Overview Pathogenesis of Acne Vulgaris Inflammatory Diseases of the skin: Acne, Rosacea, Psoriasis, Atopic Dermatitis Sebum production by the sebaceous gland Infections: Zoster P. acnes follicular colonization Pre-malignant and malignant neoplasms: Actinic Alteration in the keratinization process Keratoses, Basal Cell Carcinoma, Squamous Cell Carcinoma, Melanoma Release of inflammatory mediators into the skin, i.e. role of sebaceous lipids and inflammatory mediators including MMPs.
Inflammatory Acne Papules Comedones Pustules Open (Blackheads) Closed (Whiteheads) Acne Scarring Nodules Cysts
Strategic Approach to Acne Therapy
Role of retinoids Topical/Systemic antibiotics have no role as monotherapy Treatment of Acne Oral isotretinoin should be considered as first line in severe acne Azeleic acid is useful in pregnancy and patients with hyperpigmentation Moderate Inflammatory Acne Oral Contraceptives and Acne Treatment Hormonal Therapy Norgestimate-ethinyl estradiol Oral contraceptives may be helpful in some women Norethindrone acetate-ethinyl estradiol May take 3 months to see improvement. Drospirenone-ethinyl estradiol Spiranolactone useful in some. If acne is accompanied by irregular menses, female Use with topicals patterned hair loss or hirsutism, consider endocrine workup. As effective as oral antibiotics at 6 months
Severe Nodulocystic, Scarring Isotretinoin-Before and After or Resistant Acne
Isotretinoin Synthetic oral retinoid 16-20 week course Regular laboratory evaluation and contraceptive counseling for females Registration with iPledge Program required Acne and Diet Rosacea Powell NEJM 352;8 Feb 2005
High Glycemic index diet causes hyperinsulinemia leading to increase in IGF-1 Causes keratinocyte and sebocyte proliferation, lipogenesis
Cascade of events activates androgens Subtype 1 Subtype 3 Observational studies suggest milk consumption imparts increased risk for acne
Subtype 2 Subtype 4
Rosacea Rosacea Rosacea Rosacea Variants
Papule and pustules Opthalmic Rosacea- treatment of choice: oral antibiotics Telangiectasias Steroid Rosacea- resulting from long term topical or systemic Flushing and blushing steroid use Sebaceous hyperplasia Perioral Dermatitis- triggered or aggravated by steroid use
Triggers: cold, heat, UV, irritation, emotions, alcoholic beverages, spicy foods, hot beverages
Rosacea Treatments Rosacea Topical: clindamycin, erythromycin, metronidazole, sulfur-based lotions, azelaic acid, sunscreens, ivermectin oxymetazoline hydrochloride cream 1%, brimonidine- facial erythema Systemic: tetracyclines, erythromycin, isotretinoin Psoriasis Psoriasis An immune dysregulatory disease secondary to T-cell activation, release of TH1 based cytokines. Cytokines cause keratinocytic proliferation and recruitment of inflammatory cells into the skin 2% of the U.S. population Bimodal incidence: peaks at ages 29 and 55 Early onset associated with increased severity and family history
Generalized plaque psoriasis Guttate psoriasis
. scattered scaly papules . trunk and proximal extremities . can be associated with streptococcal infection . can be seen as first sign of disease in children or acute exacerbation in adults Inverse psoriasis Nail Findings
. nail pits
. yellowish discoloration . commonly involves axilla, groin, umbilicus beneath nail plate . may not see much scaling . higher risk of secondary infection
National Psoriasis Foundation Recommends: Triggers
