epidermis L.GUERRA, G.PRIl\/[AVERAv D.r<AsKovIc, KLPELLEGRINI. ocotisANo. s.soNDANzA.
`S.KUHN, P.PiAzzA. A.i.Ucr, F.ATZORI AND M.DE LUCA
`
`Dermatopathology
`
`Alterations in the basement membrane zone in pili annulati hair follicles as
`demonstrated by electron microscopy and immunohistochemistry K.A.GIEHL.
`D.].P.FERGUSON, D.DEAN, Y.H.CHUANG, J.ALLEN. D.A.R.D.BERKER, A.TOSTl. 1<.P.i<.DAwsr.R AND
`F.WO[NAROWSKA
`
`Epidemiology and Health Services Research
`
`Oral essential fatty acid supplementation in atopic dermatitis—a meta-analysis of
`placebo—controlled trials C.].A.W.VAN GOOL, M.P.A.ZEEG]3RS Al\D C.THIIS
`
`Therapeutics
`
`Fumaric acid esters i11 severe psoriasis, including experience of use in combination with
`other systemic modalities P.13ALAscBRAMANiAM, o.sTEvENsoN AND ]iBERTl-l—J()l\l:'S
`
`Concise communications
`
`The International Foundation for Dermatology: an exemplar of the increasingly diverse
`activities of the lnternational League of Dermatological Societies R.HAY AND R.MARKS
`Women who present with female pattern hair loss tend to underestimate the severity of
`their hair loss s.sroNDo, D.GOBLE AND R.Sll\CLAlR
`
`Case reports
`
`Disseminated linear calcinosis cutis associated with the Koebner phenomenon in an
`infant with congenital acute monocytic leukaemia E.K.S./\T'l'};'R, c.H.MAARI. K.D.MOREL,
`L.b‘.hICHENFIELD, 13.13.cUNN1NcaAM, S.F.FRIEDLANDER AND ].N.BER(.ll\/1Al\’
`
`Advanced glycation end product (AGE)-immunoreactive materials in chronic prurigo
`patients receiving a long-standing haemodialysis N.l<‘L']IMOTO AND S.TA]IMA
`In vivo and iii sita modulation of the expression of genes involved in metastasis and
`angiogenesis in a patient treated with topical imiquimod for melanoma skin
`metastases C.HF.SUNG, M.D'INCAN. S.MANSARD. FKFRANCK, A.CORBIN-DUVAL‘ C.CH}5.VENET.
`P.DECHELOT'l‘E, J—c.MADr.r.MoNT, A.VEYRE. r.sou'rsyi<AND AND Y»}.BIGNON
`
`Clinical cameo
`
`Autoerythrocyte sensitization syndrome: a form of painful purpura with positive
`intracutaneous test LMEHTA, i<.s.DHuRAT, H.R.]ERA]ANI AND SvSATYAPAL
`
`Erytheniatous lump on the abdomen P.LLORET. P.REDONDO AND F.I.VAZLJUEZ-[)OVAL
`
`Correspondence
`Adverse side—effects following attempted removal of tattoos using a non—laser
`n1ethodF..vEvsEv AND A.M.R.DowNs
`
`Treatment of oral lichen planus with topical pimecrolimus 1% cream L.ESQUIVEI.—
`PEDRAZA. L.FERi\'ANDsz—cUr.vAs. G.()RTfZ-PEDROZA, E.i<syss—ci:TiERREz AND R.0ROZCO-
`TOPETE
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`
`CONTENTS III
`
`Cutaneous altcrnariosis iii an immunocompetent patient: analysis of the internal
`transcribed spacer region of rDNA and Brm2 of isolated Alternaria alternam MONO.
`c.Nisa1GoRi, C.TAI\'AKA, s.TANAKA, M.TSUDA AND YiM[YACl-ll
`
`Successful treat.ment of pain in two patients with cutaneous leiomyomata with the oral
`alpha—1 adrenoceptor antagonist, doxazosin i<.J.DATcHELoR. C.C.LYOl\ AND A.s.HmHET
`Lichen striatus in an adult: successful treatment with tacrolimus c.soRcEN'i'ii\i,
`M.A.ALLbLVATO, MDAHDAR AND H.CABRP.RA
`
`Cutaneous infection by Fusarium: successful treatment with oral
`voriconazole FCUIMERA-MARTll\'~NEDA. M.GARCfA-BUSTl’\JDUY. A.NODA-C/\BRhR~\t
`R.S/\i\CHF.7.—GONZALEZ AND R.o.MoNTELo,\IGo
`Well—differentiated fetal adenocarcinoma presenting with cutaneous metastases
`S»CtCHAO AND ].Y-Y.LEF.
