Langerhans cell histiocytosis

Acne: Past, Present, and Emma Taylor, M.D Assistant Clinical Professor Dermatology and Dermatopathology, UCLA  Cofounder, President, and CEO of Acne: A Historical Perspective  Ancient Egyptian Aku-t -boils, blains, sores, pustules, inflamed swelling  Fuchs 1840 coined-Acne Vulgaris, Acne Mentagra and Acne Rosacea  Bloch 1931 proved relationship Acne and the First Therapies  Ancient Egypt, Greece, and Rome used sulfur treatments  1920s: Benzoyl Peroxide introduced  1970s: Tretinoin (original Retin A), antibiotics (minocycline)  1980s: Accutane introduced – >2000 women became pregnant between 1982 and 2003, majority ending in miscarriage – 160 babies with defects born – Ipledge system established Acne Epidemiology Today  Acne affects >80% of the ver 50 million people in the US, and over 150 million in the seven major markets.  It is among the top 5 most economically burdensome skin diseases in the US  Total costs predicted to exceed $3 billion 2016  However, market revenues are stagnant due to patent expirations, generic competition, lack of long term efficacy Acne Pathogenesis  Inflammation  Overgrowth Propionibacterium acnes  Increased androgens, sebum production  Abnormal differentiation of keratinocytes Acne Pathogenesis Genetic and Environmental Factors  Strong familial predisposition related to severity  Diet inconclusive-possible relation to high glycemic index  Smoking exacerbates  Hormonal influences-worsens in  Medications-lithium, corticosteroids, vitamin B12  Comedonal
 Inflammatory
 Nodulocystic
 Scarring
Current Acne Therapies – Benzoyl Peroxide – Misc (, Azaleic Acid,sulfacetamide sulfur, Dapsone gel, glycolic acid, salyclic acid, natural products) – Antibiotics (doxycycline, minocycline) – Isotretinoin – Antihormonals (Spironolactone, OCPs) – Light therapy (PDT) – Dermabrasion/Extraction/Injections US OTC Acne market $2.5B by 2016 Top compounds
US OTC Acne sales
• Benzoyl peroxide • Salycylic acid • Alpha hydroxy acids • Sulphur Rx
• Benzoyl peroxide
• Retinoids
• Antibiotics
• Dominated by generics
http://www.ibisworld.com/industry/acne-treatment-manufacturing-otc.html Kalorama 2012 Dermatology Drug Market Research Report  Retinoids-59.4%  Antibiotics-28.5%  Benzoyl Peroxide-2.5% Leading Companies with Acne  Stiefel-a GSK company-leading prescription antiacne with 30.1% of
market $501 million. – Bactroban, Dermovate, Duac, Clindamycin line, Evoclin, Rosac, and  Galderma-second with revenues of $450 million and 27.0% market
– Differin, ClindaGel, Epiduo Gel, Eryacne, Oreacea and others  Medicis-third with revenues $330 million and 25.2% market
– A/T/S, Solodyn, and Theramycin Z  Remaining 17.7% is divided – Allergan, Mylan Pharmaceuticals, Valeant, Westwood Squibb, and
various generic manufacturers Companies with Acne Therapy  Target Research Associates  Access Pharmaceuticals/Strakan  Doak/Bradley Pharmaceuticals Target Research Associates  Access Pharmaceuticals/Strakan Bayer Healthcare  Doak/Bradley Pharmaceuticals Ortho Dermatological  GlaxoSmithKline Topical Rx Acne Therapy  Benzoyl Peroxide  Topical Antibiotics  Miscellaneous – Azaleic Acid – Sodium Sulfacetamide – Topical dapsone Benzoyl Peroxide  Antimicrobial  Mild mild peeling agent  Decreases fatty acid and  Benzoyl peroxide has no P. acnes resistance  In the US, available 2.5%  2.5% BP was equivalent to the 5% and 10% concentrations with fewer side effects Benzoyl PeroxideRx educe follicular hyperkeratinization  Reduce Sebum  Increase cell turnover Topical Antibiotics  Erythromycin  Inhibit protein synthesis by irreversibly binding to the ribosomal 50S subunit of P. acnes  Erythromycin is bactericidal, clindamycin is both bactericidal and bacteriostatic Topical Antibiotics cont.  Azaleic Acid  Sodium Sulfacetamide  Dicarboxylic acid found in wheat, rye, and barley  Bacteriostatic and  Normalizes follicular  Treats hyperpigmentation  Availabe in US 20%  No bacterial resistance Sodium Sulfacetamide  Competitive antagonist to para-aminobenzoic acid (PABA), an essential component for bacterial growth.  