BP, pulse, BMI every 2 years Streptococcal infection (Guttate) HIV Fasting blood glucose, lipid levels every 5 years if no additional Drugs: Lithium, steroids, Beta-blockers, Interferons, ACE risk factors, every 2 years with risk factors inhibitors, G-CSF
Joint status every visit- 5-8% of patients with psoriasis also suffer from PsA Psoriasis Treatment-Topical Systemic Therapy
Anthralin PUVA Vitamin D3 Analogues Methotrexate Tazarotene Cyclosporine Tar Retinoids- Acitretin Topical glucocorticoids Biologic Agents- Etanercept, Efaluzimab, Adalumimab, Alefacept, Infliximab, Secukinumab Apremilast
Biologics and Psoriasis TNF-alpha Safety Warnings
• 8 FDA approved biologics for psoriasis • Serious infections • New targets in development in response to advancements in basic • Malignancies science • Demyelinating disease • Therapies targeting IL-17 and IL-23 exhibit promising potential • Congestive heart failure thus far • Hepatitis B • Further study is necessary to elucidate the long term efficacy and • Hematologic safety characteristics of these categories of drugs • Autoimmunity Rubbert-Roth A. Rheumatology. • Live vaccines 2012;51:v38-47 Bioloigics-Clinical Pearls Biologics -Psoriasis
• Adalimumab • Guselkumab –-q8-12 weeks • Etanercept • Brodalumab • Apremilast • Ixekizumab • Certolizumab - doesn’t cross placenta • Secukinumab – not associated with TB reactivation • Tildrakizumab- takes time to work (several mos) • Ustekinumab – safe in adolescents • Tofacitinib –JAK1 inhibitor for vitiligo, concomitant with light • Risankizumab/Mirikizumab
Atopic Dermatitis Atopic Dermatitis Pruritus Facial/ Extensor involvement in pediatrics Flexural lichenification in adults Personal/ Family History of atopy Atopic Dermatitis- Associated Features Atopic Dermatitis and Food
Xerosis Prenatal and postnatal probiotic supplementation decreases risk Cutaneous infections- S. aureus, Herpes, Molluscum Restriction diets helpful only if oral food challenge is positive Keratosis Pilaris Pityriasis Alba Nipple Eczema Elevated Serum IgE Orbital darkening
Fig 2 Atopic Dermatitis- Management Crisaborole ointment
Emollients are key part of treatment Topical glucocorticoids Topical calcineurin inhibitors Antihistamines Phototherapy Systemic immunosuppression in severe disease Novel therapy: Crisaborole ointment (PDE4 inhibitor) Dupilumab acetyl dipeptide cream
Journal of the American Academy of Dermatology 2016 75, 494-503.e4DOI: (10.1016/j.jaad.2016.05.046) Copyright © 2016 American Academy of Dermatology, Inc. Terms and Conditions Novel Therapy- Atopic Dermatitis Atopic Dermatitis: Advances in Therapy
Dupilumab-a monoclonal antibody that targets both interleukin-4 and interleukin-13 Dupilumab Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): A phase IIb, randomized, placebo-controlled, clinical trial in adult patients with moderate to Phosphodiesterase 4 inhibitors severe atopic dermatitis (AD) Crisaborole ointment 2% Eric L. Simpson, MD, MCR et al JAK inhibitors Journal of the American Academy of Dermatology Emerging therapies Volume 75, Issue 3, Pages 506-515 (September 2016) DOI: 10.1016/j.jaad.2016.04.054 Monoclonal Ab against IL 13 and IL 31 RA TRPV1 antagonists T-cell inhibitors
Copyright © 2016 American Academy of Dermatology, Inc. Terms and Conditions
Zoster/ Shingles
•May involve multiple dermatomes or may be generalized in immunosuppressed patients Zoster/ Shingles Zoster
