Systemic Mimickers of Genital Skin Disease
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1 Systemic Mimickers of Genital Skin Disease F EBRUARY 19, 2018 Matt Lewis, MD, MPH Clinical Assistant Professor Stanford Dermatology mlewis5@stanford.edu
2 Disclosures I have no relevant conflicts of interest I will discuss off-label uses of medications
3 Objectives I. Cutaneous Crohn s Disease II. Describe the clinical features, lab testing and treatment Genital Psoriasis Recognize frequency, impact and treatment III. Genital Pemphigus Vulgaris Recognize frequency and treatment options IV. Behçet s Disease Be aware of diagnostic criteria and skin manifestations
4 Cutaneous Manifestations in Crohn s 1. Specific (Cutaneous Crohn s) Contiguous: Fistulae Non-contiguous (Metastatic): Genital, distant sites Oral: Mucosal swelling, cobblestoning, orofacial granulomatosis 2. Reactive Aphthous ulcers Erythema nodosum, pyoderma gangrenosum, cutaneous PAN 3. Associated Psoriasiform eruptions, vitiligo Acquired acrodermatitis enteropathica Thrash B, Menter A, et al. J Am Acad Dermatol Feb;68(2):211.
5 Genital Crohn s Disease Painful vulvar edema is most common presentation Deep linear knife-like fissures - most specific but not always present in mild or early disease 60-90% also with perianal mucosal involvement fissures or tags Males with scrotal and penile swelling Histology shows noncaseating granulomas (80% of cases) Alexakis C, et al. J Crohns Colitis Apr 1;11(4): Boxhoorn L, et al. Eur J Gastroenterol Hepatol Jul;29(7): Wood SC. Clin Obstet Gynecol Sep;58(3):
6 Non-contiguous Crohn s (Metastatic) In adults, 30% precede intestinal disease In peds, 80% precede intestinal disease Non-contiguous Crohn s activity may NOT parallel intestinal Crohn s activity Dederichs F, et al. J Crohns Colitis Jan 24;12(2): Lebwohl M, et al. J Am Acad Dermatol 1984; 10: pp Kelier S, et al. Pediatr Dermatol Sep-Oct;26(5):604-9.
7 Laboratory Findings in Crohn s Disease Elevated ESR, CRP Thrombocytosis, Anemia Hypoalbuminemia Elevated fecal calprotectin Serology Positive ASCA (Anti-Saccharomyces Cerevisiae Antibody) Negative P-ANCA Specificity 91%, Positive predictive value 88% Walsham N, et al. Clin Exp Gastroenterol Jan 28;9:21-9. Clark C, Turner J. Surg Clin North Am Dec;95(6): Peeters M, et al. Am J Gastroenterol 2001; 96: pp
8 Treatment Principles in Cutaneous Crohn s Consider comorbidities (e.g. hidradenitis, psoriasis) Collaborate with GI doc involved Escalate therapy as if for intestinal Crohn s disease Topical/intralesional/oral steroids, metronidazole Azathioprine, methotrexate Adalimumab, infliximab, certolizumab Ustekinumab IVIG Laftah Z, et al. J Crohns Colitis Apr;9(4): Severs M, et al. J Crohns Colitis Dec 30. To N, et al. Aliment Pharmacol Ther Jan 7.
9 Take Away Points for Cutaneous Crohn s Painful vulvar edema is most common sign Knife-like fissures are most specific sign 30% adult vs. 80% pediatric cases precede intestinal disease ASCA, P-ANCA, fecal calprotectin are useful screening tests Escalate therapy as if for intestinal Crohn s disease
10 Genital Psoriasis 30-45% patients with genital involvement 45% patients with genital psoriasis did not discuss it with physician Associated with: Younger age of onset (<40 years old) More frequent nail, scalp, inverse involvement Considerations: Superinfection Significant effect on quality of life, psychosexual well-being Shin D, et al. Rheumatol Int Feb;36(2): Ryan C, et al. J Am Acad Dermatol Jun;72(6): Meeuwis KA, et al. Br J Dermatol 2011; 164: pp Meeuwis KA, et al. Acta Derm Venereol Jan;91(1):5-11. Wang G, et al. Eur J Dermatol May-Jun;15(3):176-8.
