Hot Topics In Podiatric Dermatology Evan Rieder, MD

Dermatologist, Psychiatrist Assistant Professor of Dermatology The Ronald O. Perelman Department of Dermatology Disclosures

Advisory Board Member: UCB Pharmaceuticals

Consultant: UCB Pharmaceuticals Unilever

The Ronald O. Perelman Department of Dermatology 2 Podiatrists & Dermatologists

The Ronald O. Perelman Department of Dermatology General Outline

Bumps Stripes Collimated Lights

The Ronald O. Perelman Department of Dermatology 4 The Power of Observation

The Ronald O. Perelman Department of Dermatology Robert Ryman, Untitled 1960-1961

The Ronald O. Perelman Department of Dermatology The Ronald O. Perelman Department of Dermatology The Ronald O. Perelman Department of Dermatology Bumps

The Ronald O. Perelman Department of Dermatology Outline

Common Podiatric Rashes Keys To Differential Diagnosis Uncommon Presentations

The Ronald O. Perelman Department of Dermatology Bumps

The Ronald O. Perelman Department of Dermatology Classic Psoriasis

Well-demarcated Erythematous plaque Silvery scale

Classic locations: Scalp, elbows, knees, buttocks

3% of the population

Nail, joint involvement common

Dx: clinical +/- biopsy

Tx: topical steroids, nbUVB, immunomodulators

The Ronald O. Perelman Department of Dermatology Psoriasis of the & Lower Leg

May appear like classic plaque psoriasis

However may have different presentation

Patchy or generalized thickening and scaling of nearly entire surface of palms / soles without redness •Keratoderma

Greater associations with and joint psoriasis

Chronic, difficult to treat

The Ronald O. Perelman Department of Dermatology Palmoplantar Pustulosis

Different presentation

Palms and soles, especially lateral Localized or entire surface

Sterile pustules admixed with yellow-brown macules +/- scaly erythematous plaques

No longer considered psoriasis

10-25% of patients with palmoplantar pustulosis also have plaque psoriasis

The Ronald O. Perelman Department of Dermatology SAPHO Syndrome

May be associated with sterile inflammatory bone lesions

Synovitis Pustulosis

AKA chronic recurrent multifocal , pustulotic arthro- osteitis

Misdiagnosis, mistreatment common

Dermatology referral

The Ronald O. Perelman Department of Dermatology Psoriasis / Palmoplantar Pustulosis

Important differential diagnosis

Tinea pedis •Pustular or bullous variant

Eczematous dermatitis •Dyshidrotic •Contact (allergic or irritant)

Scabies

Uncommon diagnoses: •Bazex syndrome •Bullous disorders

The Ronald O. Perelman Department of Dermatology Common Differential Diagnoses

The Ronald O. Perelman Department of Dermatology Tinea pedis

Pruritic Macular Scaly (thin) Erythematous Leading edge of scale

KOH+

The Ronald O. Perelman Department of Dermatology Eczematous dermatidites

Dyshidrotic:

Tense, deep-seated vesicles of palms +/- soles

Intensely pruritic

The Ronald O. Perelman Department of Dermatology Eczematous dermatidites

Contact: Well-demarcated Erythematous Diffuse scale +/-Serous drainage +/-Vesicobullae

Distribution of contactant: e.g. cream, sandal

•May need patch testing •History is relevant

Kline 2008

The Ronald O. Perelman Department of Dermatology Scabies

Interdigital burrows: > Severe pruritus Not restricted to palms and soles History is relevant

When widespread / on feet, think crusted

The Ronald O. Perelman Department of Dermatology Crusted scabies

Thick, crusted plaques Typically acral, may be generalized Dystrophic nails May not see burrows

Severe pruritus Socioeconomic considerations

The Ronald O. Perelman Department of Dermatology Uncommon Diagnoses

The Ronald O. Perelman Department of Dermatology Bazex Syndrome

Acrokeratosis Paraneoplastica

Psoriatic-appearing nails

Psoriasiform erythematous, squamous lesions of feet, ears, nose •Visible without disrobing •Not common areas for psoriasis

Assoc with UGI or respiratory malignancies Medical referral is mandatory

Sator PG et al, 2006

The Ronald O. Perelman Department of Dermatology Blistering Disorders

Bullous Pemphigoid •Erythematous wheals  tense bullae (lower abdomen, thighs, forearms)

•May result in milia with healing

•May have underlying systemic illness or medication trigger

The Ronald O. Perelman Department of Dermatology Blistering Disorders

Epidermolysis Bullosa Acquisita •Erosions of feet / hands, tense vesicobullae that may be hemorrhagic

•May also result in milia with healing

•May be associated with IBD

The Ronald O. Perelman Department of Dermatology Take Home Points

Sometimes scaly red plaques are just psoriasis

Lower leg psoriasis may have an atypical presentation

Sometimes the differential diagnosis is broad

Observation of key clinical features can be very helpful in events when diagnosis is uncertain

Dermatologic +/- medical referral to rule out atypical syndromes or underlying systemic disease

The Ronald O. Perelman Department of Dermatology Stripes

(Longitudinal) Melanonychia

The Ronald O. Perelman Department of Dermatology Outline

Non-Melanocytic Melanocytic

Tips for Diagnosis Common & Rare Conditions

Image via regionalderm.com Melanonychia

Non- Melanocytic Melanocytic

Fungal Melanocyte Melanocytic Subungual activation Nail staining Melanonychia hemorrhage hyperplasia

Benign Malignant

Single Multiple

Nail matrix Subungual nevus melanoma

Trauma- Periungual Nail apparatus induced tumor-induced Laugier- lentigo Drug/systemic Ethnic type nail Peutz Jeghers Hunziker dz-induced pigmentation syndrome syndrome

30 Non- Melanocytic

Fungal Subungual Nail staining Melanonychia hemorrhage

31 Clinical Scenario

A patient presents for a routine exam and you see yellow discoloration of multiple fingernails. How can this help you meet your Clinical Quality Measures (CQM) for meaningful use?