`
`Expression of human sperm protein 1 7 in melanophages of cutaneous melanocytic
`lesions B.FRANCESCHINI, F.GRIZZl, P.COLOMBO. c.soDA. K.BUMl\/1. P.L.HERMONAT. M,M(JN‘l'l,
`N.DIOGUARL)l AND M.CHIRIVA—INTERNA’l’1
`
`Pimecrolimus in an adhesive ointment as a new treatment option for oral lichen
`planus].DIssEMoND.s.sCHRo'1ER.T.FRANCKsoN.s.HERB1oAND M.GOOS
`Human immunodeficiency virus—associated psoriasis and psoriatic arthritis treated with
`infliximab UJSARTKE4 LVENTEN. A.KREUTER, S.GAEBAY, P.ALTMEYl-LR AND \I.H.BROCKMEYER
`
`Brachioradial pruritus: response to treatment with gabapentin s.M.w1NHovr.N.
`I.HiCOULSON AND W.W.BOTT()MLEY
`
`Pruritus induced by interruption of paroxetine therapy c.MAzzATENTA, G.PI1oi\'1A AND
`P.MARTINI
`
`Human parvovirus B19 infection showing follicular purpuric papules with a baboon
`syndrome-like distribution SLYAMADA. A.1wAsA, M.KUROKi, M.YosH1DA AND M,l'l‘()l-l
`Cutaneous hyalohyphomycosis caused by Acremonium in an immunocompetent
`patient s—i7.KAi\x T—H.'l‘SAT, C~H.HU AND W—R.L.EE
`Good response of linear scleroderma in a child to ciclosporin R.M.STRALISS, M.BHUsHAN
`AND M.].D.GO0DFIELD
`
`Topical tacrolimus in granuloma annulare and necrobiosis lipoidica W.IIARTH Ai\D
`R.LINSE
`
`Book reviews
`
`Fitzpatriclcs Dermatology in General Medicine
`REVIEWED BY N.H.cox
`
`Clinical dermatology (2 003)
`REVIEWED BY G.A.]0l-INSTON
`
`News and Notices
`
`British Society for Investigative Dermatology Annual Meeting 2004
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`rm; material may be proleaed by Copryrighl law (we 17 us. Code)
`
`”ritish journal 0fDern1utology 2004; 150: 701/705.
`
`DOI: 10.1111/j.()()()7—0963.2[)04.[)5871.x
`
`Clinical and Laboratory Investigations
`
`Onychomycosisz the development of a clinical diagnostic aid for
`toenail disease. Part 1. Establishing discriminating historical and
`
`clinical features
`
`Summary
`
`C.L.FLETCI-TFJR. R.].HAY AND N.C.SMEETON*
`St ]ohn"s Institute of Dermatology. St Thomas’ Hospital, London SE1 7EH
`“Department ofPul)lic Health Sciences. Guy ’s, King 's and St Thomas’ Schools of Medicine, Dentistry and Biomedical Sciences, London,
`U.K.
`
`Accepted for publication 9 October 2003
`
`Background The ideal method for diagnosing onyehomycosis is unclear. Mycological investigation
`is currently the method of choice, although there is a false—negative culture rate of at least 30%.
`Objectives To establish a clinical diagnostic aid which may be used alongside laboratory—based
`mycological tests and in epidemiological studies.
`Methods Patients with nail disease (n = 209) were enrolled in the study. The exan1ining clinician
`completed a questionnaire containing four historical questions and 21 questions related to the
`clinical findings. All patients had samples taken for mycological analysis. The gold standard for the
`diagnosis of onyehomycosis was a positive result on both direct microscopy and culture of nail
`samples. Following exclusions, questionnaire responses from 169 patients were analysed using
`Stata. Multiple logistic regression with forward stepwise selection of variables was performed.
