Totally Radical Pearls

THINKING OUTSIDE THE BOX Ted Rosen, MD Baylor College of Medicine Houston, Texas TOTALLY RADICAL PEARLS

Hong Kong Jade Market 2014 CONFLICT OF INTEREST DISCLOSURE NONE Ninguno Nessuno Aucun Keiner Ни один 無なし 없음 THINK DIFFERENTLY!

DIFFERENT EVIDENCE LEVEL Use drug(s) or devices off-label Never, EVER think outside the box! ROSACEA

• Conventional treatments • Topical metronidazole • Topical azelaic acid • Topical sodium sulfacetonide • Oral antibiotics • Subantimicrobial dose doxycycline • Full dose doxy or minocycline • Azithromycin • Laser and light therapy • ? Dietary modifications NEW ROSACEA TOPICAL

• Ivermectin 1% Cream (30g tube, Soolantra®) • Cetaphil® moisturizing cream is base • Applied once daily • RCT, 12 week, vrs. Control n=910 • Mean age 50, 96% white, 67% female, 76-82% moderate • Treatment success (Clear or almost clear) 38-40% versus control (12-19%) and about 75% reduction in inflammatory lesions (controls had 50% reduction) • AEs: skin burning and “irritation” • Also: superior to metronidazole 0.75%; 16 wk RCT • MOA: ? Anti-parasitic, or….Anti-inflammatory?

J Drugs Dermatol. 2014;13:316-23 and 1380-86 Br J Dermatol. 2014 Sep 16, e-pub NEW ROSACEA TOPICAL

J Drugs Dermatol. 2014;13:316-23 and 1380-86 Br J Dermatol. 2014 Sep 16, e-pub NEW ROSACEA TOPICAL IVERMECTIN

• Decreases expression of pro-inflammatory transcription (NF-κß) in vitro • Inhibits LPS-induced TNF-α, IL-1b and IL-6 in vitro and in vivo • Reduces chemotaxis of neutrophils and lymphocytes in vivo • Inhibits LPS-induced Nitric oxide and iNOS mRNA in vitro and in vivo • Upregulates IL-10 (anti-inflammatory activity) in vitro • Inhibits COX-2 activity and PGE2 production in vitro

Inflamm Res 2011;60:589-96 Int Immunopharmacol 2009;9:354-9 Fundam Clin Pharmacol 2009;23:449-55 Inflamm Res 2008;57:524-9 NEW ROSACEA TOPICAL IVERMECTIN

Inflamm Res 2011;60:589-96 Int Immunopharmacol 2009;9:354-9 Fundam Clin Pharmacol 2009;23:449-55 Inflamm Res 2008;57:524-9 HSV-2 THERMOTHERAPY GENITAL HERPES

• German prospective study; 32 women; mean age 35 yo • 21 ThermoRx + Acyclovir, 10 ThermoRx alone • Treatment initiated with first objective sign HSV-2 • Within one day, Sx gone or almost gone, with or without acyclovir as concomitant therapy • ThermoRx done with HERPOTHERM® device (administers 51-530C for 4 seconds) 1-2x daily

Clin Cosmetic Investig Dermatol 6:163-66, 2013 HERPOTHERM® (AKA “HOTKISS”)

Approved device in UK, EU, Australia, Canada, several Latin American countries; Available on either E-Bay or Amazon GENITAL HERPES: NEW RX?

• Topical zinc sulfate • Zn+2 in-vitro impairs HSV growth • Can zinc salt treat active genital HSV? • Can zinc salt reduce recurrence rate? • 100 clinical + Tzanck verified men with genital HSV treated for 6 months • To active lesion (or area): Q5d x 1mo, then Q10d x 2 mo, then Q15d x 3 mo

• ZnSO4 solution; 5 minute exposure

Indian J Sex Transm Dis. 2013;34: 32–34 GENITAL HERPES: NEW RX?