Varicella-zoster Virus 5% with non-specific prodromal symptoms 2/3 of patients are over 50 years of age Preceded by pain, paresthesia in the involved dermatome Risk factors: advanced age, malignancy, immunosuppression, xrt, Pain may mimic acute abdomen or MI HIV May involve multiple dermatomes or may be generalized in Reactivation of the virus in the sensory ganglia immunosuppressed patients Consider if pt complains of pain in dermatomal distribution for more than 24-48 hrs even in the absence of skin lesions
Zoster Zoster- Therapy
Diagnosis may be confirmed by: Treatment Tzanck smear –most rapid, non-specific Ideally initiate within 48-72 hours of rash Direct antigen detection – rapid, specific Oral antiviral agents: Viral culture Acyclovir 800mg five times/day x 7-10 days Valacyclovir 1gm TID x 7d Famciclovir 500mg TID x 7d IV Acyclovir for immunosuppressed patients Zoster- Pain Management Zoster Prevention
Treatment of Acute Pain: Treatment of Post-Herpetic Decrease number of new cases of Zoster NSAIDs Neuralgia: Decrease severity of Zoster outbreaks Short course of Opiates Oral Tricyclics +/- Systemic corticosteroids Capsaicin cream Decrease long-term consequences i.e. post-herpetic neuralgia Pain usually improves over weeks to Topical Anesthetics Acceptable cost/benefit ratio months Nerve blocks Gabapentin 1800mg-3600 mg/d Pregabalin 150-600 mg
Shingles Prevention Study Contraindications
Conclusions: Risk of Zoster reduced by 51% compared to Any patient with a history of acquired or primary immunodeficiency states placebo such as: Leukemia/lymphoma Effect greatest in 60-69 y/o AIDS FDA approved for people aged 50 years and older High dose corticosteroids Active unrelated tuberculosis Reduced burden of illness by 61% Pregnancy Reduced incidence of PHN by 66.5% Active Zoster Reduced incidence of HZ by 51% History of anaphylactic reaction to gelatin, neomycin, or other vaccine component Actinic Actinic Keratoses Keratoses
Actinic Keratosis Actinic Keratosis- Therapy
Common, pre-cursors to Squamous Cell Carcinoma- .025%- Cryotherapy 16%/yr progress to SCC Topical 5-Fluorouracil Risk factors: age, male gender, fair skin, immunosuppression, Imiquimod lifetime sun exposure, albinism/ xeroderma pigmentosum Diclofenac- NSAID UVB triggers genetic mutations in keratinocytes Ingenol Mebutate P53 most altered tumor suppressor gene in AK/ SCC Photodynamic therapy Clinical: sun exposed areas, flat, erythematous, rough scale (better Dermabrasion/ chemical peels/ laser felt than seen) Systemic retinoids- transplant Actinic Keratosis Novel Therapy Actinic Keratosis Novel Therapy
4% 5-fluorouracil (5-FU) in an aqueous vehicle cream containing KX2-391 ointment, a dual Src kinase/tubulin polymerization peanut oil applied once daily inhibitor that causes apoptosis of hyperproliferating cells Ingenol disoxate gel- stable without refrigeration, more potent VDA-1102 ointment, which selectively triggers apoptosis in activator of protein kinase C, approved for larger surface area neoplastic cells by modulating voltage-dependent anion channel 0.5% 5-FU, in combination with 10% salicylic acid, in a film- 1/hexokinase enzyme 2, with minimal impact upon surrounding forming base normal cells. SR-T100 gel - active ingredient an antiproliferative extract of Solanum lycocarpum derived from Brazilian wolf apple-phase II trials
Basal Cell Carcinoma Basal Cell Carcinoma- Clinical Subtypes
Most common cancer in the U.S. Nodular- translucent, pearly papule with telangiectasias 80% of skin cancers Superficial- pink, scaly plaque with slight pearly border Risk factors: male gender, fair complexion, UV, Morpheaform/ Sclerosing- skin-colored, pink or whitish, immunosuppression, family history, genetic syndromes, radiation indurated plaque that resembles a scar therapy UV produces genetic mutations in p53 and PTCH genes Indolent growth pattern Basal Cell Carcinoma Basal Cell Carcinoma