Recording smoking status for patients 13 years or older is a core objective

Smoking cessation medical assistance is an additional set CQM

Hardin ME, Greyling LA, Davis LS. Nicotine staining of the hair and nails.32 J Am Acad Dermatol. 2015 Sep;73(3):e105-6. doi: 10.1016/j.jaad.2015.05.020. Nail Staining

Location: Bilateral thumbnails, 2nd & 3rd fingernails of dominant hand

Causes: •Brown: hobbies, occupational exposure to Hardin ME, Greyling LA, Davis LS. Nicotine staining of the hair and nails. foods, clothing dyes J Am Acad Dermatol. 2015 Sep;73(3):e105-6. doi: 10.1016/j.jaad.2015.05.020 •Yellow: smoking, nail polish (red)

Dermoscopy of Pigment: •Irregularly shaped •Well-demarcated border, may be parallel to PNF

Tx: Easily removed w/ 15 blade

33 Jin H, Kim JM, Kim GW, et al. Diagnostic criteria for and clinical review of melanonychia in Korean patients. J Am Acad Dermatol. 2016 Jan 30. Nail Staining

Huang Guofu

www.dailymail.co.uk/news/article-1384841/The-incredible-paintings-amputee-Chinese-artist-creates-pictures-toes-mouth.html Clinical Scenario

A 39yo man presents with 1 month of discoloration of multiple toenails. He is concerned about melanoma. He has no personal or family h/o of skin cancer.

What questions are important to ask this patient? -Medication history -Trauma

Most appropriate next steps? -PAS, fungal culture, +/- PCR -Dermoscopy

Wang YJ, Sun PL. Fungal melanonychia caused by Trichophyton rubrum and the 35 value of dermoscopy. Cutis. 2014 Sep;94(3):E5-6. A Word On Dermoscopy

Non-invasive diagnostic test for evaluation of lesions of skin, hair, & nails

Low-powered microscope with contact or polarized light to reduce surface light-scatter interference

Image via: www.medicalexpo.com/prod/dermlite/product-79388-506390.html A Word On Dermoscopy

Helpful tool, low cost, portable

Eliminates biopsies

Pilot study of pigmented lesions shows that old dogs can learn new tricks

Pigmented lesions are much more difficult to assess than nails

Terushkin et al 2010

Lasers for Fungal Melanonychia

Location: toenails > fingernails •Men > Women

Causes: Most common 1) Non-Dermatophyte, dematiaceous fungus: Scytalidium dimidiatum

2) Dermatophyte, nondematiaceous fungus: Trichophyton rubrum

38 Fungal Melanonychia

Clinical clue: often spares matrix

Dermoscopy of pigment: •Pigment streak w/ distal widening •Yellowish streaks w/ jagged borders composed of spikes

Dx: KOH, fungal Cx (cycloheximide-free media)

Tx: Azole (Fluconazole, Itraconazole); Allylamine (Terbinafine)

Wang YJ, Sun PL. Fungal melanonychia caused by Trichophyton rubrum 39 and the value of dermoscopy. Cutis. 2014 Sep;94(3):E5-6. Fungal Melanonychia: Dermoscopy

• Pigmented streak • Distal widening

• Yellowish streaks • Jagged borders • Spikes

Ohn et al, JAAD 2017

Wang YJ, Sun PL. Fungal melanonychia caused by Trichophyton rubrum 40 and the value of dermoscopy. Cutis. 2014 Sep;94(3):E5-6. Clinical Scenario

A 35yo construction worker presents to your clinic after slamming his hand in a door. You notice that the nail bed edges are disrupted. Would you perform a nail bed trephination for evacuation of the subungual ? Are there any additional exams that you would order?

41 Bharathi RR, Bajantri B. Nail bed and deformities of nail. Indian J Plast Surg. 2011 May;44(2):197-202. doi: 10.4103/0970-0358.85340. Subungual Hemorrhage

Location: single or multiple nails; toes > fingers (great )

Causes: trauma (overt episode, exercise)

Dermoscopy of pigment: purple- black: homogenous, globular & peripheral fading patterns

42

Photos courtesy: Dr. Jennifer Stein Subungual Hemorrhage

Dx: Serial dermoscopy (color fading & distal movement of features), does not involve matrix

Radiology: X-Ray of affected digit to r/o: • Fracture of distal phalanx • Extensor tendon avulsion of distal phalanx

Tx: Drainage indicated when: •1) Pain present & 2) Nail edges intact • Previously: nail bed trephination only for subungual hematomas <25-50% of nail surface (>25-50%, tx avulsion with repair of any underlying nail bed laceration) • More recently: if nail plate is partially adherent, not displaced out of PNF may leave nail plate in place and subungual may be trephined