P. acnes resistance has not been recognized  Antiinflammatory  Antimicrobial  Treats neutrophilic – Dermatitis herpetiformis Natural Products  Tea tree oil  Alpha hydroxy acid (from citrus fruits)  Green Tea Extract  Brewers yeast (CBS 5926-oral)  "There's also other stuff out there to treat your pimples that might work. You might hear about herbal and natural treatments, but so far there's no proof that they work" AAD.org Natural Products  PO antibiotics  Isotretinoin  Antihormonals – Spironolactone Oral Antibiotics  Minocycline/Doxycycline  Antibiotic properties  Anti-inflammatory  Treatment lasts weeks to  Only acne treatment that addresses all factors in ac ne pathogenesis  Reverses follicular hyperkeratination,  Antimicrobial against P.  Involutes sebaceous  Ani-inflammatory. Reduces the resistance of P. acnes on the skin  Spironolactone – Decreases virilization  Androgenic acne  Increased hair  Increased sebum A Sample patient:Treatments often
do not resolve disease Multiple visits
Acne patient
Trial OTC BP or
Trial Rx PO
Development of
salicylic acid
antibiotics
Resistance
( 73% in 1995)
Trial Rx Combo
Development of
irritation/
pical Abx
 BP induces downregulation by lysosomal receptor degredation  Azelaic acid inhibits mitichondrial ATP  Tetracyclines inhibit expression FGR2b downstream matrix metalloproteinases  Retinoids attentuate FGFR2  Erythromycin inhibits retinoid Bodo C Melnik1, Gerd Schmitz2 and Christos C Zouboulis3Anti-Acne Agents Attenuate FGFR2 Signal Transduction in Acne. Journal of
Investigative Dermatology (2009) 129, 1868–1877; doi:10.1038/jid.2009.8; published online 19 February 2009
Challenges to current Therapy  Stagnant Market  Side effects leading to  Increasing antibiotic  Treatment to the disease not the individual  While top 5 performing anti-acne topicals had sales exceeding 950 million in 2013, all had expired patents, no innovative targets, and limited market growth.  90% in the preclinical pipeline consist of
reformulated versions of retinols and/or antibiotics.  Of the 74 clinical trials actively recruiting
acne patients > 45% are using antibiotics, BP or retinoids as the intervention. Rx in Development Side Effects Topicals  Photosensitivity Side effects Oral Rx  Isotretinoin – Nausea/vomiting – Photosensitivity – DISH (diffuse – Hyperpigmentation interstitial skeletal hyperostosis) – Psuedotumor cerebri – Photosensitivity – Long term risk IBD cholesterol/TGs/LFTs Antibiotic Resistance  PO and topical antibiotics mainstay of acne therapy  5 million prescriptions for oral antibiotics are written  Resistance in acne has continued to rise from 20% in 1978 to 72.5% in 1995,  Investigations linking resistant strains to higher counts of P. acnes and therapeutic failure  Resistance to P. acnes develops in 50% of individuals following treatment with both topical and oral antibiotics. Antibiotic Resistance  Antibiotic-resistance occurs when genetic elements, such as transposons and plasmids, are transferred to other strains or species within the resident skin flora  However, with erythromycin, clindamycin, and tetracyclines, resistance is associated with point mutations in rRNA  Most resistance of P. acnes to erythromycin is cross-resistant to clindamycin Acne Future: Addressing the  Innovative Targets  Tailored/personalize Innovative Targets Looking to Nature  Salix tree-salicylic acid-(Aspirin)  Pacific Yew-Taxols-(Paclitaxel)  Opium poppy-(Morphine)  Resveratrol (3,5,4'- trihydroxystilbene) polyphenol  Red wine, colored berries,  Fresh grape skins contain 50-  Red wine contains 1.5-3 Resveratrol's role in plants  Expression correlated to environmental stress and pathogenic attacks  Stressors: sunlight, arthropod  High stress environments increase resveratrol production. Resveratrol and Health  Cancer prevention (colon, liver, myeloma, lymphoma)  Protects the heart  Protects the brain (ie.  Reverses diabetes  Improves obesity  Aging

 Decreased mortality in  High saturated fat diet  Increased red wine Resveratrol Applications  Wound healing  Anti-inflammatory  Photoprotection  Chemotherapy  Antimicrobial Acne Pathogenesis Inflammation * Overgrowth P. acnes * Increased androgens, sebum * Abnormal differentiation of Impaction of follicles Antibacterial against P.acnes Taylor EJ, Yu Y, Champer J, Kim J. Resveratrol Demonstrates Antimicrobial Effects Against Propionibacterium acnes In
Vitro.Dermatol Ther (Heidelb). 2014 Dec;4(2):249-57. doi: 10.1007/s13555-014-0063-0. Epub 2014 Sep 17.
Antibacterial against P.acnes  Inflammatory phase – Antioxidant-balances ROS  Migratory and Proliferative phase – Increases VEGF, angiogenesis  Remodeling Phase – Accelerates wound contraction Resveratrol Acne Study  Clinical assessment-Resveratrol gel 53.75% mean reduction in the GAGS score compared with vehicle 6.10%  Histologic analysis- Resveratrol gel 66.7% mean reduction in microcomedones compared with vehicle 9.7%  All patients satisfied with treatment  No side effects Combination Therapy  Combine BP (no resistance) with other topical therapies (retinoids, antibiotics)  5% benzoyl peroxide/1% clindamycin combination topical gel is superior to clindamycin monotherapy  Reformulations of generic compounds creating novel combinations has become standard Comparative Bactericidal Taylor EJ, Yu Y, Champer J, Kim J. Resveratrol Demonstrates Antimicrobial Effects Against Propionibacterium acnes In
Vitro.Dermatol Ther (Heidelb). 2014 Dec;4(2):249-57. doi: 10.1007/s13555-014-0063-0. Epub 2014 Sep 17.
Combination Resveratrol/BP  Combination is more effective than either compound alone in vitro  Evaluating whether this translates to enhanced efficacy, better tolerability at lower therapeutic doses of benzoyl peroxide  Resveratrol has anti-androgenic, anti- inflammatory, and antibacterial properties that may target three of the four major pathogenic factors in acne formation. Personalized Medicine  Treat the individual, not just  Data informatics – 23&me-Disease risk assessment – Foundation Medicine  Tailored therapy – Pharmacogenomics  Cancer Immmunotherapy  Herceptin for Her2 positive  BRAF inhibitors for BRAF mutated melanoma Personalized Acne Therapy  Profile a patients cutaneous flora  Address hormonal contributions  Target specific type of acne – Inflammatory (BP, antibiotics, isotretinoin) – Comedogenic (retinoids) – Cystic/Scarring (isotretinoin)  Developed tailored therapy to above Personalized Acne Therapy  Acne patients had different "pathogenic" P.acnes strains than compared to healthy skin  Diagnostic kit can profile skin at baseline (prior to treatment) and monitor response to treatment Personalized Therapy  Pathogenic P.acnes strains have different metabolism than healthy strains  Develop drug targets specific to killing pathogenic stains or enhancing strains associated with a healthy skin biome  Deliver Probiotics of healthy skin flora Personalized Acne Therapy Profile Flora
Acne patient
Trial OTC BP or
Tailored
Long term
salicylic acid
resolution
Maintain with
healthy flora
Formulation questions  Benzoyl peroxide highly volatile with oxygen – Vacuum/pump dispensors  Stabilize resveratrol (antioxidant) with benzoyl peroxide (oxidant)  Probiotic stability and bioavailability – Culture viability – Storage methods (room temp, refrigeration) Grant, RNR. The History of Acne. Section of the History of Medicine. Proceedings of the Royal Society of Medicine. March 7, 1951 Rimm EB et al. Lancet 338, 464 (1991) Reynaud S, Gueguen R, Siest G, Salamon R. Wine, beer, and mortality in middle-aged men from eastern Franc. Arch Intern Med. 1999; 159: 1865-70 Sen, C.K., Khanna, S., Gordillo, G., et al. Oxygen, Oxidants, and Antioxidants in Wound Healing. An Emerging Paradigm. Ann.N.Y. Acan. Sci 957: 239-249 (2002) Baur JA, Sinclair DA et al. Therapeutic potential of Resveratrol: the in vivo evidence.Nature Rev Drug Discovery, 5 493-506 (2006) Jang, M. et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218-20 (1997). Baur, J.A, Pearson, K.J., Price, N.L., et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 144: 337-42. Morganti AG, Digesu C, Panunzi S et al. Radioprotective effect orf moderate wine consumption in patiens with breast carcinoma. Int J Radiat Oncol Bio Phys. 2009 Aug 1;74 (5): 1501-4 Gehm, B. D., McAndrews, J. M., Chien, P. Y. & Jameson, J. L. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A 94, 14138-43 (1997). 10. Docherty, J. J., McEwen, H. A., Sweet, T. J., Bailey, E. & Booth, T. D. Resveratrol inhibition of Propionibacterium acnes. J Antimicrob
Chemother 59, 1182-1184 (2007).
