Nail Disease: Approach to the Ugly Yellow Toenail
Tracey C. Vlahovic, DPM FFPM RCPS (Glasg) Associate Professor, J Stanley and Pearl Landau Faculty Fellow Temple University School of Podiatric Medicine Philadelphia, PA Disclosure Statement Research Grants Pharmaderm, Valeant, Merz, Cipher Nail Dystrophy
• Generalized term • Roughness, beau’s lines, onychorrhexis, ridging • Acrocyanosis • Alopecia areata • Congenital • Lichen planus • Occupational • Psoriatic • Asymmetrical Gait Nail Unit Syndrome • Onychomycosis Where is the pathology?
Follow Follow shape the shape of the PNF: of the Lunula: Exogenous conditions internal; systemic
Zaiac & Daniel: Dermatol Therapy 2002, 15 (2) Onychomycosis—Clinically Speaking • Charting may include • Onychauxis (thickened nails) • Subungual debris • Discoloration (yellow, brown, white, green) • Moldy odor • Brittleness • Dystrophy • Pain—specifically which nail(s) • Photographs • Number of nails and percentage of involvement in each nail unit
Picture: T. Vlahovic Why Treat Onychomycosis?
• Estimated 35 million people in US have onychomycosis • Expected to increase by 20% by 20201 • Only 6.3 million diagnosed, only 2.5 million treated • 30+ million are fine with it! • It’s easy to be cavalier about it • HOWEVER • It is chronic • It has medical consequences • It is more than just a cosmetic problem
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1. www.companiesandmarkets.com. Progressive, Recurring Infection Requiring Treatment1,2 • Psychological • May decrease quality of life3 • Symptomatic • Pain on ambulation3 • Risk for further complications • Diabetic, peripheral vascular disease, immunocompromised4 • Reservoir for infection • Spread to other nails and anatomic sites3 • Spread to other individuals4 • Systemic or multisystem involvement • Spread of fungal infection3 • Source of cellulitis4 • Trigger for allergic symptoms in rare cases5
1. Tosti A et al. Dermatology. 1998;197:162-166. 2. Drake LA. J Am Pod Med Assoc. 1997;87:507-511. 3. Drake LA et al. J Am Dermatol. 1999;41(2 Pt 1):189-196. 4. Gupta AK. Eur J Dermatol. 2000;10:379-384. 5. Gupta AK et al. Drug Saf. 2000;22:33-52. Onychomycosis and Quality of Life • 258 patients • Pain = 48% “I wear a bandaid over my big toe so no one sees • Embarrassment = 74% how ugly it is during the summer” • Nail pressure = 40% --42 yr old female, Philadelphia • Shoe discomfort = 38% • Physician visits = 3.8 per year
“I wear socks at the beach because I don’t want anyone to see my toes” —50 year old male, Philadelphia
Drake LA, et al. J Am Acad Dermatol. 1998:38(5 Pt 1):702-704. Overview
• Need accurate diagnosis • Cannot treat solely based on looks—unless clinical evidence of tinea pedis1 • ≈50% treated based on presentation—nail looks abnormal or was traumatized—doesn’t get better because it wasn’t onychomycosis in first place • Underappreciated, often misdiagnosed, definitely undertreated • Primary reason for office visit? • Dermatologist: often not • Podiatrist: often yes • Neither clinician nor patient cares about diagnosing or treating it… unless consequences sufficiently bothersome
1. Walling HW et al. J Am Acad Dermatol. 2007;56(6):945-948. 9 Treatment Considerations in Onychomycosis Management of Patient Expectations • Involve them in treatment decisions • Education is needed to explain: • Treatment may require several months to see results • Therapies need to be used as directed • New habits may need to be adopted to help prevent recurrence • Toenails may never regain a normal appearance • Strategies to help patients • Take “before” photos to show them later how their toenails have improved • Draw schematics showing the amount of affected toenail at each visit • Measure toenail involvement at each visit • Calendar reminders for treatment, laboratory tests, and follow-up visits Elewski BE. Clin Microbiol Rev. 1998;11:415-429. Bikowski J. Practical Dermatology. May 2013. Cervantes et al. Podiatry Today. www.podiatrytoday.com/article/2704. Topical Agents