11 Genital Psoriasis - Diagnosis A Clinical Diagnosis - Biopsy usually unnecessary Biopsy if treatment resistant to exclude SCC, Paget s Klaassen KM, et al. Br J Dermatol 2013; 169: pp Herron MD, et al. Arch Dermatol 2005; 141: pp
12 Vulvar Psoriasis 201 Vulvar psoriasis patients Symptoms: Itching (95%), pain (45%), dyspareunia (28%) Exam: 90% sharp edge, 20% plaques, 17% scale Superinfection: 20% of adults with C. albicans or S. aureus 94% responded to topical therapy alone Kapila S, et al. J Low Genit Tract Dis Oct;16(4):
13 Treatment Inverse Psoriasis Genital Psoriasis Low to mid potency steroid x 2-4 weeks Mid to high potency steroid x 2-4 weeks Switch to topical calcineurin inhibitor or Vitamin D analogue Consider need for topical antimicrobial Consider Botox or Excimer Escalate to systemic therapy Kalb RE, et al. J Am Acad Dermatol. 2009;60(1): Merola JF, et al. J Drugs Dermatol Aug 1;16(8): Meeuwis KA, et al. Acta Derm Venereol Jan;91(1):5-11. Guerrero A, et al. Clin Obstet Gynecol Sep;58(3):
14 Summary for Genital Psoriasis 30-45% of patients have genital involvement Biopsy is unnecessary unless refractory Huge impact on quality of life Treat possible co-infection Vast majority of cases may be controlled with topical therapy Brief courses of mid to high potency topical steroids Maintenance with topical calcineurin inhibitors, vitamin D analogues
15 Pemphigus Vulgaris Incidence 1-50 million/year, varies by geographic region Increased prevalence: Indians, Iranians (HLA-DQB1*0503) Ashkenazi Jews (HLA-DRB1*0402) Triggers may include: infections, medications, tumors CLL, NHL, myeloma Loss of tolerance to desmoglein 3 Majority enter remission within 7-10 years Pollmann R, et al. Clin Rev Allergy Immunol Jan 8. Kridin K, et al. J Am Acad Dermatol Dec 2. Schmidt E, et al. J Invest Dermatol Jun;137(6): Herbst A, Bystryn JC. J Am Acad Dermatol 2000; 42:422-7.
16 Genital Pemphigus 45-50% PV patients with vulvar involvement labia minora > labia majora > vagina, cervix 25-30% show acantholytic cells on Pap smear Associated with SEVERE disease, nasal mucosal involvement Unclear proportion of men affected likely similar to women Glans, coronal sulcus most common Kavala M, et al. J Am Acad Dermatol Oct;73(4): Fairbanks Barbosa ND, et al. J Am Acad Dermatol Sep;67(3): Akhyani M, et al. Br J Dermatol Mar;158(3): Stieger M, et al. Acta Derm Venereol Mar 27;93(2):248-9.
17 Pemphigus Vulgaris No universally accepted diagnostic criteria Diagnosis (1) Clinical presentation (2) Consistent histology (3) Presence of pathogenic autoantibodies (by DIF, or if needed by ELISA) Titers by ELISA or IIF usually correlate with disease activity Treatment: Induce remission, then maintain remission Harman KE, et al. Br J Dermatol Nov;177(5): Herbst A, Bystryn JC. J Am Acad Dermatol 2000; 42:422 7.
18 Treatment Principles in Genital Pemphigus Topical therapy: R/o superinfection if worsening itch/pain/drainage Dilute bleach baths, as for atopic dermatitis Topical steroids for symptoms Topical pimecrolimus may accelerate healing in the oral mucosa Systemic Therapy: Prednisone (1mg/kg) with slow taper to induce remission Start steroid-sparing agent simultaneously to maintain remission Atzmony L, et al. J Am Acad Dermatol Aug;73(2): Harman KE, et al. Br J Dermatol Nov;177(5): Iraji F, et al. J Drugs Dermatol Jun;9(6):684-6.