43 Summary: Non-Melanocytic

Not all brown discoloration of the nail is due to melanin

Dermoscopy and non-invasive diagnostic testing may be of utility

Nail bed trephination may be indicated for hematomas of any size if the nail edges are not disrupted •If edges are disrupted  higher likelihood of nail bed & associated distal phalanx fx  may lead to a secondary nail deformity if not surgically repaired

44 Melanonychia

Non- Melanocytic Melanocytic

Fungal Melanocyte Melanocytic Subungual activation Nail staining Melanonychia hemorrhage hyperplasia

Benign Malignant

Single Multiple

Nail matrix Subungual nevus melanoma

Trauma- Periungual Nail apparatus induced tumor-induced Laugier- lentigo Drug/systemic Ethnic type nail Peutz Jeghers Hunziker dz-induced pigmentation syndrome syndrome

45 Melanonychia: Melanocytic

Melanocyte activation: • Normal # of melanocytes with increased production of melanin  epithelial hyperpigmentation

Melanocyte hyperplasia: • Increased # of melanocytes (proliferation)

46 Dermoscopy: Melanocytic Activation v Proliferation

Melanocyte activation: thin, regular gray lines on grayish background

v Melanin Melanocytes Melanocyte proliferation: homogenous brown color of background band with:

- regular pattern of brown lines: longitudinal parallel lines w/ regular spacing & thickness

-irregular pattern of brown to black lines: w/ irregular spacing & thickness, disruption of parallelism

Braun RP, Baran R, Le Gal FA, et al. Diagnosis and management of nail pigmentations. J Am Acad Dermatol. 2007 May;56(5):835-47. 2007 Feb 22. Melanonychia

Non- Melanocytic Melanocytic

Fungal Melanocyte Melanocytic Subungual activation Nail staining Melanonychia hemorrhage hyperplasia

Benign Malignant

Single Multiple

Nail matrix Subungual nevus melanoma

Trauma- Periungual Nail apparatus induced tumor-induced Laugier- lentigo Drug/systemic Ethnic type nail Peutz Jeghers Hunziker dz-induced pigmentation syndrome syndrome

48 Melanocytic

Melanocyte activation

Single Multiple

Trauma- Periungual Nail induced tumor- apparatus induced lentigo Laugier- Peutz Drug/systemic Ethnic type Hunziker Jeghers dz-induced nail pigmentation syndrome syndrome

49 Melanocyte activation: single nail involved

Trauma-induced: •Location: fingernails > toes (thumb, 2nd nail)

•Causes: occupational trauma, , overt trauma w/ nail plate deformity, repeated minor trauma to toe/s (may involve multiple digits)

•Dermoscopy of pigment: thin, regular gray lines on grayish background; abnormal surface of nail plate; (+) blood spots

50 Trauma-induced Melanonychia

Don’t try this at home!

Photo courtesy: Dr. Shane Meehan 51 Melanocyte activation: single nail involved

Periungual tumor-induced: •Location: fingernails, toenails

•Causes: digital mucous , warts, fibromas, SCC, onychomatricoma

•Dermoscopy of pigment: thin, regular gray lines on grayish background; abnormal surface of nail plate; (-) blood spots

52 Melanocyte activation: single nail involved

Nail apparatus lentigo: •Location: fingernails (L thumb/2nd), toenails (R great toe)

•Cause: epithelial hyperpigmentation

•Dermoscopy of pigment: thin, regular gray lines on grayish background

53 Nail apparatus Lentigo

Photos courtesy of: Dr. Jennifer Stein

54 Melanocytic

Melanocyte activation

Single Multiple

Trauma- Periungual Nail induced tumor- apparatus induced lentigo Laugier- Peutz Drug/systemic Ethnic type Hunziker Jeghers dz-induced nail pigmentation syndrome syndrome

55 Melanocyte activation: Multiple nails involved

Drug/Systemic disease-induced:

•Location: fingernails > toenails

•Causes: Medications: .Antiretrovirals (Zidovudine, Lopinavir) .Chemotherapeutics (5-FU, MTX) .Antimalarials (Hydroxychloroquine) Systemic Disease: . Scleroderma, SLE, HIV, Addison’s Dz (Bissell’s lines)

56 Drug-induced melanonychia

G. Micali, F. Lacarrubba (Eds.) Dermatoscopy in clinical practice: beyond pigmented lesions. Informa Healthcare Ltd, London; 2010.

57 Melanocyte activation: Multiple nails involved

Ethnic type nail pigmentation: •Location: fingernails > toenails dark-skinned (Type V, VI) > light-skinned patients

•Dermoscopy of pigment: thin, regular gray lines on grayish background

58 Ethnic type nail pigmentation

Photo courtesy: Dr. Jennifer Stein

59 Melanocyte activation: Multiple nails involved

Laugier-Hunziker syndrome: •Adult onset; sporadic, AD

•Location: fingernails, oral mucosa (lips, buccal mucosa, tongue), genitals

•Dermoscopy of pigment: thin, regular gray lines on grayish background

60 Melanocyte activation: Multiple nails involved

Peutz Jeghers syndrome: •Congenital/Childhood onset; AD (STK11 mutation)

•Location: oral mucosa + genital + digits (rarely)

•Dermoscopy of pigment: thin, regular gray lines on grayish background

•Malignancy risk: GI, breast, others

61 Melanonychia

Non- Melanocytic Melanocytic

Fungal Melanocyte Melanocytic Subungual activation Nail staining Melanonychia hemorrhage hyperplasia