`Results Both microscopy and culture results were positive in 32% of cases and negative in
`42%. Dermatophytes formed the majority of isolates. Four parameters were found to be signi-
`ficantly related to positive myeology results: a history of tinea pedis in the last year. scaling on
`one or both soles, white crumbly patches on the nail surface, and an abnormal colour of the
`nail plate.
`Conclusions Our results have shown one historical feature and three clinical features to be strongly
`
`associated with onyehomycosis. The questionnaire has been revised to include only these stems and
`is being tested further with the aim of achieving a binary definition.
`
`Keywords: diagnostic aid, onyehomycosis
`
`5
`The incidence of onyehomycosis is increasingl’ and
`the development of newer, more effective antifungal
`gents has led to a renewed interest in this condition,
`both in the n1edical and the public domains. Despite
`the advances in antifungal
`treatments,
`the optimal
`aethod for diagnosing onyehomycosis
`in routine
`practice
`remains unclear. Most mycologists
`and
`dermatologists agree that mycological investigation is
`he method of choice. However, even in the best
`
`“orrespondencc: Dr C.L.Fletcher, Dermatology Department, Kingston
`Hospital, Galsworthy Road, Kingston—upon—Thames. Surrey KT2
`‘QB, U .K.
`E—mail: clflctcher@doct0rs.org.ul<:
`
`1?) 2004 British Association of Dermatologists
`
`laboratories there exists a false—negative culture rate of
`approximately 30%.“ Additionally, the sensitivity of
`direct microscopy is dependent upon many factors,
`including the skill of the operator and the quality and
`quantity of nail
`samples obtained. Various other
`procedures have been employed to improve the accur-
`acy of diagnosis, such as the histological examination
`of periodic acid—Schiff—stained nail clippings6'7 and
`in viva confocal mierosc0py,S but these are not widely
`available, nor in general use. We hope to develop a
`clinical diagnostic algorithm to be used as an adjunct
`to mycological investigation. It may also be helpful in
`epidemiological studies where large-scale mycology
`sampling may not be feasible.
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`702
`
`C.L.FLETCHER et al.
`
`Materials and methods
`
`A questionnaire was designed which contained four
`
`historical questions largely concerned with eliciting a
`history of tinea pedis or a family history of nail
`problems. Twenty—one further questions were related
`to the
`clinical
`examination and included those
`
`known to be associated with onychomycosis such
`as nail bed thickening and onycholysis. Ethics Com-
`mittee approval was obtained. The questionnaire was
`piloted and refined and was subsequently applied to
`patients with abnormal nails, regardless of what was
`felt
`to
`be
`the underlying cause,
`attending the
`dermatology and chiropody clinics at Guy's and St
`Thomas’ Hospitals Trust. Four other large teaching
`hospitals in the U.K. and the Chelsea School of
`
`Podiatry in London contributed patients to this study
`(43 and 58 patients, respectively). The only exclusion
`criterion employed was that subjects should be over
`10 years of age.
`
`All questionnaires were completed by the observing
`clinician. Full—thickness nail clippings and subungual
`debris. when present, were collected from one repre-
`sentative nail. Skin signs of local dermatophyte infec-
`tion were also sought and skin scrapings taken for
`mycologieal analysis.
`
`Laboratory methods
`
`All samples were processed in a single laboratory.
`Direct microscopy was carried out using wet prepar-
`ations with 30% potassium hydroxide solution. Addi-
`tional calcofluor white staining was performed and the
`specimens were examined under ultraviolet radiation.
`Nail samples were cultured on modified Sabouraud’s
`
`agar, both with and without cycloheximidc. incubation
`at 26 °C was maintained for at least 2-3 weeks under
`controlled humidity.
`
`As the objective was to determine signs of nail
`disease that were significantly associated with o11y—
`chomycosis.
`the ‘gold standard’ for
`the diagnosis of
`onychomycosis in this study was taken as positive
`results on both direct microscopy including calcofluor—
`treated nails. and culture of nail samples.
`
`Statistical methods
`
`Questionnaire responses were collated and entered into
`
`a database (Microsoft Excel). Responses were recorded
`in binary format except for one question concerning
`
`the number of abnormal nails. which was recorded
`
`numerically. Details were taken of the age and sex of
`each patient.