• Benefits vs systemic agents • Fewer AEs • No need for lab monitoring • Disadvantages • Lower cure rates than systemic agents • Use limited to infections affecting <50% of nail plate or only 1 or few toes1 • Poor patient adherence • Patient concerns over topical agents • Not effective, protracted course, too long to see results, lose interest in therapy • Clinicians reluctant to prescribe topicals for same reasons
1. Pariser D et al. Semin Cutan Med Surg. 2013;32(2 Suppl 1):S13-S14. 12 Efinaconazole 10% Solution
• Approved June 9, 2014 for DLSO • Topical azole specifically developed for onychomycosis1 • Broad spectrum of antifungal activity in vitro • More potent than ciclopirox against common onychomycosis pathogens • Lower keratin binding and quicker drug release from keratin vs ciclopirox or amorolfine • Greater in vivo activity • CYP inhibitor: low/no potential for drug interactions2 • Low resistance potential • Low systemic exposure when applied topically2 • 15%-17.8% complete cure rates in phase 2 trials3
1. Tosti A. Cutis 2013;92(4):203-208. 2. Jarratt M et al. J Drugs Dermatol. 2013;12(9):1010-1016. 3. Gupta AK et al. Expert Opin Investig Drugs. 2014;23(1):97-106. 13 Efinaconazole 10% Solution (continued)
• MOA similar to triazoles • Does not require nail debridement and does not need to be removed/reapplied biweekly1,2 • Effective for DLSO with <65% nail involvement, excluding matrix2 • Can also go on and under nail—gets put directly where infection is
MOA, mechanism of action 1. Patel T et al. Drugs. 2013;73(17):1977-1983. 2. Elewski BE et al. J Am Acad Dermatol. 2013;68:600-608. 14 Efinaconazole 10% Solution: Studies • 2 Phase 3 studies • Study P3-01: efinaconazole (n=656), vehicle (n=214) • Study P3-02: efinaconazole (n=583), vehicle (n=202) • Study sites: US, Canada, Japan • Patients (aged 18-71 y) with mild-to-moderate onychomycosis • 20%-50% toenail involvement with/without matrix involvement • Randomized 3:1 • Efinaconazole 10% solution QHS at bedtime x 48 wk • Vehicle QHS at bedtime x 48 wk • Treatment applied to clean dry nail plate surface, lateral and proximal nail folds, hyponychium, and undersurface of nail plate • No debridement allowed
Elewski BE et al. J Am Acad Dermatol. 2013;68(4):600-608. 15 Efinaconazole 10% Solution: Outcome Measures at Week 52*
Complete Cure Mycologic Cure 60% 55.2% 53.4% 50%
40%
30%
17.8% 20% 16.8% 15.2% 16.9%
10% 5.5% 3.3% 0% Efinaconazole StudyVehicle 1 Efinaconazole StudyVehicle 2 *P<.001 for both studies
Elewski BE et al. J Am Acad Dermatol. 2013;68(4):600-608. 16 Efinaconazole 10% Solution: Study Results • Safety data • Rates of discontinuation due to adverse effects • Efinaconazole: 1.9%-3.2% • Vehicle: 0%-0.5% • Most common AEs leading to treatment discontinuation: local tolerability reactions (application site dermatitis, vesicles)
Elewski BE et al. 2013. J Am Acad Dermatol. 2013;68(4):600-608. 17 Tavaborole 5% Solution
• Approved July 8, 2014 for toenail onychomycosis due to T rubrum or T mentagrophytes • New class of compounds: boron-based benzoxaborole1-3
• Boric acid: nontoxic, LD50 similar to regular table salt (≈3000 mg/kg) • Antifungal with fungicidal activity • Protein synthesis inhibitor • Developed to optimize nail penetration, maintain antifungal activity after application • Solution (dries quickly) • Small molecule with high water solubility • Penetrates nail plate, even in presence of nail polish4 • Broad spectrum, low keratin binding • MOA • Fungal tRNA binding impaired protein synthesis fungal cell death • Inhibits LeuRS to eliminate fungal infection2 • Does not require debridement or product removal
Dermatology Conference 2014; Jan. 17-22, 2014; Kona, LeuRS, Leucyl-tRNA synthetases 1. Elewski BE et al. Presented at: Desert Foot 2013; Nov. 20-22, 2013; Phoenix, AZ. 2. Rock FL et al. Science. 2007;31(5832):1759-1761. 3. Del Rosso JQ et al. J Clin Aesthet Dermatol. 2014;7(2):13-21. 4. Coronado D et al. Presented at: 2014 Winter ClinicalHA. 18 Tavaborole 5% Solution: Clinical Trials • 2 identical pivotal phase 3 trials1 • Multicenter, randomized, double-blind, vehicle controlled • Population: ≈1200 men/women aged ≥18 (18-88 y) • Distal subungual onychomycosis of target great toenail • 20%-60% involved ≥3 mm clear nail from proximal nail fold • ≤3 mm distal toenail plate thickness • +KOH wet/+ fungal culture for dermatophyte • No debridement allowed; nail trimming controlled to <1 mm from hyponychium • Randomized 2:1 • Tavaborole QD x 48 wk (n=400) • Vehicle solution QD x 48 wk (n=200)