Benign Malignant

Single Multiple

Nail matrix Subungual nevus melanoma

Trauma- Periungual Nail apparatus induced tumor-induced Laugier- lentigo Drug/systemic Ethnic type nail Peutz Jeghers Hunziker dz-induced pigmentation syndrome syndrome

62 Melanocytic

Melanocyte hyperplasia

Nail matrix Subungual nevus melanoma 63 Melanocyte Proliferation

Nail matrix nevus: •Location: fingernails > toenails; single nail > multiple nails

•Dermoscopy of pigment: homogenous brown color of background band w/ regular pattern of brown lines: longitudinal parallel lines w/ regular spacing & thickness

64 Nail Matrix Nevus

G. Micali, F. Lacarrubba (Eds.) Dermatoscopy in clinical practice: beyond pigmented Braun RP, Baran R, Le Gal FA, et al. Diagnosis and management of nail pigmentations. J Am lesions. Informa Healthcare Ltd, London; 2010. Acad Dermatol. 2007 May;56(5):835-47. Epub 2007 Feb 22.

65 Melanocyte Proliferation

Subungual melanoma: •Location: thumb > great toe > index

•(+) Hutchinson’s Sign, (+/-) nail dystrophy

•50% of pts recollect preceding trauma

66 Subungual Melanoma

Worrisome features: 1) Pigment wider at the base 2) Multiple, variegated uneven bands 3) Destruction of nail plate/associated dystrophy 4) Pigment beyond nail/Hutchinson’s sign

67 Longitudinal Melanonychia Dermoscopy Summary

Ohn et al JAAD 2017. ABCDEFs of Subungual Melanoma

(A) Age: peak incidence in 5th to 7th decades of life, AA, Asians, Native Americans (in whom subungual melanoma accounts for ≤ 1/3 of all melanoma)

(B) Brown-black band w/ breadth greater than 3 mm with variegated borders

(C) Change in nail band or lack of change in morphology despite adequate tx

(D) Digit most commonly involved: thumb > great toe > index finger

(E) Extension of the brown-black pigment onto the proximal and/or lateral nailfold (+ Hutchinson’s sign)

(F) Family or personal history of dysplastic nevus or melanoma

Levit EK, Kagen MH, Scher RK, et al. The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol. 2000 Feb;42(2 Pt 1):269-74.

69 Longitudinal Melanonychia - Conclusions

Most melanonychias are benign, but it is essential to r/o subungual melanoma

Detailed history, clinical exam & medication review are important for diagnosis

Dermoscopy may aid in diagnosis & monitoring

If in doubt, perform a nail matrix biopsy

70 Collimated Lights

Lasers for Onychomycosis

The Ronald O. Perelman Department of Dermatology Emerging Therapeutics in

Onychomycosis •Lasers •Photodynamic Therapy •Iontophoresis

Psoriasis •Lasers •Intense Pulsed Light

The Ronald O. Perelman Department of Dermatology Outline

Why lasers? Mechanisms Data Future Directions

Lasers for Onychomycosis Background

Onychomycosis: the most common nail disease affecting ~14% of the population • Multiple modalities of treatment • Orals • Topicals • Multimodal treatment

Challenges: • Nail plate • Patient compliance • Low cure rates • High rates of relapse • Uncertain follow-up time • Potential adverse events (e.g. hepatotoxicity, drug-drug interactions) de Berker, 2009. Elewski BE, Charif MA. Gupta AK, et al 2000. Ghannoum MA, et al, 2000.

Lasers for Onychomycosis Why Lasers?

Principle of Selective Thermolysis •Selective targeting of fungus? •Better penetration, reduced side effects, physician control

Six Lasers FDA Cleared for the “temporary increase of clear nail of patients with onychomycosis” •Based on Equivalence Data •Not on RCTs

•5 are Nd:YAG (1064nm), 1 is a diode (635/405nm)

FDA.gov

Lasers for Onychomycosis Mechanisms of Action

Ideally based on TRT of fungi or melanin

•Time required for heated tissue to lose 50% of heat through diffusion •Related to size of target chromophore •If time >TRT, target is not treated but collateral damage inflicted

In reality, most mechanisms are uncertain

Kalokasidis K et al. 2013. Ortiz AE et al, 2014. Carney et al, 2013. Haedersdal M et al, 2016. Gupta & Versteeg, 2017

Lasers for Onychomycosis Mechanisms of Action

Nd:YAG: bulk heating

Selective photothermolysis? • T ↑  induced by energy absorption by lipids and moisture within fungal & host cells  heat shock response  affects transcription / translation  death by induced cell imbalance • T. rubrum death within 15 min of exposure at 50ºC • T> 45ºC  pain, necrosis in humans • Theoretically**, pulses should alleviate this • Lower temperatures can lead to fungistasis, but later spore germination

Fungistasis or fungicide?

Kalokasidis K et al. 2013. Ortiz AE et al, 2014. Carney et al, 2013. Haedersdal M et al, 2016. Gupta & Versteeg, 2017; Carney et al 2013

Lasers for Onychomycosis Mechanisms of Action

QS lasers: selective photothermolytic and photomechanical effects • Which are target chromophores: melanin in cell wall or fungi?