Recurrence rate over 6 months Distilled water control 80%

1% Zinc sulfate 33.33%

2% Zinc sulfate 20%

4% Zinc sulfate 3.33%

Indian J Sex Transm Dis. 2013;34: 32–34 Indian J Sex Transm Dis. 2013;34: 32–34 Warts From Hell ZINC! ORAL ZINC

• Experience w/ case series: normal hosts • Zn: Acetate, Gluconate, Sulfate • QD 10mg/kg (3 doses, always pc); 2-3 months total Rx

• 100mg ZnSO4 = 22.5mg Zinc (max 150mg elemental zinc) • ? MOA; Maybe increases APC activity • Off label; FDA-approved: Zinc deficiency • AE: GI distress; up to gastric perforation (microcytic anemia, copper deficiency) • Binds: PCN, TCN, Quinolone, phytates ORAL ZINC

• 62.5-87.7% success rate reported • Failures ascribed to too low a dose, noncompliance due to GI symptoms, or too short treatment regimen • Patients do better when serum Zn levels rise (quadruples, on average) • Br J Dermatol 2002;146:423-31 • JAAD 2009;60:706-708 • Ann Bras Dermatol 2009;84:23-29 • Clin Exp Dermatol 2009;34:e984-85 • J Dermatol 2011;38:541-45 ZINC (3 MONTHS RX) HIDRADENITIS AND ZINC

• Zinc sulfate 10mg/kg to max of 400-600mg daily • Divided doses (TID) with food • Must be given over 3-6 months to see effect • Everyone responds, but better response with earlier and less severe disease

Dermatology. 2007;214:325-7 HIDRADENITIS: METFORMIN

• Refractory to Rx • 25 patients (non-diabetic) • Metformin 500mg BID to TID maximum, for 6 mo • Majority (18/25) had improved Sartorious score, DLQI and PGA • JEADV 27:1101-1108, 2013 • I often add finasteride (men) 5mg/d • J Dermatol Treat 16:75-8, 2005 ADALIMUMAB HIDRADENITIS SUPPURATIVA? • PIONEER I Phase 3 trial: 36-week, (n=307) • investigational use in moderate-to-severe HS, • 160 mg at week 0, 80 mg at week 2 and 40 mg once weekly (n = 153) starting at week 4 • 40 mg weekly achieved a significantly greater response versus those on placebo at week 12 (41.8% versus 26%, p = 0.003).

Semin Cutan Med Surg 33(3 Suppl):S57-9, 2014 ANTIBIOTICS ANYONE?

• IF you are hell bent on using antibiotics for hidradenitis….. • Study of 69 HS patients, 75% moderate to severe disease • All overweight to overtly grossly obese • Tetracyclines (64.4%), macrolides (57.6%), trimethoprim/sulfamethoxazole (54.2%), lincosamides (50.8%) • Recommend: Amoxicillin+clavulanate or fluoroquinolones • Majority polymicrobial (< 5 different species isolated) • Most common pathogens: Proteus mirabilis (13.6%), S. aureus (13.6%), Enterococcus faecalis (11.9%) and E. coli (5.08%) • Most isolates resistant to: tetracyclines • Matusiak L, et al. Acta Derm Venereol 2014;94:699-702 Genital Warts From Hell GENITAL WARTS FROM HELL: IDEA #1

• Application of 5% KOH daily x 12 weeks • Trial versus commercial 0.5% 5-FU-Salicylic acid 10% • (Similar to USA compounded WARTpeel® 2% 5-FU, Salicylic Acid 17%)

Clear or almost clear: 70% Int J Dermatol 2014;53:1145-50 GENITAL WARTS FROM HELL: BRIGHT IDEA

• Two PREGNANT females with significant EGW • Thermotherapy • Application of heat (Tungsten-Halogen lamp (440C x 30 min) • No skin contact; Heat radiated to skin from 12 inches away • Once daily x 3; Repeated following week • Small study (n=2), EGW short duration; One HPV 6, One HPV 11 • All warts cleared within 5-7 weeks • Moderate burning and pain (rated 4-5 on 10 point scale) • No recurrence at 6 months

[440C= 1110F] Dermatol Ther 27:109-12, 2014 Dermatol Ther 27:109-12, 2014 At 12” produces heat measured 108-1120F GENITAL WARTS FROM HELL: IDEA #3

• Application of ingenol mebutate, either 0.015% or 0.05% ONCE • ONE APPLICATION • Small study (n=10), all with EGW of at least 6 months duration • All verified by histology; All were HPV6+ by PCR • Placebo gel (vehicle) controlled • All warts cleared within 3-7 days where treated with active No sites treated with vehicle cleared • No recurrence in 3 months at sites which cleared • Mild to moderate burning x 1-2 days • WAY OFF LABEL!