Elewski BE et al. Presented at: Desert Foot 2013; Nov. 20-22, 2013; Phoenix, AZ. 19 Tavaborole 5% Solution: Outcome Measures at Week 52*
Complete Cure Mycologic Cure 40% 35.9% 35% 31.1% 30%
25%
20%
15% 12.2% 9.1% 10% 6.5% 7.2% 5% 0.5% 1.5% 0% Tavaborole Vehicle Tavaborole Vehicle Study 1 Study 2 *P≤.001 for both studies
Elewski BE et al. Presented at: Desert Foot 2013; Nov. 20-22, 2013; Phoenix, AZ. 20 Tavaborole 5% Solution: Clinical Trial Results • Well tolerated • Majority of AEs mild, not considered related to tavaborole • No serious AEs considered treatment-related • Rate of treatment discontinuation due to AEs • Tavaborole: 0.8%-2.5% • Vehicle: 0.5%-1.5%
Elewski BE et al. Presented at: Desert Foot 2013; Nov. 20-22, 2013; Phoenix, AZ. 21 Tavaborole 5% and Nail Polish Use Cadaveric fingernails from 8 female donors Group 1: 4 coats of salon brand polish Group 2: 1 coat of salon brand polish Group 3: 2 coats of home brand polish Group 4: 1 coat of home brand polish Group 5: untreated control Tavaborole 5% solution applied daily (25 µL/cm2) to each nail for 14 d
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Elewski BE et al. An in vitro study demonstrating nail penetration of tavaborole from tavaborole topical solution, 5% through multiple layers of nail polish. Presented at: 2014 Annual Meeting of the Society for Investigative Dermatology, May 7-10, 2014; Albuquerque, NM. Tavaborole 5% and Nail Polish
Use (continued) Mean cumulative tavaborole penetration
Through 1 layer of nail polish Through multiple layers of nail polish
23 Conclusion: tavaborole able to penetrate up to 4 layers of nail polish
Elewski BE et al. An in vitro study demonstrating nail penetration of tavaborole from tavaborole topical solution, 5% through multiple layers of nail polish. Presented at: 2014 Annual Meeting of the Society for Investigative Dermatology, May 7-10, 2014; Albuquerque, NM. Efinconazole 10% and Nail Polish Use Polish applied to cadaveric thumbnails from multiple donors Group 1: 2 coats of Dior 999 Red Royalty polish Group 2: 2 coats of Essie 488 Forever Yummy polish Group 3: 2 coats of Revlon 550 Cherry polish Group 4: untreated control Nails dried over the weekend at room temperature Efinaconazole 10% solution applied daily (12.7 mg/cm2) to each nail on Days 1, 2, 3, 4, 7 24
Zeichner JA et al. J Clin Aesthet Dermatol. 2014;7(9):34-36. Efinaconazole 10% and Nail
Polish Use (continued) Mean cumulative efinaconazole penetration through 2 layers of nail polish
Conclusion: 2 coats of nail polish did not appear to inhibit 25 permeation of efinaconazole through the nail
Zeichner JA et al. J Clin Aesthet Dermatol. 2014;7(9):34-36. Topical Placement
• MILD – MODERATE disease • ALTERNATIVE therapy for patients who cannot or will not take an oral antifungal • Potential ADJUNCTIVE therapy along with orals (inside-out/outside-in) for Moderate – Severe disease • Potential PREVENTIVE therapy to avoid reinfection once a nail has been cleared Decision Tree
OSI severe: orals (multiple courses), with/without adjunctive OSI topical treatment Onychomycosis Comorbid OSI moderate: orals Conditions? and/or topical OSI mild: topical Abnormal monotherapy Nail
Not Differential Appropriate Treatment Onychomycosis Diagnosis
OSI, onychomycosis severity index 27 Differential Diagnosis
• Psoriasis (nails)1 • Traumatic onycholysis and nail trauma • Lichen planus2 • Reactive arthritis3 • Twenty nail dystrophy • Allergic or irritant contact dermatitis • Subungual tumors, including SCC and melanoma • Other infections2 • Systemic medications2 • Yellow nail syndrome • Onychogryphosis SCC, squamous cell carcinoma 1. Jiaravuthisan MM et al. J Am Acad Dermatol. 2007;57(1):1-27. 2. Rich P et al. Semin Cutan Med Surg. 2013;32(2Suppl 1):S5-S8. 3. Moll JM. Baillieres Clin Rheumatol. 1987;1(2):289-314. 28 Tinea…. or Something Else?