• Light absorption peak for t. rubrum is 415nm

• Chitin, xanthomegnin, and melanin produced by t. rubrum • Pigments are virulence factors that protect fungi from host immune responses and ROS  with destruction there could be an antifungal effect

• At 532nm QS Nd:YAG can suppress t. rubrum due to large amounts of xanthomegnin it contains • However only wavelengths 750 – 1300nm can penetrate the nail plate • At 1064nm, wavelength is beyond absorption spectrum

Kalokasidis K et al. 2013. Ortiz AE et al, 2014. Carney et al, 2013. Haedersdal M et al, 2016. Gupta & Versteeg, 2017; Carney et al 2013

Lasers for Onychomycosis Mechanisms of Action

Nd:YAG Outstanding Issues

• TRTs of mycelia and spores are not precisely known

• Are short pulses sufficient for fungicide or only fungistasis?

• How long do elevated temperatures need to be sustained to kill spores without damaging surrounding tissues?

• Is there a mismatch between the wavelength needed to penetrate the nail plate and that required to target necessary chromophores?

Kalokasidis K et al. 2013. Ortiz AE et al, 2014. Carney et al, 2013. Haedersdal M et al, 2016. Gupta & Versteeg, 2017; Carney et al 2013

Lasers for Onychomycosis Mechanisms of Action

Diode: antimicrobial plus increased immune response? • Dual wave, Non-thermal or “low level laser”

Antimicrobial • 405nm (blue) light: antimicrobial, antibacterial, antifungal effects

Increased immune response • 635nm (red) light: increase immune response by increasing circulation

Theory of photomodulation to increase immune activation: • Light exposure  target chromophore (iron and copper-containing enzyme cytochrome C oxidase in the mitochondrial respiratory chain)  increased production of mitochondrial products  PMNs stimulated to generate additional ROS  increased fungicidal capacity

Gupta & Versteeg, 2017; Bhatta et al, 2017

Lasers for Onychomycosis Mechanisms of Action

Erbium and CO2: ablative v fractionated • Vaporization of nail bed +/- enhanced topical drug delivery

fCO2 Photothermal effects On fungus

• ↑ tissue T  direct fungicide as H2O converted to steam  swelling, pressure  microexplosions in fungi On microenvironment • Exfoliation and vaporization of target tissues  remodeling and destruction of fungal growth environment

Enhanced topical drug delivery • Enhanced absorption via microscopic holes in nail bed

Kalokasidis K et al. 2013. Ortiz AE et al, 2014. Carney et al, 2013. Haedersdal M et al, 2016. Gupta & Versteeg, 2017

Lasers for Onychomycosis General Data

Fraught with limitations Most reports are case series, uncontrolled trials without placebo or randomization Numbers of subjects are low Treatment numbers range from 1 – 12 sessions Follow-up ranges from 0 – 12 months Few pure laser studies: often use concomitant antifungals Measurements: no consistency • Type of onychomycosis • Species • Diagnosis (Culture / PAS) • Clinical measurements • How cure and clinical improvement defined • Fingers v toenails

47% of 1064nm device trials reported a positive response 60% reported clinical and mycologic cure in >50% of treated subjects

Francuzik et al 2016

Lasers for Onychomycosis Randomized Studies With A Comparison Group

Author Year Laser Wavelength (nm) No. of treated No. of nails Follow- CRR (%) MCR (%) Rand Controlled Source patients up (mo) omized Landsman et al. 2010, 2012 Diode 870, 930 26 26 9 35 38 Yes YesP

Zhang et al. 2012 Nd:YAG 1064 33 154 6 51-53 NA Yes YesA Hollmig et al. 2014 Nd:YAG 1064 17 57 12 0.24M 33** Yes Yes Li et al. 2014 Nd:YAG 1064 37 112 (50*, 62) 6 62.5 74* Yes YesB 83.9 Ortiz et al. 2014 Nd:YAG 1320 10 10 3 40C 50 Yes YesS Xu 2014 Nd:YAG 1064 15 31 6 64.52 77.42 Yes YesT1 El-Tatawy et al. 2015 Nd:YAG 1064 20 NA 6 100 80 Yes YesT2 Kim et al 2016 Nd:YAG 1064 56 217 6 76 15 Yes YesT3 Karsai et al 2017 Nd:YAG 1064 20 82 12 0 0 Yes Yes Park et al 2017 Nd:YAG 1064 128 NA 0 NA 72 Yes YesT4

CRR - Clinical Response Rate; Defined by linear clearing of the nail unless otherwise noted MCR - Mycologic Cure Rate; Defined by negative fungal culture unless otherwise noted * Fingernails **At 3 months M Reported as mean proximal nail plate clearance in millimeters C Reported as clinical clearance rate P Placebo-controlled S Subjects served as their own controls Nd:YAG n = 352 A Nd:YAG with half the number of treatments served as control group B Fingernails and toenails served as control groups for each other CRR = 0-100% T1 Oral terbinafine served as control group MCR = 0-84% T2, T3, T4 Topicals served as control group (T2 – terbinafine, T3 – naftifine, T4 – amorolfine) f/u = 0-12 mo Adapted from Wiznia et al, 2016; Karsai et al; Park et al; Kim et al

