Editor
`Boni Elewski
`
`Univ. ·of. Minn.
`Bio-Medical
`Library
`9 16 97
`
`Editor-in-Chief
`Michael D. Tharp
`Editorial Board
`Elise Olsen
`Georg Stingl
`Hachiro Tagami
`
`CFAD v. Anacor, IPR2015-01776
`ANACOR EX. 2003 - 1/5
`
`

`
`DERMATOLOGIC
`THERAPY
`
`Edito r-in-Chief
`
`Mi chael D. Tharp, Chicago, IL, USA
`
`[;'ditorial Board
`
`Eli se Olsen, Durham, NC, USA
`
`Geo rg Stin g!, Vienna, Au s tria
`
`1-Iach iro Tagami, Sendai, Japa n
`
`DEHMATOLOGIC THERAPY has bee n c reated to fill an
`important void in the dermatologic lite rature: the la ck of
`a readily available so urce of up-to-date inform atio n on
`the treatment of specific cutane ous di seases and the
`practical application of s pec ifi c treatment modalities.
`Each issue of the journ a l cons ists of a se ries of schol arly
`review articles written by leade rs in dermatology in
`which they describe, in very s pecific term s , how they
`treat particular cu taneous diseases and how they use
`spec ific therape utic age nts. The inform ation contained
`in ea ch issue is so practical and detailed that the reade r
`should be ab le to directly app ly various treatment ap(cid:173)
`proaches to daily clinical s ituations. Because of the s peci(cid:173)
`fic and practical nature of this publication, DEHMATOL(cid:173)
`OG!C THERAPY is not only a re adily available resou rce
`for th e day-to-day treatment of patients, but also a thera(cid:173)
`peutic textbook for the treatment of dermatologic dis (cid:173)
`eases.
`
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`ANACOR EX. 2003 - 2/5
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`

`
`Dernwwlogic ri1empy. \lo/. 3, 1997, '13- 45
`Prinled in /Jelllllark · All rig/us reserued
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`Copy rig /11 tD M un ks gaard 199 7
`
`DERMATOLOGIC T HERAPY
`ISSN 1396-0296
`
`A historical perspective on
`onychomycosis
`
`MARIA A . CHAR I F & BONI ELEWSKJ
`
`Onychomycosis is a disease of modern civilization.
`The history of onychomycosis parallels that of th e
`dermatophyte Trichophyton rubrum. This dermato(cid:173)
`phyte, now th e major cause of tinea pedis and
`onychomycosis, was originally restri cted to small
`geographic regions of west Africa, Southeast Asia,
`northern Australia, and Indonesia(]). Before T rub(cid:173)
`rum appeared in Eu rope, tin ea pedis was extremely
`rare. It may be surpris ing to co nsider th at the first
`report of plantar dermatophytosis was by Pellizza ri
`(2) only 150 yea rs ago. This case was caused by Trich (cid:173)
`ophyton tonsurans. Whitfield reported th e first case
`of tinea pedis in Great Britain in 1908 (3). The
`"father" of mycology, Dr. Sabouraud and the emi(cid:173)
`nent dermatologist, Dr. Whitfield both beli eved tinea
`pedis to be a very rare infection caused by the same
`pathogens as tinea capitis (4) . It was also believed
`that tinea pedis was sporadic and nonrecurrent.
`Onychomycos is was described as a very rare occur(cid:173)
`rence and was predominantly reported in fingernail s
`among caregivers and people with tinea capitis. In a
`text on derma tophytosis by Adler Smith (5). pub(cid:173)
`lished in 1882, infected fingernail s were described as
`"dry, opaque, thickened, furrowed,
`fiss ured and
`brittle". Exposure to tinea capitis was th e only ident(cid:173)
`ifia bl e risk fa ctor, propelling the belief th at onycho (cid:173)
`mycos is, particularly the pedal variety, was quite
`ra re.