`Data analysis was performed with the aid of the
`Stata statistical software package. Crude sensitivities
`and specifieities for each question were determined
`and x2 tests performed. The relative value of each
`question was calculated by adding the sensitivity and
`specificity of each and subtracting 100 (Youden’s ,1
`statistic).
`
`The number of variables in the regression analysis
`was limited by entering those with a P—value <0-1
`along with questions that were felt
`to be clinically
`relevant (onycholysis. nail bed thickening and abnor-
`mal colour of the nail plate). Multiple logistic regression
`with forward stepwise selection of variables was
`performed, using mycology results as the dependent
`variable and questionnaire responses. age and sex as
`the independent variables.
`
`Results
`
`A total of 209 questionnaires and corresponding nail
`samples was received. There were only 14 fingernails
`sampled and due to the lower prevalence of fingernail
`onychomycosis in comparison with toenail
`involve-
`
`ment, we decided to exclude the corresponding ques-
`tionnaires
`from further
`analysis. A further
`26
`
`questionnaires were excluded for the following reasons:
`samples
`taken from both fingernails and toenails
`(ri : 3); missing data for site of nail samples (n = 7):
`growth of nondermatophyte moulds and contaminants
`
`that were negative on direct
`(n 2 4); and nails
`examination but culture positive (11 : 12).
`In all,
`169 questionnaires were available for data analysis.
`Demographic information was obtained for 164 sub-
`
`jects: 57% were male and 43% female. The age range
`was 10-95 years (mean 549; median 555).
`
`Mycology results
`
`Of the nails sampled. 32% had positive results on both
`direct examination and culture for fungi, 42% had
`entirely negative results. and 20% were positive on
`direct microscopy but culture negative. Almost all
`isolates were dermatophytes (92%), comprising Tricho—
`phyton rubrum (44 cases) and T. mentagrophyt.es var.
`inlerdigitale (11 cases). One case was positive on culture
`for Scytalidium dimidiatam. There were more males than
`
`females with onychomycosis, 36% compared with 19%.
`
`© 2004 British Association of Dermatologists, British Iournal of Dermatology, 150, 701-705
`
`CFAD V. Anacor, IPR2015-01776 ANACOR EX. 2038 - 7/1 0
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2038 - 7/10
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`
`DIAGNOSIS OF TOENAIL ONYCHOMYCOSIS
`
`703
`
`Signs suggestive of local dermatophyte infection were
`identified in 65 individuals and skin samples were
`taken from the foot, and,
`in one case,
`the body for
`mycological testing. Half of these had positive results
`on direct microscopy for fungal elements although only
`one—fifth were culture positive. Of the skin samples
`which were positive both on direct examination and on
`culture, 19% were associated with onychomycosis. The
`same organism was cultured in all cases.
`
`Number of abnormal nails
`
`One question concerned the total number of abnormal
`fingernails and toenails. The fifth toenails were exclu-
`ded, as these are often abnormal due to pressure from
`footwear, giving a maximum total of 18. The mean
`number of abnormal nails was 5-1 (median 3, range
`1-18).
`
`Data analysis
`
`Three separate data analyses were performed. In the
`first analysis, questionnaire responses relating to nails
`with positive mycology results were combined with
`
`those relating to nails with entirely negative results.
`representing 133 individuals. In the second, question-
`naire responses relating to nails that were positive on
`direct microscopy but were culture negative were
`analysed along with the mycology-negative nails.
`making a total of 113. For the final analysis. the two
`previous datasets were combined, giving a total of 169
`patients.
`Initial analysis of the data to determine the sensi-
`tivities and specificities of the questionnaire st.ems
`revealed the same results for the first and third sets of
`data. Results for
`the third dataset are shown in
`Table 1.
`
`Analysis of the second set of data corresponding to
`questionnaires
`from direct microseopy—positiVe/cul-
`ture-negative nails and those with entirely negative
`results showed fewer statistically significant question-
`naire stems. The seven that had significant P-values
`were also found in the other two analyses. However,
`the following questions failed to reach significance: dry
`scaly skin on the soles/palms. scaling on one/both
`soles, peeling/maceration/vesicles in the toe webs,
`abnormal
`toenails. swelling of the nail folds, white
`crumbly areas on the nail surface, pitting and oil spots.