Lasers for Onychomycosis Compelling (?) Data: Erbium & CO2

Author Year Fractionated Wavelength (nm) Fluence No. of patients No. of nails Follow-up (mo) CRR (%) MCR (%) Controlled (J/cm2) or Power (W) Apfelberg et al. 1984 No 10600 NA 9 NA 6 NA 67* No Borovoy et al. 1992 No 10600 8-10 W 200 NA 36 75 NA No Lim et al. 2014 Yes 10600 160mJ 24 119 3 71 50 No Bhatta et al. 2016 Yes NA 99mJ 75 356 6 73 80 No Zhang et al. 2016 Yes 2940 35-62J/cm2 9 20 3 90 75 No Zhou et al. 2016 Yes 10600 10-15mJ 60 233 6 73A 57B Yes*** Shi et al. 2017 Yes 10600 15mJ 31 124 3 69* 74** No

Fractionated CO2 CRR - Clinical Response Rate; Defined by linear clearing of the nail unless otherwise noted n = 190 A Greater than 60% clear B Less than 5% nail affected MCR - Mycologic Cure Rate; Defined by negative fungal culture unless otherwise noted CRR = 69-90% **Negative fungal microscopy (KOH) MCR = 50-80% ***CO2 arm served as control v CO2 + topical 3-12 tx, q2-4 wk Adapted from Wiznia et al; Shi et al; Zhang et al; Zhou et al daily antifungal

Lasers for Onychomycosis Adverse Effects

•Pain •Necrosis, especially in diabetics •Risk of

Leverone et al, 2015

Lasers for Onychomycosis How to Approach This?

Assume that lasers do not work and do not use them • A recent ”real-world” study (Rivers et al)

Use lasers for only selected indications • DLSO, in patients intolerant / unwilling to use prescriptions, those with better prognosis

Employ multimodal treatment • Time, money

Attempt fractionally ablative methods

Consider the language that is being used

Rivers et al 2016

Lasers for Onychomycosis Education

Dispel the notion of treatment of onychomycosis • Temporary increase in clear nail • Offer treatment for cosmesis only • Analogous to botulinum toxin, hyaluronic acid fillers

Set expectations

Recognize your own moral compass

Image via greaterspringfield.nimbledeals.com

Lasers for Onychomycosis Future Studies: Standardization

Lasers as monotherapy

How best to identify controls • Untreated digit of contra foot v untreated individuals

Follow-up times

Treat all affected nails to control for reinfection

Separate by onychomycosis subtype, location (fingers v toes) • Growth rates differ between fingers and toes as will time to treatment endpoints and measurements

Methods for quantifying clinical improvement • Cure rates – clinical and mycological • Cosmesis • Treatment

Gupta et al 2016

Lasers for Onychomycosis Lasers: The Bottom Line

Studies generally of poor quality, without standardization Comparisons difficult to make

The optimal non-ablative laser needs • Activity against melanin/fungal elements AND pulse duration matching TRT • Adequate nail penetration

Fractionated Erbium and CO2 • Initial data look promising • Mechanism makes sense

Lasers for Onychomycosis Conclusions

The differential diagnosis of podiatric rashes is broad and includes uncommon systemic conditions

Careful clinical examination can help narrow differentials

Most melanonychias are benign

Following an algorithm helps to demystify these conditions

Detailed history and examination, including dermoscopy, can help

Lasers hold promise for the cosmetic / medical treatment of onychomycosis

Data are early, methodologies are unsound, improved standards will help

The Ronald O. Perelman Department of Dermatology Acknowledgements

APMA Council for Nail Disorders

Chris Adigun, MD Kristen Lo Sicco, MD Euphemia Mu, MD Nicola Quatrano, MD Jennifer Stein, MD, PhD Antonella Tosti, MD Lauren Wiznia, MD

Questions: [email protected] @drevanrieder

The Ronald O. Perelman Department of Dermatology References – Bumps

1. Kline A. Allergic contact dermatitis of the foot after use of Mastisol skin adhesive: a case report. Foot and Ankle Online Journal 2008. doi: 10.3827/faoj.2008.0102.0002 2. Sator PG, Breier F, Gschnait F. Acrokeratosis paraneoplastica (Bazex's syndrome): Association with liposarcoma. J Am Acad Dermatol 2006; 55:1103.

All other clinical information and photos obtained from:

UpToDate VisualDx Dermnetnz.com

The Ronald O. Perelman Department of Dermatology References – Stripes

1. Bae SH, Kim NH, Lee JB, et al. Total melanonychia caused by Trichophyton rubrum mimicking subungual melanoma. J Dermatol. 2016 Apr 9. doi: 10.1111/1346-8138.13386. [Epub ahead of print] 2. Beggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010 Jul;59(7):975-86. 3. Braun RP, Baran R, Le Gal FA, et al. Diagnosis and management of nail pigmentations. J Am Acad Dermatol. 2007 May;56(5):835-47. Epub 2007 Feb 22. 4. Centers for Medicare and Medicaid Services. Medicare and Medicaid EHR incentive program: meaningful use stage 1 requirements overview, 2010. Published online July 28, 2010. Available at: URL: http://www.cms.gov/Regulations-and Guidance/Legislation/EHRIncentivePrograms/downloads/MU_Stage1_ReqOverview.pdf. Accessed May 11th, 2016. 5. Terushkin V et al. Analysis of the benign to malignant ratio of lesions biopsied by a general dermatologist before and after the adoption of dermoscopy. Arch Dermatol 2010; 146(3): 343-344. 6. Ohn J et al. Dermoscopic patterns of fungal melanonychia: a comparative study with other causes of melanonychia. J Am Acad Dermatol 2017; 76: 488-493. 7. Dean B, Becker G, Little C. The management of the acute traumatic subungual haematoma: a systematic review. Hand Surg. 2012;17(1):151-4. 8. Finch J, Arenas R, Baran R. Fungal melanonychia. J Am Acad Dermatol. 2012 May;66(5):830-41. 9. Hardin ME, Greyling LA, Davis LS. Nicotine staining of the hair and nails. J Am Acad Dermatol. 2015 Sep;73(3):e105-6. doi: 10.1016/j.jaad.2015.05.020 10. Jabbari A, Gonzalez ME, Franks AG Jr, Sanchez M. Laugier Hunziker syndrome. Dermatol Online J. 2010 Nov 15;16(11):23. 11. Jin H, Kim JM, Kim GW, et al. Diagnostic criteria for and clinical review of melanonychia in Korean patients. J Am Acad Dermatol. 2016 Jan 30. 12. Lee SW, Kim YC, Kim DK, et al. Fungal melanonychia. J Dermatol. 2004 Nov;31(11):904-9. 13. Levit EK, Kagen MH, Scher RK, et al. The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol. 2000 Feb;42(2 Pt 1):269-74. 14. Piraccini BM, Iorizzo M, Tosti A. Drug-induced nail abnormalities. Am J Clin Dermatol. 2003;4(1):31-7. 15. Wang YJ, Sun PL. Fungal melanonychia caused by Trichophyton rubrum and the value of dermoscopy. Cutis. 2014 Sep;94(3):E5-6. 16. Youngchim S, Pornsuwan S, Nosanchuk JD, et al. Melanogenesis in dermatophyte species in vitro and during . Microbiology. 2011 Aug;157(Pt 8):2348-56. doi: 10.1099/mic.0.047928-0. Epub 2011 May 12.

The Ronald O. Perelman Department of Dermatology References – Collimated Lights

• Amichai B, Nitzan B, Mosckovitz et al. Iontophoretic delivery of terbinafine in onychomycosis: a preliminary study. Br J Dermatol 2010; 162: 46-50. • Apfelberg DB, Rothermel E, Widtfeldt A, Maser MR, Lash H. Preliminary report on use of carbon dioxide laser in podiatry. J Am Podiatry Assoc 1984;74:509-13. • Bhatta AK, Keyal U, Huang X, Zhao JJ. Fractional carbon-dioxide (CO2) laser-assisted topical therapy for the treatment of onychomycosis. J Am Acad Dermatol 2016. • Borovoy M, Tracy M. Noninvasive CO 2 laser fenestration improves treatment of onychomycosis. Clin Laser Mon 1992;10:123-4. • Carney C, Cantrell W, Warner J, Elewski B. Treatment of onychomycosis using a submillisecond 1064-nm neodymium:yttrium-aluminum-garnet laser. J Am Acad Dermatol 2013;69:578-82. • de Berker D. Clinical practice. Fungal nail disease. N Engl J Med 2009;360:2108-16. • El-Tatawy RA, Abd El-Naby NM, El-Hawary EE, Talaat RA. A comparative clinical and mycological study of Nd-YAG laser versus topical terbinafine in the treatment of onychomycosis. J Dermatolog Treat 2015;26:461-4. • Elewski BE, Charif MA. Prevalence of onychomycosis in patients attending a dermatology clinic in northeastern Ohio for other conditions. Arch Dermatol 1997;133:1172-3. • Francuzik W, Fritz K, Salavastru C. Laser therapies for onychomycosis - critical evaluation of methods and effectiveness. J Eur Acad Dermatol Venereol 2016. epub ahead of print’ • Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol 2000;43:641-8. • Gupta AK, Foley KA, Daigle, D. Clinical trials of lasers for toenail onychomycosis: the implications of new regulatory guidance. J Dermatol Treat 2017; 28(3): 264-270. • Gupta AK, Foley KA, Versteeg, SG. Lasers for onychomycosis: current status. J Cut Med Surg 2017; 21(2): 114-116.

The Ronald O. Perelman Department of Dermatology References – Collimated Lights

• Gupta AK, Jain HC, Lynde CW, Macdonald P, Cooper EA, Summerbell RC. Prevalence and epidemiology of onychomycosis in patients visiting physicians' offices: a multicenter canadian survey of 15,000 patients. J Am Acad Dermatol 2000;43:244-8. • Gupta AG and Versteeg SG. A critical review of improvement rates for laser therapy used to treat toenail onychomycosis. JEADV 2017; 31: 1111-1118. • Haedersdal M, Erlendsson AM, Paasch U, Anderson RR. Translational medicine in the field of ablative fractional laser (AFXL)-assisted drug delivery: A critical review from basics to current clinical status. J Am Acad Dermatol 2016. • Hollmig ST, Rahman Z, Henderson MT, Rotatori RM, Gladstone H, Tang JY. Lack of efficacy with 1064-nm neodymium:yttrium-aluminum-garnet laser for the treatment of onychomycosis: a randomized, controlled trial. J Am Acad Dermatol 2014;70:911-7. • Karsai S et al. Treating onychomycosis with the short-pulsed 1064-nm-Nd:YAG laser: results of a prospective randomized controlled trial. JEADV 2017; 31: 175-180. • Kalokasidis K, Onder M, Trakatelli MG, Richert B, Fritz K. The Effect of Q-Switched Nd:YAG 1064 nm/532 nm Laser in the Treatment of Onychomycosis In Vivo. Dermatol Res Pract 2013;2013:379725. • Kim TI et al. A randomized comparative study of 1064nm Neodymium-doped yttrium aluminium garnet (Nd:Yag) laser and topical antifungal treatment of onychomycosis. Mycoses 2016; 59: 803-810. • Landsman AS, Robbins AH, Angelini PF, et al. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure. J Am Podiatr Med Assoc 2010;100:166-77. • Landsman AS, Robbins AH. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure: some follow-up observations at 270 days. J Am Podiatr Med Assoc 2012;102:169-71. • Leverone A, Guimaraes D, Bernardes-Engemann A, Orofino-Costa R. Partial necrosis of the hallux in a patient treated with laser for onychomycosis: is this procedure really worthwhile? Dermatol Surg 2015; 41(7): 869-72. • Li Y, Yu S, Xu J, Zhang R, Zhao J. Comparison of the efficacy of long-pulsed Nd:YAG laser intervention for treatment of onychomycosis of toenails or fingernails. J Drugs Dermatol 2014;13:1258-63. • Lim EH, Kim HR, Park YO, et al. Toenail onychomycosis treated with a fractional carbon-dioxide laser and topical antifungal cream. J Am Acad Dermatol 2014;70:918-23.