J Invest Dermatol 134:S90-107, 2014 July, 2013

Oral ketoconazole should not be used as first-line therapy for ANY fungal infection Ketoconazole should be used only for treatment of life-threatening mycoses when the potential benefits outweigh the risks and alternative therapeutic options are not available or not tolerated Oral ketoconazole is no longer indicated for dermatophyte or Candida infections Oral ketoconazole is not indicated for fungal infections of the skin or nails Contraindicated in any individual with liver disease TINEA VERSICOLOR

• Alternative orals (off label) • Itraconazole 400mg/d x 3d or 200mg/d x 5d J Dermatolog Treat 2002;13:185-7 • Fluconazole 300mg QWk x 2 Mycoses 2007;50:311-13 GRANULOMA ANNULARE

• Spontaneous resolution ½ of all lesions within 2 years • Topical steroids (+ occlusion) • Intralesional steroids • Topical TCI • “Scarification” • Dapsone • Cyclosporine • Phototherapy (PUVA) • Chlorambucil 1-6 mg/day GA DISSEMINATED

• Chlorambucil (“Leukeran”) • Alkylating agent approved for CLL, Lymphoma • Usual dose 0.1-0.2mg/kg for 4-6 weeks, then 0.1mg/kg • For GA: lower dose 1-6mg/d • Neutropenia (watch CBC)

• GI upset Mayo Clin Proc 69:1163-5, 1994 Arch Dermatol 119:451-2, 1983 Arch Dermatol 115:1212, 1979 Dermatologica 158:443-50, 1979 Arch Dermatol 114:216-20, 1978 GA: EXCIMER LASER

• 308 nm • Fluence of 300mJ/cm2 • FIVE doses per session, weekly • Four months Rx: Refractory GA resolved • No recurrence at 6 months

J Clin Aesthet Dermatol 5:43, 2012 GA: EXCIMER LASER UNKA TEDDY’S METHOD

• 308 nm • Fluence of 300-450mJ/cm2 • TWO doses per session, weekly • Four-Six months Rx: Refractory GA resolved • No recurrence at 6 months

J Clin Aesthet Dermatol 5:43, 2012

Excimer Laser, 308nm, 450J/cm2, Two passes per weekly session, Pre, x16 weeks and x 20 weeks

POST-HERPETIC NEURALGIA

• 10-20% of those with shingles, with highest risk in those >50 y.o. • Prevention: early Rx with antivirals and neuroleptic drugs (eg gabapentin) • Treatments: Antivirals, p.o. steroids, tricyclic antidepressants, opioid analgesics, oral gabapentin or pregabalin, nerve block, DRG destruction, TENS stimulation, topical capsaicin or lidocaine, acupuncture • There are many failures of above Rx steps POST-HERPETIC NEURALGIA TWO PEARLS • Topical gabapentin • “Cryoanalgesia” • Median age 83 (n=3) • Liquid nitrogen sprayed • PHN for 9 months with near along affected dermatome maximal sleep disruption • Distance 6 inches • 6% gabapentin cream • Spray for 30 seconds applied TID • Weekly; mean number =3 • 2/3 responded w/ decreased • 94% good to excellent pain pain and increased sleep relief by sixth treatment • Br J Dermatol Dec 18, 2014 e-pub • Int J Dermatol 50:746-50, 2011 Aphthous Ulcers from Hell HONEY

• RCT with 94 patients • Minimum 6 attacks/yr • Honey vrs TAC in Orabase vrs Orabase • All Rx applied QID x 5 days • Fastest healing, greatest reduction in pain and erythema was with….honey

Quintessence Int 45:691-701, 2014 VITAMIN B12

• RCT with 58 patients • Minimum 6 attacks/yr • 1000mcg sublingual B12 QD versus placebo x 6 mo • Active Rx: decreased number aphthae/month, decreased duration of each ulcer, decreased pain associated w/ ulcer • By 6 mo, 74% ulcer-free

J Am Board Fam Med 22:9, 2009 ALOPECIA AREATA

ALOPECIA AREATA ?FEXOFENADINE?