19 Management of Pemphigus Vulgaris Mild Moderate Severe Topicals: steroids, lido, pimecrolimus minocycline + nicotinamide, dapsone Prednisone 1mg/kg + Rituximab or MMF, AZA Prednisone 1-3mg/kg + rituximab +/- IVIG May need to add MMF, AZA, or cyclophosphamide Prophylaxis MMF=mycophenolate mofetil AZA=azathioprine Calcium + Vitamin D + bisphosphonate (in most) Clotrimazole troches for oral disease, cream for genital disease TMP-SMX 3x/week in moderately immunosuppressed Harman KE, et al. Br J Dermatol Nov;177(5): Joly P et al. Lancet 2017; 389:
20 Take Away Points for Genital Pemphigus Vulgaris Genital pemphigus is associated with more severe disease Topical steroids are most useful for symptoms Pimecrolimus may accelerate healing Consider dilute bleach baths Increase in pain/itching should raise concern for superinfection Rituximab becoming 1 st line agent for mod/severe disease Majority enter remission within 7-10 years
21 Differential Diagnosis for Vulvar Ulcer Infectious Viral (HSV, VZV, EBV, CMV, HIV) Candida Group A Strep Mycoplasma Syphilis Inflammatory Aphthae Contact dermatitis Lichen planus Lichen sclerosus Hidradenitis Cutaneous Crohn s Behçet s Autoimmune Pemphigus Mucous membrane pemphigoid Reactive/Drug Bullous fixed drug Erythema multiforme/sjs Malignancy Squamous cell carcinoma Extramammary Paget s Genetic Hailey-Hailey Mechanical Excoriation Abuse
22 Behçet s Disease 1937 Described by Hulusi Behçet A vasculitis affecting vessels of all sizes Onset years old Need to be followed over time Men>Women in Middle East Women>Men in US Turkey>Middle east>asia>us>uk HLA-B51 Davari P, Fazel N et al. J Dermatolog Treat. 2016;27(1):70-4. Yazici H, Hatemi G et al. Nat Rev Rheumatol Feb;14(2):
23 International Criteria for Behçet s Disease Need 4 points to make diagnosis Oral ulcers Genital ulcers Ocular signs Skin lesions Vascular signs Neurologic signs Pathergy test Uveitis, iritis, retinal vasculitis Erythema nodosum, pustules Arterial/venous thrombosis, phlebitis Aseptic meningitis, encephalitis, TIA transverse myelitis J Eur Acad Dermatol Venereol. 2014;28(3): Yazici H, Hatemi G et al,. Nat Rev Rheumatol Feb;14(2):
24 Oral Ulcers in Behçet s Occur in % of cases Tongue, lips, buccal mucosa, gingiva, soft palate Minor, Major, Herpetiform Self-limited, resolves in 1-4 weeks Biopsy of a classic aphthous ulcer is not usually helpful, except to exclude other diagnoses Within 4 years of oral ulcer onset, 95% meet diagnostic criteria for Behçet s Shahram, F et al. Int J Rheum Dis Jan;19(1): Alpsoy E. J Dermatol Jun;43(6): Davatchi F, et al. Expert Rev Clin Immunol Jan;13(1):57-65.
25 Genital Ulcers in Behçet s 60-80% of cases Men: 90% on scrotum Women: majority on labia, can be in introitus, cervix May be inguinal creases, perineum, perianal skin Larger, deeper, fewer than oral ulcers à may scar Self-limited, resolves in 2-6 weeks More likely to manifest epididymitis Senusi A, et al. Orphanet J Rare Dis Sep 22;10(1):117. Mendes D, et al. J Autoimmun May-Jun;32(3-4):
26 Pustular lesions Occur in 50% of cases Dome-shaped pustule with a red halo Extremities>trunk Usually not folliculocentric Neutrophilic infiltrate, vasculitis Dtsch Dermatol Ges Jan ;4(1):49-64.
27 Pathergy Test 1. Cleanse volar forearm with alcohol 2. Use 20 gauge needle, 2-3 puncture sites hours later, observe for papule/pustule Mat MC, et al. Clin Dermatol Jul-Aug;31(4):
28 Erythema nodosum-like lesions in Behçet s
29 Apremilast for Behçet s Ulcers Genital Ulcers: 100% in the apremilast group (n=10) vs. 50% in the placebo group (n=6) had resolution of genital ulcers by week 12, P=.04. Hatemi G, et al. N Engl J Med 2015;372:
30 Behçet s Treatment Approach Prevent irreversible organ damage Minimize morbidity of ulceration
31 Treatment of Aphthous Ulcers in Behçet s Driven by severity of symptoms 1 st 2nd 3rd Triamcinolone paste, pimecrolimus Lactobacilli lozenges Oral corticosteroid taper Pentoxifylline (better for oral than genital ulcers) Colchicine (better for genital ulcers than oral) Apremilast Azathioprine Adalimumab, etanercept, infliximab Anakinra, canakinumab Thalidomide Cyclosporine, interferon-alpha Alpsoy E. J Dermatol Jun;43(6): Ozguler Y, et al. Curr Opin Rheumatol Jan;28(1): Dalvi SR, et al. Drugs Dec 3;72(17): Rotondo C, et al. Mediators Inflamm. 2015; Yazici H, et al Clin. Exp. Rheumatol. 24 (Suppl. 42), S83 S86. Cush, J New EULAR guidelines on Behçet's. RheumNow.
32 Take Away Message for Behçet s Disease Use 2013 International Criteria for Behçet s Disease Genital ulcers occur commonly on the scrotum and labia, may heal with scarring Escalate treatment for ulcers as much as it bothers the patient Colchicine is first line systemic therapy for genital ulcers Apremilast is an emerging therapy for aphthous ulcers.
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