Controversies in Women s s Health:

Transcription

1 Controversies in Women s s Health: Hot Topics: Dermatology 2008 Jack Resneck, Jr, MD Assoc Prof, UCSF Dept of Dermatology Assoc Prof, UCSF Institute for Health Policy Studies Dermatology Residency Director & Faculty Practice Director

2 Disclosures No Financial Conflicts of Interest Many off-label uses Will note them verbally as we go Almost everything we do in derm is off-label

3 Outline Controversies in Women s s Health: Dermatology 2008 Hair Loss in Women The Older Woman with the Red Leg Treatment-Resistant Acne in Adult Women Isotretinoin Safety and the FDA Genital Wart Treatments Topical Treatment of Skin Cancer and Photodamage Sunscreens, Cancer Prevention, and Vitamin D

4 Hair Loss (Alopecia) in Women Common (30% Lifetime Incidence) Distressing Difficult to work up, diagnose, and treat

5 Hair Biology, A Quick Review Scalp has 100,000 Hairs 90% Anagen (3 years (range 2-6), 2 growing) 1% Catagen (2 weeks, apoptosis outer root sheath) 9% Telogen (3 months, resting) Normal loss: per day 1cm growth / month

6 Hair Loss The First Fork in the Road Scarring (cicatricial) Non-Scarring

7 Scarring Alopecias Discoid Lupus Folliculitis Decalvans Lichen Planopilaris Dissecting Cellulitis

8 Scarring Alopecias Traction Alopecia Trichotillomania Many other scarring alopecias

9 Scarring Alopecias High Stakes Difficult to diagnose and manage Referral encouraged

10 Approach to Non-Scarring Alopecias Use history/physical to identify cases where diagnosis is clear Consider labs/biopsy in remaining cases Anagen/Telogen Pull Test Tug Test

11 Case 1 Evolved rapidly + Pull Test at Periphery Non-scarring

12 Alopecia Areata Evolved rapidly + Pull Test at Periphery Non-scarring

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14 Alopecia Areata Auto-immune etiology, active T-cells T target follicular melanocytes Anagen effluvium, hairs taper and break Assoc with higher incidence SLE, autoimmune thyroid dz, diabetes, vitiligo DDx: Syphillis, tinea, early scarring, May consider RPR, KOH, bx (but usually not required) Treatment: Mainstay: Intralesional Kenalog, 10mg/cc (scalp). Limit of 30mg/tx. Treat once/month. Checkerboard pattern, careful to inject into dermis (not epidermis or s-q). s Other options Prognosis

15 Case 2 Began heavy shedding 3 mos post-partum partum Evolved rapidly Non-scarring + Pull Test (>25) Telogen hairs

16 Telogen Effluvium Abrupt shift to telogen (often 30% of hairs) Triggers: Pregnancy, major illness, major surgery Nutritional deficiency (abrupt low-protein diet) Drugs (oral retinoids,, heparin, interferon alpha, lithium, terbinafine, valproate, warfarin,, beta- blockers, ACE-inhibitors) Hypothyroidism? Iron deficiency? Most regrow over period of months

17 Case 3 Help me I used to have such thick hair, but now it s s all coming out I see way more hair in the shower than I used to look at this photo of how thick my hair was. Evolved slowly Often + fam hx Non-scarring - Pull Test (<5) - Tug Test Mostly vertex/frontal No change in hairline No bald spots Not hirsuit,, menses nl.

18 Female Pattern Hair Loss Androgenetic Alopecia

19 Female Pattern Hair Loss Androgenetic Alopecia? 38% prevalence by age 70 Usually central frontal or vertex, sparing frontal hairline

20 Female Pattern Hair Loss Approach Eliminate scarring alopecia, external causes (traction from hair care practices, trichotillomania) If male pattern, hirsuit,, or irregular menses, check androgens Consider recent telogen effluvium unmasking existing female pattern (can take up to 50% loss to be evident) Consider nutrition, ferritin,, thyroid, KOH, RPR

21 Female Pattern Hair Loss Treatment Reassurance Topical minoxidil (2% vs 5%*) Sprironolactone and OCPs? Finasteride not effective Surgery 2% minoxidil is only rx FDA approved for hair loss in women