• Widely utilized in Japan as an adjunctive or even primary monotherapy • Mechanism of action: may prevent mast cell degranulation; ? part of AA etiology • Cheap, safe, can be used long term • Dose: 120-180mg/d (adult) 15-30mg/d (child > 6mo) • Available: 30, 60,180mg tab, 30mg/5cc susp and 30mg dissolving tab

J Dermatol 39:1063, 2012 J Dermatol 36:323, 2009 J Dermatol 34:852, 2007 Fexofenadine 180mg/d x 3.5 mo (monoRx) Fexofenadine 180mg/d x 4.0 mo (monoRx)

PRE 2 mo 4 mo ALOPECIA TOTALIS

• Basically hopeless • Case report of patient with full regrowth during therapy with tofacitinib for psoriasis • Tofacitinib (Xeljanz®) is a selective janus kinase inhibitor (JAK3) approved for RA (soon for psoriasis) • Blocks transmission of extracellular signals to nucleus which upregulate inflammatory cytokines • More study needed (Phase 2: ClinTrials.gov: NCT02299297)

J Invest Dermatol June 18, 2014 e-pub VITAMIN D DEFICIENCY & SKIN DISEASE

• Hidradenitis: 16 patients; mean age 39, duration 15yr • Vitamin D measured immunoassay; winter, spring and summer; Ireland • 63% had level < 30 nmol/L • Br J Dermatol 2014;170:1379 • Alopecia areata: 86 patients • Vitamin D measured liquid chromatography; all year; Turkey • 91% had level <20 ng/mL • Br J Dermatol 2014;170:1299 • Vitamin D: inhibits IL-12, IL-17, dendritic cell activity • Dietary? Non-exposure to sun? Other factors?

NAIL PSORIASIS: THE CURE? NAIL PSORIASIS

• 31 patients w/ bilat symmetric psoriatic nail dystrophy • Indigo naturalis oil (Lindioil) versus olive oil • One drop, applied BID x 12 weeks • Objective NAPSI score used to compare groups • ~50% improvement in score with active compared to <20% improvement in score with control oil • Chinese trial. Can you get this in USA?

www.etsy.com www.indigo-botanicals.com

Phytomedicine 2014;21:1015-20 JAMA Dermatol. 2015, Mar 4. JAMA Dermatol. 2015, Mar 4. SARCOIDOSIS IF ANTI-MALARIALS, MTX AND STEROIDS FAIL SARCOIDOSIS AND MINOCYCLINE

• REFERENCE RESPONDED? COMMENT • Dermatol Online J 2014 Aug 17;20(8) 1 of 1 Skin only • JAMA Dermatol 2013;149:758-60 20 of 27 Skin only • J Drugs Dermatol 2012;11:385-89 1 of 1 Hypopigmented • Clin Rheumatol 2008;27:1195-97 1 of 1 Ocular + Lung • Arch Ophthalmol 2007;125:705-09 1 of 1 Ocular + Skin • Arch Dermatol 2001;137:69-73 10 of 12 Skin only • All at dose of 200mg/day

Multiple mechanisms whereby minocycline might be anti-inflammatory in sarcoid (such as ↓TNF-alfa and others), it also directly inhibits granuloma formation Arch Derm 1994;130:748-52 WHAT IF “STANDARD” THERAPY DOESN’T WORK OR IS NOT TOLERATED? • Failed prednisone at 60mg/day (↑BP) • Failed MTX 30mg/week • Failed chloroquine & hydroxychloroquine at maximal doses • Potent topical steroids: no change • IL steroid: minimal improvement • Failed Minocycline 200mg/day

INFLIXIMAB 5MG/KG IV (0,2,6 WEEKS) INFLIXIMAB 5MG/KG IV FIVE DOSES FOUR YEARS LATER INFUSIONS Q10 WEEKS; 5MG/KG

Pre-Rx

Rosen T: Dermatol Online J 13(3):14, 2007 TONSILS OUT…PSORIASIS GONE! • Meta-analysis from 20 reports (5 controlled) • 290/410 pts (>70%) improved • 30% to 90% decrease in PASI scores (p<0.001) compared to controls • Iceland study: Post-tonsillectomy: 13/15 patients (86%) improved PASI and symptoms • Risks of relapse • “Evidence is still immature to make a definitive conclusion; Studies needed to determine more clearly the extent and persistence of benefit ”

J Am Acad Dermatol 72:261-75, 2015 The ULTIMATE in cheap & safe, outside-the-box oral therapy FLUSHING AND ICE JAMES PATRICK WATSON AUTHOR, SPEAKER, LIFE COACH (1960-) THINK OUTSIDE THE BOX! USE RADICALLY DIFFERENT PEARLS

Ted Rosen, MD Professor of Dermatology Baylor College of Medicine Houston, Texas