The Ronald O. Perelman Department of Dermatology References – Collimated Lights

• Nair AB, Vaka SRK, Murthy SN. Transungual delivery of terbinafine by iontophoresis in onychomycotic nails. Drug Dev Ind Pharm 2011; 37: 1253-1258. • Nair AB, Vaka SRK, Sammeta SM et al. Trans-ungual iontophoretic delivery of terbinafine. J Pharm Sci 2009; 98: 1788- 1796. • Ortiz AE, Avram MM, Wanner MA. A review of lasers and light for the treatment of onychomycosis. Lasers Surg Med 2014;46:117-24. • Ortiz AE, Truong S, Serowka K, Kelly KM. A 1,320-nm Nd: YAG laser for improving the appearance of onychomycosis. Dermatol Surg 2014;40:1356-60. • Park, KY et al. Randomized clinical trial to evaluate the efficacy and safety of combination therapy with short-pulsed 1064-nm Neodymium-doped Yttrium Aluminum Garnet laser and amorolfine nail lacquer for onychomycosis. Ann Dermatol 2017; 29 (6): 699-705. • Rivers JK et al. Real-world efficacy of 1064-nm Nd:YAG laser for the treatment of onychomycosis. J Cut Med Surg 2017; 21(2): 108-113. • Shi J et al. The efficacy of fractional carbon dioxide laser combined with terbinafine hydrochloride 1% cream for the treatment of onychomycosis. J Cos Laser Therapy 2017; 19 (6): 353-359. • Sotiriou EK-ET, Chaidemenos G, Apalla Z, Ioannides D. Photodynamic therapy for distal and lateral subungual toenail onychomycosis caused by Trichophyton rubrum: Preliminary results of a single-centre open trial. Acta Derm Venereol 2010; 90(2): 216-217. • Xu Y, Miao X, Zhou B, Luo D. Combined oral terbinafine and long-pulsed 1,064-nm Nd: YAG laser treatment is more effective for onychomycosis than either treatment alone. Dermatol Surg 2014;40:1201-7. • Wiznia LA, Quatrano, NA, Mu EW, Rieder EA. A clinical review of laser and light therapy for psoriasis and onychomycosis. Derm Surg 2016; accepted for publication

The Ronald O. Perelman Department of Dermatology References – Collimated Lights

• Zang K, Sullivan R, Shanks S. A retrospective study of non-thermal laser therapy for the treatment of toenail onychomycosis. J Clin Aesth Dermatol 2017; 10(5): 24-30. • Zhang J et al. Combination therapy for onychomycosis using a fractional 2940-nm Er:YAG laser and amorolfine lacquer. Lasers Med Sci 2016; 31: 1391-1396. • Zhang RN, Wang DK, Zhuo FL, Duan XH, Zhang XY, Zhao JY. Long-pulse Nd:YAG 1064-nm laser treatment for onychomycosis. Chin Med J (Engl) 2012;125:3288-91. • Zhou, BR et al. The efficacy of fractional carbon dioxide (CO2) laser combined with luliconazole 1% cream for the treatment of onychomycosis. Medicine 2016; 95: 44.

The Ronald O. Perelman Department of Dermatology Novel Therapeutics: Photodynamic Therapy

•Mechanism: free radicals

•Treatment parameters varied: 1-22 sessions, q1-8wks, wavelengths of light 470 – 750nm, fluence 18 – 228J/cm2

•Recent meta-analysis: 17 studies, 214 patients total, one RCT

•Strengths: minimal side effects, targeted, may work where other treatments have failed, across dermatophytes, molds, yeast; endonyx

•Weaknesses: early data, impractical – time intensive – requires significant debridement / avulsion / nail softening / nail drilling or fractionation

Bhatta et al, 2016

The Ronald O. Perelman Department of Dermatology Novel Therapeutics: Iontophoresis

•Mechanism: application of small current to increase transport of molecules via co-transport with water or ion flux

•May hold promise for enhancing absorption of topical antifungals

•Data: in vitro and one pilot study with questionable results

Sotiriou et al, 2010; Amichai et al, 2010

The Ronald O. Perelman Department of Dermatology