22 Pt referred for persistent cellulitis One year chronic sore red legs (relapsing/remitting) despite multiple courses of: Cephalexin Dicloxacillin Clarithromycin Azithromycin Clindamycin

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24 What would you do? A. Admit for IV Antibiotics B. Prescribe one pound of Triamcinolone C. Biopsy for histopath and tissue culture D. Begin vasculitis workup E. Refer for patch testing

25 What would you do? A. Admit for IV Antibiotics B. Prescribe one pound of Triamcinolone C. Biopsy for histopath and tissue culture D. Begin vasculitis workup E. Refer for patch testing

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28 Stasis Dermatitis Often bilateral Itchy and/or painful Eczema may be weepy or dry, scaling, lichenified. Red, hot, swollen legs may mimic cellulitis No fever, elevated WBC, LAD, or streaking Look for: edema, hemosiderin deposition, hyperpigmentation Superimposed contact dermatitis common Treatment: Compression, emollients, liberal use of topical steroids Watch out for venous ulcers

29 Infection of the dermis/subcutis subcutis Strep pyogenes and Staph aureus Rapidly spreading Erythematous,, tender plaque, swollen but not fluctuant Preceded by fever Occ.. LAD, streaking WBC often nl Blood Cx often neg Rarely bilateral Treat tinea pedis (portal of entry) DDx: Cellulitis

30 Ddx: Leukocytoclastic Vasculitis Small post-capillary venules Immune Complex Mediated Palpable purpura is hallmark May also be vesicular, pustular, ulcerated. Early fevers and erythema may mimic cellulitis

31 LCV Etiologies Infectious: Staph aureus Group A Strep Hepatitis B M. Tuberculosis M. Leprae Hepatitis A & C HSV Influenza Many parasitic infections HIV-associated Neisseria Meningitidis RMSF DGC Bacterial Endocarditis Salmonella, Yersinia Drug-Induced: Penicillins Sulfas Thiazides Allopurinol NSAIDs Montelukast (Often Churg-Strauss) Tamoxifen,, G-CSF, G OCPs, Influenza Vaccine, Alpha Interferon, Minocycline,, COX-2 Inhibitors, Methotrexate, Furosemide,, B-Blockers, B Blockers, Anti- Seizure (Hydantoins( Hydantoins), Phenothiazines Co-exisiting d/z SLE, Sjogren s Rheumatoid Arth Behcet s Mixed cryos (CTD, Lymphoproliferative, Hepatitis) Ulcerative Colitis Lymphoproliferative Lung, Colon, Ovarian, Renal, Prostate, or Breast Cancer

32 Genital Warts / Condylomata HPV Point Prevalence Rates >60% in Sexually Active Young Women (PCR) Lifetime Risk exceeds 80% Latent Infection common. Mean duration uncertain

33 Original Study of UW Female Undergrads Those with +HPV followed up 147 Patients, 1 or 2 visits only Median 10 Years Later Cervical and vulvovaginal swabs obtained 50% HPV Positive 33% of them had same genotype as before

34 Human Papilloma Virus Correlation between HPV type and clinical lesions produced Low risk types (6,11) = Condyloma High risk types (16,18,31,45) = Dysplasia Virtually all exophytic external genital warts are caused by low risk types So HPV typing is not indicated for external genital warts Quadrivalent vaccine: 6/11/16/18

35 Genital Warts Treatment Goal of treatment: Get rid of the warts That s s why the patient is in the office Counsel patient appropriately Don t t confuse relationships Support through patient education Detect early cervical dysplasia Treat other STDs

36 Genital Warts Transmission Risk of transmission after clearance with treatment unknown Bottom line: Transmission is still possible, but probably already occurred Monogamous couples, barrier protection when warts are present; they decide what to do when warts are gone

37 Genital Warts Overzealous Treatment Patients immunity will eventually control the infection (why the immunosuppressed are so hard to treat) Treatment should not be worse than the disease: Don t t produce long-term sequelae (physical or psychological)

38 Genital Warts Destructive Therapies No Proven Reduction in Transmission or Progression to Neoplasm 25% Podophyllin Applied in Office (40%) 0.5% Podophyllotoxin at Home (60%) Cryotherapy (80%) Electrofulguration (95%) Laser (90-95%) Clin Infect Dis Jan;28 Suppl 1:S37-56.