Acne. N Engl J Med2005 Apr 7;352(14):1463-72. The Dermatology Market Outlook to 2013 [database on the Internet]. 2008 10. Bickers DR, Lim HW, Margolis D, Weinstock MA, Goodman C, Faulkner E, Gould C, Gemmen E, Dall T. The burden of skin diseases: 2004. A joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. Journal of the American Academy of Dermatology2006;55(3):490-500 11. Packaged facts, the US Cosmeceuticals Market 2008 12. Cooper AJ. Systematic Review of Propionibacterium Acnes Resistance to Systemic Antibiotics. Med J Aust. 1998. Sept 7; 169(5): 259-61 Crandall M. The Worldwide Market for Prescription Dermatological Drugs. Kalorama Information2010 April.2010 [cited 2010 November 15]; Available from Harper, J. C. An update on the pathogenesis and management of acne vulgaris. J Am Acad Dermatol 51, S36-8 (2004). Espin, J. C., Garcia-Conesa, M. T. & Tomas-Barberan, F. A. Nutraceuticals: facts and fiction. Phytochemistry 68, 2986-3008 (2007). Hung, C. F., Lin, Y. K., Huang, Z. R. & Fang, J. Y. Delivery of resveratrol, a red wine polyphenol, from solutions and hydrogels via the skin. Biol Pharm Bull 31, 955-62 (2008). Baxter, R. A. Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. J Cosmet Dermatol 7, 2-7 (2008) Sen, C. K. et al. Oxygen, oxidants, and antioxidants in wound healing: an emerging paradigm. Ann N Y Acad Sci 957, 239-49 (2002). Calabrese, G. Nonalcoholic compounds of wine: the phytoestrogen resveratrol and moderate red wine consumption during menopause. Drugs Exp Clin Res 25, 111-4 (1999). Goldberg, D.M. Hahn, S.E., Parkes, J.G., 1995. Beyond alcohol: beverage consumption and cardiovascular mortality. Clin. Chem. Acta. 237, 1155-187 Jeandet, P., Bessis, R., Sbaghi, R., Meunier, M., 1995. Production of the phytoalexin resveratrol by grapes as a response to botryis attack under natural conditions. J. Phytopathol. 143, 135-139 Verdier-Sevrain S, Bonte F, Gilchrest B. Biology of estrogens in skin; implications for skin aging. Exp Dermatol 2006; 15: 83-94 Kundu JK, Shin YK, Kim SH, Surh YJ. Resveratrol inhibits phorbol ester-induced expression of COX-2 and activation of NF-kB in mouse skin by blocking IkB kinase activity. Carcinogenesis. 2006. 27(7): 1465-1474 Babich H, Reisbaum G, Zuckerbraun HL. In vitro response of human gingival epithelial S-G cells to resveratrol. Toxicol Lett 2000; 114:143-53 Holian O, Walter RJ. Resveratrol inhibits the proliferation of normal human keratinocytes in vitro. J Cell Biochem 2001; 36(Suppl): 55-62. Taylor EJ, Yu Y, Champer J, Kim J. Resveratrol Demonstrates
Antimicrobial Effects Against Propionibacterium acnes In Vitro.Dermatol
Ther (Heidelb). 2014 Dec;4(2):249-57. doi: 10.1007/s13555-014-0063-0.
Epub 2014 Sep 17.

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