`
`Table 1. Sensitivity and specificity of
`questionnaire stems (questionnaires relating
`to direct microscopy positive/culture positive.
`direct microscopy positive/culture negative
`and direct microscopy negative/ culture
`negative nails: 11 = 169)
`
`Question
`
`History
`Tinea pedis in the last year?
`Household contacts with tinea pedis?
`Close family with nail problems?
`Dry, scaly skin on soles/palms?
`Examination
`
`Scaling on one/both soles?
`Peeling/maceration/vesicles on toe
`webs?
`Scaling on one/both palms?
`Abnormal toenails?
`Abnormal fingernails?
`Nails on both hands affected?
`Swelling of nail folds?
`Erythema of nail folds?
`Pain on pressing nail folds?
`Discharge on pressing?
`Thickened nail plate?
`Onycholysis?
`Lateral onycholysis?
`Thickened nail bed?
`Abnormal colour of nail plate?
`White crumbly areas on nail surface?
`Partial/complete loss of nail plate?
`Pitting?
`Oil spots?
`Koilonychia?
`
`Sensitivity Specificity
`(9/0)
`ct.»
`
`yl
`
`P—value
`
`Relative
`value
`
`50-0
`13-()
`13-0
`59-8
`
`68-5
`67-4
`
`10-9
`100-0
`20-7
`7-6
`8-7
`
`4-3
`0-0
`51-6
`69-6
`61-5
`84-4
`92-4
`27-2
`15-2
`7-6
`1-1
`1-1
`
`80-5
`92-2
`84-4
`64-9
`
`54-5
`55-8
`
`83-1
`6-6
`52-6
`68-8
`80-5
`80-5
`
`90-9
`100-0
`51-3
`35-1
`40-8
`10-7
`1 8-2
`88-3
`79-2
`78-9
`86-8
`97-4
`
`21-0
`1-2
`0-2
`10-3
`
`0-000
`0-2 70
`O-637
`0-00]
`
`0-003
`9-1
`92 0-002
`
`1-3
`6-2
`8-]
`
`4-2
`
`0-2'36
`0-013
`0-004
`0-000
`0-042
`0-464
`
`0-213
`1-6
`—
`—
`0-2 O-703
`0-4
`0-522
`0-2
`0-632
`0-9
`0-3 58
`4-3 O-038
`6-3
`0-012
`0-9
`0-3-16
`6-4
`0-012
`9-9
`0-002
`()-6 O-458
`
`— 26-7
`— 23-6
`— 10-8
`— 43
`
`— 4-8
`0-0
`2-9
`47
`2-3
`— 4-9
`10-6
`1 5-5
`— 5-6
`— 13-5
`— 12-1
`— 15
`
`Questions in bold type have significant P-values or were felt to be clinically significant.
`
`-O 2004 British Association of Dermatologists, British Iunrnal of Dermatology. 150, 701—7OS
`
`CFAD V. Anacor, |PR201 5-01 776 ANACOR EX. 2038 - 8/“IO
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2038 - 8/10
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`

`
`704
`
`C.L.FLETCHER et al.
`
`Symptom/ sign
`
`Tinea pedis in the last year?
`Scaling on one/both soles?
`White crumbly areas on nail surface?
`Age
`Abnormal colour of nail plate?
`
`9 5%
`confidence interval
`
`Table 2. Results of multiple logistic regres-
`sion
`
`138-732
`1-10-5-04
`1252-13-51
`095-] -0()
`l‘08—l4‘5l
`
`0038
`
`Multiple logistic regression
`
`Three separate sets of data were analysed, as detailed
`above. The third, and largest, set of da1.a confirmed the
`findings seen in the other two analyses. The parameters
`shown in Table 2 were found to be discriminating for
`onychomycosis.
`
`Discussion
`
`Five subtypes of onychomycosis are recognized:9 distal
`lateral onychomycosis. proximal
`subungual ony-
`chomycosis. superficial onychomycosis, total dystrophic
`onychomycosis, and endonyx onychomycosis. These
`subtypes cause a large number of possible changes in
`the nail apparatus. The purpose of this study was to
`determine the most reliable predictor for the diagnosis
`of onychomycosis. The resulting clinical diagnostic
`aid would be used alongside mycological analysis and
`as such it cannot be expected to identify all patients
`with onychomycosis. A particular area where its use
`will be limited is in subjects with other causes of nail
`dystrophy. Psoriasis
`in the nails can mimic ony-
`chomycosis,
`and indeed the two conditions may
`coexist“)
`
`Interestingly, only two clinical signs in the nail
`apparatus were found to be significantly associated
`with onychomycosis: white crumbly areas 011 the nail
`surface, and an abnormal colour of the nail plate. A
`history of tinea pedis, or signs of this on the soles, and
`increasing age, were also significant. Tinea pedis is a
`known risk
`factor
`for
`toenail onychomycosis.”
`Although peeling/maceration/vesicles in the toe webs
`had a significant P—value in the initial analysis ( 0-002)
`and the third highest relative value (23-2), it did not
`maintain significance following multiple logistic regres-
`sion analysis.
`Further evaluation of the data showed that increas-
`
`ing age was linearly associated with onychomycosis;
`there was no apparent cut—off above which onychomy-
`cosis became more likely. However. the low odds ratio
`suggests that age has a poor predictive value for
`onychomycosis. intraclass correlation studies failed to
`
`show any association between the number of abnormal
`toenails observed and the likelihood of onychomycosis.
`It
`is
`interesting that onycholysis.
`a commonly
`reported sign in onychomycosis, did not reach statis-
`tical significance as a predictive sign. Although often
`traumatic, onycholysis was present in 73% of the nails
`which were found to have positive mycology results. in
`spite of its unremarkable P—value (0522) in univariate
`analysis.
`it was included in the regression analysis
`along with lateral onycholysis (P—value 0-632) and nail
`bed thickening (P—value 0358), both of which were
`also felt to be important clinically. None of these three
`signs was discriminating for onychomycosis.
`An abnormal colour, or discoloration, of the nail is
`
`frequently seen in onychomycosis. No additional
`information was collected in this study regarding any
`specific Colour changes observed. However, it is possible
`that some of the clinicians noted the opacity of the nail
`plate secondary to separation from the nail plate as ‘an
`abnormal colour of the nail plate’ rather than onycl1o-
`lysis per se. This effect, however, is likely to be small, as
`80% of the questionnaires were completed by one
`clinician (C.L.F.).
`White crumbly areas on the nail surface are gener-
`ally associated with superficial white onychomycosis.
`This pattern of nail
`infection is most commonly
`associated with T. mentagrophytes var.
`interdigitale. In
`this study, only 11 nail samples grew this organism
`and in only 23% of the corresponding questionnaires
`was there a positive response to this question. This
`suggests that perhaps more severe cases of onychomy-
`Cosis were picked up in this study, including those with
`a total dystrophic pattern of nail disease. Certainly
`more than half of the patients were recruited from
`dermatology clinics, with the remainder coming from
`chiropody clinics.
`in part, for the false-negative
`VVe tried to control,
`culture rate in the laboratory by including in the data
`analysis questionnaires relating to nails that were
`direct microscopy
`positive but
`culture
`negative
`(ii : 77). Some of
`these patients may also have
`received antifungal
`therapy before inclusion in this
`study. No data were collected to investigate this
`
`© 2004 British Association of Dermatologists, British [ournal ofmrnirztnlogy, 150, 701-705
`
`CFAD V. Anacor, |PR20’|5-01776 ANACOR EX. 2038 - 9/1 0
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2038 - 9/10
`
`

`
`DIAGNOSIS OF TOENAIL ONYCHOMYCOSIS
`
`705
`
`further, although it would be prudent to exclude from
`further studies individuals who had recently received
`
`systemic antifungal therapy. The false-negative rate in
`the laboratory was additionally reduced by taking skin
`scrapings
`from the soles or
`toe webs whenever
`possible.
`The questionnaire has been refined to include only
`the discriminating questions and is being validated by
`applying it to patients over It) years of age presenting
`with abnormal
`toenails to primary care. Following
`further