39 These products contain propane or dimethyl ether LN2 is -196 degrees Celsius

40 Imiquimod (Aldara) Local Interferon Inducer Application Schedule (3x/week) 72% Total Clearance in Women 33% Total Clearance in Men 70% Partial Response in Men? Lower Recurrence Rates $700 for 3 month supply

41 Patient-Administered Therapies Imiquimod vs. Podofilox IMIQUIMOD PODOFILOX 0.5% 8-12 weeks to clear 2-66 weeks to clear Burn: 26% (F) 9%(M) Burn: 37% Erosion: 30% Erosion: 27% Complete Clearance Complete Clearance Females: 72% Females: 50% Males: 33% Males: 45% - 63% Recurrence: 20% Recurrence: 30% Pregnancy: Cat B Pregnancy: Cat X Cost: $230/month Cost: $190/month

42 A very expensive placebo Imiquimod has poor efficacy away from mucosal sites

43 What about Imiquimod Here?

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45 Imiquimod Treatment of Success Rates: Basal Cell Carcinoma 80-90% in Superficial BCC (FDA approved) 60-80% in Nodular BCC (not FDA approved) Very Low in Micronodular,, Invasive, & Morpheaform Patient selection is the key Long courses (months) may be required Biopsy to confirm diagnosis before Tx Biopsy to confirm cure after Tx

46 Imiquimod for BCCs Not ideal for most patients Inflammation may be severe and lengthy Cure rates suboptimal May be useful for Patients who are surgery-averse Patients with relative contraindication to surg. Pre-surgical reduction in tumor burden in cosmetically sensitive areas

47 Photodamage / Dermatoheliosis The Treatment of Sun-Damaged Skin I am not an expert on cosmetic use of lasers, intense pulsed light, chemical peels, abrasive physical techniques, or OTC cosmeceuticals for sun damaged skin Medical treatments to treat photodamage and precancerous lesions: OTC Alpha Hydroxy,, Glycolic, and Lactic Acids and Retinols (minimal effect) Top. Retinoids (Effective for photodamage,, mild improvement) 5-Fluorouracil (Effective for AKs,, tolerability an issue) Imiquimod (Effective for AKs,, tolerability an issue) Oral Retinoids (Useful in transplant and high risk populations) Photodynamic Therapy (Jury is still out)

48 Topical Tretinoin Tretinoin 0.02% or higher qhs effective for mild improvement of hyperpigmentation and fine wrinkles in photodamaged skin. Histologic evidence of new dermal collagen, keratinocyte damage repair Reasonable expectations: 4-66 months time course for initial benefit Erythema,, irritation, scaling can be significant Both benefit and side effects are dose- dependent Interventions for photodamaged skin. Cochrane Database Syst Rev Jan 25;(1):CD

49 Topical Treatment of Actinic Keratoses 5-Fluorouracil 5% cream twice daily x weeks 5-Fluorouracil 0.5% microsponge cream daily x weeks Imiquimod 5% cream 2x / week x 16 weeks Off Label: 3x / week x 12 weeks 3x / week, 4 wks on, 4 wks off, 4 weeks on

50 Must counsel patients about significant side effects and select only those who are eager and willing

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52 Efficacy Comparison? Clearance Rates 1-2 months after end of therapy Sustained field clearance rates 12 months after end of therapy A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol Dec;157 Suppl 2:34-40.

53 Sunscreens & Skin Cancer Sunscreens can block vitamin D At least some sunlight is necessary to stay healthy By Robert Bazell Correspondent NBC News Scientists: Sunshine May Prevent Cancer Rickets Makes A Comeback WASHINGTON Debate over the Benefits of Sun Exposure I BEG TO DIFFER A Dermatologist Who's Not Afraid to Sit on the Beach

54 $150,000 Grant from Indoor Tanning Association (Tobacco???)

55 Dr. Holick s Work growing mountain of scientific evidence that proves regular and moderate exposure to ultraviolet (UV) light has a profound positive effect on health Insufficient levels of the vitamin lead to medical maladies, including heart disease, stroke, multiple sclerosis, Type 1 diabetes mellitus, rheumatoid arthritis, and cancers of the breast, colon, and prostate; children are also more prone to rickets. validated research has established that more cancer deaths are due to insufficient UV exposure (30,000) than to too much UV exposure.

56 Evidence supporting Holick s work High higher incidence some cancers, latitude cardiac disease, Type 1 DM, MS Lower vitamin D levels Retrospective association between vitamin D intake or levels and: colon cancer & breast cancer (both incidence and survival rates). No impact on prostate ca risk, increased risk for pancreatic ca? Retrospective association between vitamin D intake and mortality in meta-analysis analysis not reproduced in large prospective study in JNCI Nov 2007 Outdoor workers get prostate cancer later Vitamin D receptor polymorphisms associated with skin cancer risk, breast cancer risk

57 Are We All Vitamin D Deficient? Traditional definition of deficiency (IOM): 25-hydroxyvitamin D < 11 ng/ml Less than 5% deficient (US Non-Hispanic white adults) Evolving definition of deficiency: 25-hydroxyvitamin D < 20 ng/ml About 30% deficient Proposed definition of deficiency: 25-hydroxyvitamin D < 30 ng/ml About 80% deficient

58 From Hyperbole to Evidence: Vitamin D Six Cases of Rickets in USA reported in 1990s Associated with prolonged breastfeeding in dark-skinned babies Studies of Children with Xeroderma Pigmentosum

59 From Hyperbole to Evidence: Vitamin D and Prospective Trials JNCI 2007 RCT : 36,000 p-m women 400u vs placebo 7 yrs Designed for hip fracture No difference in breast ca. High D = Low BMI NEJM 2006 Same cohort No difference in colorectal cancer incidence or tumor characteristics Hypertension 2008 Same cohort No difference in HTN

60 From Hyperbole to Evidence: Vitamin D and Prospective Trials NEJM 2006, RCT 36,000 p-m women in WHI CA + 400u D3 vs placebo No difference in hip fractures Increased kidney stones Osteoporosis 2007 RCT : 3,440 elderly 100,000u q4mo vs placebo x 3 yrs No difference in fractures

61 From Hyperbole to Evidence: Vitamin D and Prospective Trials Arch Intern Med 2005, RCT 208 black postmenopausal women 800u qd x2 yrs, then 2000u qd x 1yr No difference in BMD or bone loss vs placebo Circulation 2007, RCT 36,000 postmenopausal women 400u qd x 7 years No difference in stroke or MI

62 From Hyperbole to Evidence: Non-Melanoma Skin Cancers Basal Cell Carcinoma Incidence: >1,000,000 per year in US Squamous Cell Carcinoma Incidence: 200,000 per year in US Mortality: 2,500 per year in US Most Sun-Inducted Cumulative exposure Less controversial

63 From Hyperbole to Evidence: Incidence: 120,000 / Year Melanoma 60,000 Invasive / Year (1/55 lifetime risk) 2,000% Increase since 1930 Mortality: 7,800 / Year Leading cause of cancer death in young women age Second most prevalent cancer in young adults age Cause Less Well Understood Histologic subtypes have unique molecular genetics Acral-Lentiginous and Mucosal Melanomas: Not UV-related Head/Neck of elderly: Chronic Sun Exposure Trunk and extrems of young adults with many moles: Intermittent sun exposed skin / history of some burns BRAF mutations (MAP kinase gene)

64 Sunscreen & Melanoma Case-Control Control Studies The Existing Evidence Mixed results Meta-analyses analyses showed no association Retrospective Recall Bias Limited choices never sometimes always Poorly Controlled Confounders Sun sensitivity, Skin type (fair skinned are both more likely to use sunscreen and more likely to get melanoma) Use of sunscreen to prolong time in sun in era when sunscreens had h little UVA protection -> > more UVA exposure Need better data

65 EWG Claims: 1. Many sunscreens lack adequate UVA protection 2. Misleading claims (water resistance) 3. Products break down in sun 4. Products (especially oxybenzone) absorbed in bloodstream and are toxic??

66 My current recommendations Use sunscreen! UVB: SPF of 30+ UVA: Contains: Avobenzone (Parsol 1789), or Helioplex (Neutrogena), or Mexoryl (Anthelios), or Physicial Blockers (Titanium( Titanium or Zinc) New FDA Proposed Rule on UVA If worried about toxins, use a physical blocker only Daily moisturizers with sunscreen Often SPF 15 Many now contain UVA blockers above Consider oral Vitamin D supplementation

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68 JAMA. 2006;296:

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70 Case 32 year old woman Acne since age 17 Moderate, inflammatory, affecting chin and jawline Normal menses, Not hirsuit Poorly controlled with oral doxy, oral MCN, topical bp, topical retinoids, topical clinda Two courses of oral isotretinoin led to clearance, but followed by relapse months after treatment

71 What would you do? A. Chronic low dose isotretinoin B. Oral SMZ/TMP C. Oral azithromycin 3x/week D. Oral spironolactone E. Oral contraceptives

72 What would you do? A. Chronic Low Dose isotretinoin B. Oral SMZ/TMP C. Oral Azithromycin 3x/week D. Oral spironolactone E. Oral Contraceptives

73 Acne Vulgaris in Adult Women Occasionally related to true excess androgen PCOS Metabolic Syndrome Adrenal Tumor Ovarian Tumor Meds

74 Acne Vulgaris in Adult Women Occasionally related to excess androgen In most others, may be excess androgen sensitivity of hair follicles: Other features of androgen excess are often not present irregular menses, hirsuitism, glucose intolerance, alopecia, etc. Serum free testosterone and DHEA-S S are often normal

75 Acne in Adult Women OCPs (estrogen-containing, minimally androgenic progestin) Ortho Tri-Cyclen & Estrostep FDA-approved Yasmin & Alesse also shown effective (off-label) Sprironolactone 50mg-100mg daily with or without OCPs can be very effective Especially helpful in subset of women with nodular acne of the lower face and neck resistant to other treatments N Engl J Med Apr 7;352(14): (Excellent Review Article on Treatment of Acne)

76 Acne that Isn t

77 Acne that Isn t

78 Acne that Isn t

79 Question These patients initially presented with lip pruritus and were treated with topical steroids. With each effort to taper the steroids, they presented with this rash. The best treatment is: A. Increase Potency of Topical Steroids B. Add topical pimecrolimus C. Add oral Doxycycline & Taper Steroids D. Add oral Keflex & Taper Steroids E. Patch Test for Contact Allergies

80 Question These patients initially presented with lip pruritus and were treated with topical steroids. With each effort to taper the steroids, they presented with this rash. The best treatment is: A. Increase Potency of Topical Steroids B. Add topical pimecrolimus C. Add oral Doxycycline & Taper Steroids D. Add oral Keflex & Taper Steroids E. Patch Test for Contact Allergies

81 Perioral Dermatitis Very, very common Almost exclusively a disease of women Most prevalent in ages Papules and small pustules around the mouth, with a narrow spared zone around the lips (can also be peri-orbital). Asympotmatic or mild burning sensation Often triggered by topical steroids

82 Perioral Dermatitis Treatment Stop topical steroids Hold use of cosmetics, sunscreens Oral TCN, Doxy, or MCN (primary tx) Sometimes replace topical steroids with: Topical Antibiotics (limited use) Topical pimecrolimus or tacrolimus to bridge off of steroids Will get worse before it gets better

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84 Isotretinoin and Depression A series of case reports: Son of member of Congress (Stupak) Tampa teen pilot FDA: 165 Suicides vs 220 Predicted Suicides 9 Studies Failed to Show Association Am J Psychiatry May;162(5):983. PET Scan 18 Accutane patients Decreased metabolism in the orbitofrontal cortex Funded by Plantiff s s Litigators

85 Isotretinoin and the FDA Depression/Suicide Debate Pressure to more aggressively regulate Pregnancy & Pregnancy Terminations Registry (modeled on Thalidomide) No Rx s s without registering after March 1, Exposed Pregnancies (no change) of 92,000 patients treated in first year

86 28% Birth Control Pills 25% Contains Drugs/Medicine 8% Contains Hormones/Vitamins specially for women 7% Don t t Know 19% Don t t Take if Pregnant 1% Don t t Get Pregnant While Taking Teratology 64: (2001)