Basal Cell Carcinoma Basal Cell Carcinoma Morpheaform Basal Cell Carcinoma Basal Cell Carcinoma- Therapy
Excision- 4mm margin, 5-yr cure rate 89.9% (primary), 82.6% (recurrent) Curettage and electrodessication- 5 yr cure 92.3% Mohs surgery indicated for large, high-risk lesions (96-99%) Radiotherapy, 5-Fluorouracil, Imiquimod, Cryosurgery Vismodegib- Advanced/ Metastatic
Basal Cell Carcinoma Vismodegib
Advanced basal cell carcinoma in poor surgical/ radiation candidates Hedgehog pathway inhibitor Metabolized by CYP 150mg daily GI, fatigue, weight loss, muscle spasms, arthralgias Sonidegib Squamous Cell Carcinoma
Hedgehog pathway inhibitor Second most common skin cancer, incidence increasing in U.S. 200mg on empty stomach daily 20% of non-melanoma skin cancers 58% reponse, lasted 2-19 mos Risk factors: male gender, age, life-time sun exposure, fair skin, chemical carcinogens, immunosuppression, chronic ulcers, burn Muscle spasms, headache, fatigue, GI, pain, itching scars, genetic syndromes, HPV, BRAF inhibitors Rare: rhabdomyolysis Clinical : firm, skin-colored/ pink papules, plaques, head and neck of elderly May be associated with itching, pain, bleeding
Squamous Cell Carcinoma Squamous Cell Carcinoma
Mortality approximates renal and oropharyngeal carcinomas in Rate of metastasis approx 5% southern and central U.S. High risk Local recurrence/ Metastases associated with diameter >2cm, Large (>2cm), deep (>4mm), recurrent perineural involvement Involvement of bone, muscle, nerve Ears, lip, scalp, central face Arising in scars, ulcers, burns, sinus tract, genitalia Immunosuppressed Arsenic exposure Squamous Cell Carcinoma Squamous Cell Carcinoma
Clinical Types SCC in situ (Bowen’s Disease) Erythematous, scaly plaque Nodular Erythematous, hyperkeratotic papule or nodule, exophytic or indurated Oral White plaque or ulceration Higher risk of metastasis
Squamous Cell Carcinoma Squamous Cell Carcinoma- Therapy Actinic Keratosis/ Squamous Cell Carcinoma
Excision SCC: Indurated erythematous lesions Mohs micrographic surgery- cure rate as high as 98.1% (<2cm), Treatment: surgical 74.8% (>2cm) AK: pre-cursor to SCC Curettage and electrodessication UV radiation/ tanning bed use cause skin cancer Radiation- aggressive, recurrent, large, inoperable, poor surgical candidates P53 most altered tumor suppressor gene in AK/ SCC Cryotherapy 10-yr survival with regional mets- 20%, distant- less than 10%
Melanoma Melanoma Incidence rates increasing for 30 years Estimated 76,380 new cases anticipated this year Fastest rising cancer, 1 person/hr will die of disease this year Caucasians and men over 50 years are at highest risk Steepest incidence rates: men>60yrs, lower Socioeconomic level Most common cancer ages 25-29 yo, second most Men have poorer survival common 15-29yo Most common locations: back, chest, upper and lower extremities 10,130 expected deaths due to melanoma 5 year survival: before spread 98% regional spread 62% Distant spread 16% Melanoma Melanoma
May arise de novo or in a pre-existing mole (congenital nevus) Lifetime Risk Risk factors 1 in 1500 born in early 1900s Personal or Family History of melanoma 1 in 50 born in 2014 1 in 200 for Hispanics, 1 in 1000 African Americans Fair skin Sun exposure (esp childhood sunburns)/ Indoor tanning Presence of dysplastic nevi Childhood cancer, immunosuppression/ Parkinsons?