Reactive arthritis (Reiter’s Syndrome)
Photograph courtesy of Ted Rosen, MD. All rights reserved. 29 Is It Dystrophy or Onychomycosis? • Following antifungal therapy, some dystrophy may remain or you may not be dealing with a fungal infection • Treatment options • Urea nail preparations • Genadur (Medimetriks) • Nuvail (Innocutis) • KeryFlex (PodAdvance) for cosmesis Fifth Toenail Dystrophy from Biomechanics/ Shoegear, Not Caused by Onychomycosis Psoriatic Onychodystrophy
. Nail psoriasis can occur in all psoriasis subtypes . Fingernails are involved in ~ 50% of all patients with psoriasis. . Toenails in 35% . Isolated nail dx: 5-10% . Changes include:
• Pitting: punctate depressions of the nail plate surface • Onycholysis: separation of the nail plate from the nail bed • Subungual hyperkeratosis: abnormal keratinization of the distal nail bed • Trachyonychia: rough nails as if scraped with sandpaper longitudinally 32 Psoriasis vs onychomycosis
Dogra A, Arora AK. Nail psoriasis: The journey so far. Indian J Dermatol 2014;59:319-33 Mycosis or psoriasis? Pustular Psoriasis, KOH/culture neg, Dermoscopy: onycholysis with discolored border Mycosis or psoriasis? SECONDARY ONYCHOMYCOSIS
Both, KOH/culture pos, with corynebacterial erythrasma and psoriatic patches Mycosis or psoriasis? Psoriasis, KOH/Culture neg, dermoscopy positive at onycholysis Koebnerization Diagnosis
• Look for the obvious and ASK!!! • KOH/Culture; PAS; PCR • Radiographs to look for arthritic changes in DIPJ • Biopsy of suspected psoriatic patch • Nail punch biopsy
• Even with secondary onychomycosis, parakeratosis is more pronounced in psoriasis Lichen Planus Lichen Planus Nail with Keryflex Alopecia Areata Eczema Asymmetrical gait nail unit syndrome (AGNUS)
• Toenail unit changes secondary to shoe friction that looks like onycho, but culture negative • 49 patients with onycholysis, nail dystrophy, subungual keratosis, hyperkeratosis of distal toe skin • Familial, Asymmetrical gait (“ubiquitous uneven flat feet”), unilateral, but can be b/l • 70-73% of nails that are culture negative? • Predispose to non-dermatophyte mold, not dermatophytes • Colonize available spaces • Wear open toed shoes as much as possible
Zaias N et al SkinMed 2012 July-Aug, Zaias N et al JEADV 2014 AGNUS Nuvail™ ( poly- ureaurethane, 16%) nail solution • Cipher • FDA approved for managing signs and symptoms of nail dystrophy • Indications: Nail splitting and nail fragility, protection against everyday trauma, friction, and adverse effects of moisture; for intact or damaged nails. 12 month progression (6 months of using poly-ureaurethane)
Subjects that were dermatophyte negative at the end of 6 months using NUVAIL (62%) were asked to come back 6 months later at month 12. Product was discontinued during this 6 month period (from month 6 to month 12) and of the subjects that returned, 19 of 25 had no recurrence and were still clear. 6 months of no additional therapy and yet almost 80% of subjects had no relapse.
Nasir,A., Swick, L., et al., “Clinical Evaluation of Safety and Efficacy of a New Topical Treatment for Onychomycosis”. J. of Drugs in Dermatology. 2011;10;10;1186-1191. Thank you!!!!