`T ruhrum ori ginated in west Africa (present day
`Nige ria, Senegal and th e Ivory Coast) , Southeast Asia
`(present clay India, Thailand , Laos, Vietnam, Korea,
`Bangladesh, Malaysia, east China and the Philippine
`Islands), Indonesia, and northern Australi a, and
`peo ple residing in th ese end emic regions suffered
`from chronic and extensive tinea corpo ris (l ). Native
`populations d id not develop tinea pedis, probably
`beca use of th e lack of footwear. In th e late 19th cen(cid:173)
`tury, European soldiers and colon ialists provided T
`rubrum with a new niche, th e "shod foot" (1). The
`custom of footwear and its implications - occlusion,
`hyperhidrosis a nd maceration - provid ed a highly
`
`favorable environment for this dermatophyte. Rip(cid:173)
`pon (I) has charted the geographic origins of T rub (cid:173)
`rum and its subsequ ent distribution to Europe,
`No rth America and South America in th e late 19th
`and ea rly 20th century (Fig. 1). Increased population
`mobility during th e late 1800s and early 1900s in th e
`form of migration and recreational travel and th e ad(cid:173)
`vent of World War I played a major rol e in translocat(cid:173)
`ing T rubrwn from its original endemic area of Sou (cid:173)
`th east Asia and Africa and introducing it to new eco(cid:173)
`logic environments in Europe and th e American
`co ntinents. The first case of tinea pedis in th e United
`States was actually re ported in Birm ingham, Ala(cid:173)
`bama shortly after World War I (6) . The second World
`War, Ko rean and Vi etnam wars, the frequ ent use of
`gyms, health clubs and occlusive footwear (such as
`joggin g shoes), as well as the jumbo jet have more
`recently contributed to an increased incidence of
`both tinea pedis and onychomycos is. After the Viet(cid:173)
`nam conflict, T rubrum surpassed T m.en.tagrophytes
`as the most common dermatophyte worldwide (3).
`Interestingly, the fa ct that T rubrum seldom causes
`tinea cap itis has probably affected the geographic
`distribution of this dermatophyte. A person with
`tin ea capitis, particularly favu s, would have been de (cid:173)
`nied entry into the United States at Ellis Island. How(cid:173)
`ever, health authoriti es at United States ports of en(cid:173)
`try were not looking for tinea pedis, and infected
`peo ple were neither denied entry nor were th ey
`quarantined. Therefore, th e global distribution of
`this derm atophyte remained unchecked and unre(cid:173)
`stricted , allowing tinea pedis and tinea unguium to
`become a sco urge in the 20th century.
`Rippon now estimates that dermatophyte fungi
`can be recovered from the plantar surfaces of up to
`70% of th e United States population (1, 7). Tinea
`pedis has been speculated to be the most common
`dermatophytosis wo rldwide and onychomycosis th e
`most common nail disease in ad ults. However, what
`is th e actual prevalence of onychomycosis'? Reports
`on th e prevalence of this disease have been conllict-
`
`43
`
`ANACOR EX. 2003 - 3/5
`
`

`
`Charif & t'lewski
`
`~--
`
`~ ..
`... ·.
`
`Fig. 1. The origins of Trichophyton rubrum in west Africa,
`Southeast Asia, northern Australia and Indonesia, its
`transport to Europea and its migration to the American
`
`co ntinents. Adapted and reproduced, with permission
`from Hippon (1).
`
`Trichophyton rubrum
`
`ing. Prevalence figures of 2-3% have been quoted in
`the
`literature
`(8, 9). Za ias
`(10) es timated
`tha t
`onychomycosis occurs in at least 15% of the popula(cid:173)
`tion aged 40- 60 yea rs. However, th ere have been no
`recent ep idem iologic surveys of onychomycosis in
`the United States to support this figure. In a repre(cid:173)
`se ntative sample of 20,000 indi viduals exam ined by
`dermatologists in the north easte rn Uni ted States in
`the late 1970s, the United States Health and Nu (cid:173)
`trition Examination Survey (HANES I) found th e
`ove rall prevalence of fun gal nail infecti on to be
`2. 18% (8). More recently, population-based su rveys
`have been conducted in the United Kingdom, Spain,
`and Finland to determine th e prevalence of onycho(cid:173)
`mycosis in those co untri es. In 1992, H.oberts (9) re(cid:173)
`ported the resu lts of a questionnaire-based con(cid:173)
`s um er survey o f a represen tat ive sample of9932 sub (cid:173)
`jects aged 16 o r older in the United Kin.gdo m . A
`questionnaire co ntaining photographs o l. va no~t s
`nail dystrophies was give n to s tudy partiCipants Ill
`order to id entify cases. Subjects we re exam med by a
`dennatologist, but mycologic cu ltures we re no t ob(cid:173)
`tained. He found the overall prevalence of onyc ho -
`s·s to be 2 8% in m en and 2.6% in women. The
`myco. 1
`·
`.
`.
`revalence of nail infection was 1.3% In the 16-34
`p
`p -111clt·ose to 4 7% in those 55 years or older.
`age grou
`'
`· ,
`.
`.
`. .
`.
`He also found that only 34% of affected mdi vidu als
`
`had so ught medical attention. A si mil a r ques(cid:173)
`tionn aire-based survey was cond ucted by Sa ias e t a t.
`(II) in Spain , using a compute r-assisted telep hone
`intervi ew system. A total of I 0,007 people rep resen (cid:173)
`tative of the Span ish popula ti o n were inte rvi ewed
`between 1992 and 1993. The overall point prevalence
`was 1.7% and was noted to be significantly hi gher in
`wome n (1.8%) than in men (0.8%) As with Roberts,
`an increased prevalence was noted in older age
`groups. Heikkila & Stubb ( 12) in vestiga ted 800 per(cid:173)
`so ns aged 6- 80 yea rs in Finland. In contrast to the
`above stud ies, subjects were directly exa mined by a
`dermatologist and di agnos is was co n fi rm ed by a der(cid:173)
`m atoph yte positive fungal culture. Their results
`yielded highe r prevalence figures of 13.0% in men,
`4.3% in wome n and 8.4% in the e ntire population
`studi ed.
`To add anothe r chapter to the histo ry of onycho(cid:173)
`mycosis, we assessed the prevalence of dermato(cid:173)
`phyte onychomycosis in northeastern Oh io (13). A
`pilot, cross-sectional stud y was cond ucted over a
`period of 6 months on a total of 1038 subj ects. Sub(cid:173)
`jects includ ed patients a nd acco mpanying people
`presenting to two clinics a t the Department of Der(cid:173)
`matology a t th e University Hospitals of Cleveland .
`To el iminate selection bias, patients presenting fo r
`onychomycosis a nd /o r tinea pedis we re excluded.
`
`44
`
`ANACOR EX. 2003 - 4/5
`
`

`
`Onychomycosis was diagnosed based on mycologi(cid:173)
`cal evidence of a nail pathogen as defin ed by a posi(cid:173)
`ti ve de rm a toph yte funga l culture. The results in the
`popu lation surveyed revealed a preva lence of der(cid:173)
`matophyte nai l infection of 8.7% , 6.5% in fem ales
`a nd 13.3% in ma les. In th e group aged < 18 yea rs the
`prevale nce dropped to 1..1 % as opposed to 28. 1% in
`those aged > 60 yea rs. These resu lts a re comparable
`to the prevale nce va lue of 8.4% re ported in Finland,
`but hi gh er than those obtain ed in the United King(cid:173)
`dom a nd Spain and by the HANES survey.
`As with th e previo us surveys, an increased preva(cid:173)
`le nce was no ted with adva ncing age. This may be a
`conseq uence of poor peripheral circul a tion, di a(cid:173)
`be tes, repeated na il traum a, longe r exposure to der(cid:173)
`matophyte fun gi, and dec reased immune function.
`Onychomycosis was significantly m ore common in
`m ales (1 3.3%) than in fema les (6.5%, P< O.OO 1). a
`trend also obse rved by Heikki la. This m ay be du e to
`more frequent foot and toena il trauma sustain ed by
`men. By co ntrast, onychomycosis appea red to be
`more co mmon in wome n (1 .8%) tha n in m en (0.8%)
`in Spain, a nd Roberts (9) found no sexua l d ifferences
`in th e United Kingdom . If onyc homycosis is purely
`a n autosoma l dom in a nt d isease, th en the expected
`incide nce in m en a nd wome n would be similar. The
`in northeastern
`m ale/ fe male discrepancy noted
`Ohio by Heikki la & Stubb (12) and by Sa ias (ll ) sug(cid:173)
`ges ts that th e pathogenesis of this disease is com (cid:173)
`plex.
`Subj ects in old er age groups tend ed to have more
`ex tensive disease invo lvin g seve ral or all toena ils a nd
`a hi gher frequency of tota l dys trophi c onycho (cid:173)
`mycosis. It is li kely th ere is a window of opportu nity
`durin g wh ich th e disease is most ame nab le to th er(cid:173)
`apy, whi ch wou ld occur in earl y stages of infection
`particularly in yo un ge r pati ents. Fa ilure to treat at
`this earl y stage may res ult in total dys trophic na ils
`that require prolonged trea tm en t or respond poorly
`to th e ra py.
`Patients with dys trop hi c nails we re ge ne rall y
`awa re tha t their nails were a bnorm al but not th a t
`the ir co nd ition was du e to a fun ga l infection or was
`ame nab le to treatment. Many patie nts believed their
`dystrophi c nail s we re a normal occ urrence with ag(cid:173)
`ing. Subj ects with m inim al nail in vo lvement were
`frequent ly un aware of th eir disease. The majority of
`subj ects who did have onychomycos is had no t
`sought m edi ca l advi ce eith er beca use th ey were un (cid:173)
`awa re of th eir disease or d id not reali ze th at treat (cid:173)
`m e nt was ava il ab le.
`
`A historica l perspective on onychomycosis
`
`Several authors have speculated that the preva(cid:173)
`len ce of onychomycosis has steadily increased in de(cid:173)
`veloped coLmtries over the past few decades (10, 14).
`Our results an d those of Heikkila & Stubb (12) cer(cid:173)
`tainly seem to support this view. Onychomycosis
`started as a relatively insignificant a nd ra re disorder
`but is now co nsidered by many (10, 14, 15) to be
`quite problem ati c, and is certainly not rare as ou r
`survey results and those of Heikkila & Stubb (12)
`de mons trate. Edu cational efforts that increase pub(cid:173)
`lic awareness of the disease, encourage affected pa (cid:173)
`th e rapy a nd p romote knowledge
`tie nts to seek
`a mon g m edi cal provid ers may eventuall y have th e
`same success in halti ng the current onychomycos is
`ep idemic as they did with the previous ti nea capitis
`epidemic. But if th ese effo rts fai l, how co mmon will
`onychomycosis be in the 21st century'?
`
`References
`
`I. Hi ppon JW. Med ica l myco logy: th e pathoge ni c fun gi
`and th e pathoge ni c actin omyce tes. 3rd edn. Phil a d e l(cid:173)
`phia: WB Sa und e rs Co., 1988: 169-275 .
`2. Pe lli za ri C. Reche rche s ur Trichopilylon tonsurans. G
`!ta l Ma ll attie Ve ne ree 1888: 29: 8- 40.
`3. Elewski BE. Tin ea pedis a nd tin ea m a num . In: De mis
`JD, eel . Clinica l d e rm ato lo gy. Ph il ad e lph ia: ) 1:3 Lippinco tt
`Co. 1993: 3: 1- 10.
`4. Elewski BE. Ed it o ri al. Adv De rma tol 9: I 10- 1 I l.
`5. Smith A: Hin gwo rm: its d iagnos is a nd trea tm e nt. 2nd
`e dn. London: HK Lewis, 18B2: 64.
`6. We idman FD. Labora tory as pec ts of d e rm atop hytos is.
`Arch De rmatol 1927: 15: 4 15-450.
`7. Gano r S. Pe ra th MJ. Ha u bitschek I·: Tin ea pedis in
`schoo l childre n: a n e p ide miologic s tud y. Der m ato logica
`1963: 126: 253- 258.
`B. Edi tori a l. Preva le nce. morbidity and cos t o f dermato lo(cid:173)
`gical di seases. J Invest De rm ato l I 979: 75: 395-401.
`9. Robe rts DT Preva le nce of d e rm ato phyte onyc ho(cid:173)
`m ycos is in the Uni ted Kingdom: results of a n o mni b us
`s urvey. Br J Dermatol 1992: 126(s uppl. 39): 23-27 .
`10. Za ias N. Onychomycos is. Dermatol Clin 1985: 3: 445-
`460.
`II. Sa ias G, Ju ggla A, Peyri J. Preva le nce o f d e rmatoph yte
`o n yc ho m ycos is in Spain: a cross-secti ona l study. Br J
`Dermatol 1995: 32: 758- 76 1.
`12. He ikk il a 1 I. Srubb S. Th e preva le nce of o n yc hom ycosis
`in Finl and . Br J Derma tol 1995: 133: 699- 703 .
`J:l. Cha rif MA, Elews ki l:lE. The prevale nce of onycho(cid:173)
`m ycos is in northeas te rn Ohio. Submitted .
`14. Coh e n J L, Sche r HK, Pappe rt AS. Th e nail an d fungu s
`infecti o ns. In : Elewski UE, eel. Cutan eous fun ga l infec(cid:173)
`ti o ns. New York: lgaku -Scho in, 1992: I 06- 123.
`15. No rton LA. Diso rd e rs of th e nail. In : Mosche ll a SL. Hur(cid:173)
`ley HJ. eel. De rm atology. Philad e lp hi a: WB Sa un d e rs
`Co., 1992: 1563-1585.
`
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`ANACOR EX. 2003 - 5/5