ABCD’s of Melanoma Melanoma
A-Asymmetry
B-Border
C-Color
D-Diameter-6mm
E-Elevation, enlargement Melanoma Melanoma
Cumulative and prolonged exposure to UVB and/ or UVA Refer or biopsy if meets two of ABCD Tanning bed use increases risk for melanoma by 75% criteria or E Ugly Duckling Sign
Familial Melanoma Melanoma- Clinical Subtypes
Genetic basis (CDKN2A, CDK4, BRCA2, p53) Superficial Spreading Melanoma- 70%, ABCDE Primary family member with melanoma increases risk Acral Lentiginous Melanoma- predominant type in those of >3 family members, consider medical genetic referral Asian, Latin, and African descent 50% no mutation Nodular Melanoma- Sudden appearance and growth Lentigo Maligna Melanoma- 6th-7th decade of life, sun-exposed areas Superficial Spreading Melanoma Acral Lentiginous Melanoma
More common in people with darker skin color/ African or Asian ancestry Diagnosis often delayed Check feet
Most common type Back: men Legs: women
Acral Lentiginous Melanoma Nodular Melanoma Rapid growth Aggressive Lentigo Maligna Melanoma Subungual Melanoma
Chronically sun-damaged skin Most common on great toe or thumb More common in elderly Often history of trauma Slow progression Refer to dermatology >6mm width of dark streak Asymmetric Involves proximal nail fold Nail dystrophy
Amelanotic Melanoma
May resemble psoriasis, dermatitis, basal cell, squamous cell carcinoma in situ Difficult diagnosis Clue: recent change or growth Seborrheic Keratosis Lentigo
Melanonychia Pyogenic Granuloma Melanoma Melanoma-Therapy
Excisional Biopsy Key prognostic factors Management Thickness Lymph node evaluation for intermediate Ulceration and thick lesions Number of mitoses Lymph node involvement, distant metastasis
Melanoma- Management Stage IV Melanoma
Excision: margins- 0.5cm- in situ, 1 cm <2mm, 2 cm > 2mm Ipilimumab (Intravenous) CTLA-4 antibody Adjuvant therapy: interferon-alpha Vemurafenib (Oral): target therapy for patient with BRAF mutation Palliative: radiation, chemotherapy, biologic therapy. -improves survival, rapid response Average survival of 6mos for Stage IV -BRAF mutation decreases with age Novel therapy improves survival in some but key to management Nivolumab (PD-1 antibody) is early detection Pembrolizumab (PD-1 antibody) Melanoma Web Based Learning Useful Resources
INFORMED- Internet based program for early detection INFORMED Skin Cancer Education www.skinsight.com/info/for_professionals/skin-cancer-detection- Primary care doctors who review resources double likelihood of informed/skin-cancer-eduationc detection Assessing risk for melanoma http://www.cancer.gov/melanomarisktool/
Skin Cancer Prevention Skin Cancer Prevention
SPF> 30 Use caution near water, snow, sand Broad Spectrum Get Vitamin D safely (diet and exercise) Water Resistant (40-80 minutes) Avoid tanning beds 1 oz Protective clothing Shade (peak hours are 10am-4pm) Skin Cancer Prevention and Early Detection
Educate patient about risks Teach patients about self skin exams Integrate skin exam into routine physical exams, esp. high risk patients
Conclusion References Inflammatory Diseases of the skin: Acne, Rosacea, Psoriasis, Atopic Dermatitis Infections: Zoster Ftizpatrick, TB Color Atlas and Synopsis of Clinical Dermatology, 6th Ed., McGraw-Hill, 2009. Pre-malignant and malignant neoplasms: Actinic Micali G et al. Topical pharmacotherapy for skin cancer. J Am Acad Derm Keratoses, Basal Cell Carcinoma, Squamous Cell 2014;70: 965-76. Carcinoma, Melanoma Mayer JE et al. Screening, early detection, education, and trends for melanoma: current status (2007-20013) and future directions, Parts I and II. J Am Acad Derm 2014;71:599-609, 611-20. Sosman JA. Survival in BRAFV600 mutant advanced melanoma treated with Vemurafenib NEJM 2012;366: 707-14. Fox MC. Management options for metastatic melanoma in the era of novel therapies a primer for the practicing dermatologist J Am Acad Derm 2013; 68: 1- 13 References
Larkin J et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma NEJM 2015;373: 23-34. Migden M et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial