12:50 - 1:50pm Disclosures

Can't Miss Dermatology Diagnoses: The following relationships exist related to this presentation: Cutaneous Manifestations of ► Daniela Kroshinsky, MD MPH: No financial relationships to disclose. Systemic Disease SPEAKER Daniela Kroshinsky, MD MPH

Off-Label/Investigational Discussion

► In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

Overview

• Identify cutaneous manifestations of systemic disease and their associated risk factors 58 yo woman referred for unresponsive drug rash • Review treatment options

• Learn other mimicking cutaneous conditions

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Dermatomyositis

• Ragged cuticles, fold telangiectasias • Extensor limb rash, including knuckles • Shawl‐distribution poikiloderma with extension into scalp • Periorbital edema, heliotrope rash • Diffuse facial erythema, malar erythema • Holster sign • More violaceous and pruritic than lupus • Erosions, ulcerations

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Forms • Resembles polymyositis; symmetric proximal muscles usually • Skin findings precede muscle in most cases

• Classic (with muscle disease)

• Amyopathic (myositis may evolve over time)

• Hypomyopathic dermatomyositis (no clinical muscle weakness, but myositis present on radiographic or laboratory testing)

Other systems Malignancy Association • Estimated 10% to over 50% of patients • Pulmonary disease occurs in approximately 15–30% • Generally presents as a diffuse interstitial fibrosis • Genitourinary (esp ovarian) and colon malignancies may be overrepresented, nasopharyngeal in some SE Asian populations • Cardiac disease is not commonly symptomatic • Common others: breast, lung, gastric, pancreatic, lymphomas • Usually presents as arrhythmias or as conduction defects (including non‐Hodgkin)

• The risk of malignancy may normalize after 2–5 y • Frequent and thorough medical histories, repeated ROS, complete physical exams, and screening labs

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Malignancy Screening Mimickers

• Urinalysis, stool occult blood testing • Serum prostate‐specific antigen • Serum CA125 • Mammogram and transvaginal pelvic U/S • CT of chest, abdomen and pelvis • Colonoscopy‐ if age‐appropriate, iron deficiency anemia, fecal occult blood, or symptoms • Upper endoscopy – if colonoscopy negative in the setting of iron deficiency anemia, fecal occult blood, or symptoms

31 yo W with anxiety, palpitations, and recurrent cellulitis

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. • Three weeks prior to presentation, she developed redness, pain and swelling of her left leg • 31yo W h/o bipolar disorder, anxiety, hypothyroidism • U/S negative, pelvic MRI negative and deep vein thrombosis on warfarin • Course of clindamycin

• Presents to ED with anxiety, palpitations, and left calf • Two weeks later, develops same symptoms on edema, pain, and erythema right leg, started on levofloxacin 500mg qd and furosemide with improvement by day 5

• New left leg pain, swelling and erythema

Chart Review

• 10/2013 had similar incident and was found to have L leg DVT in absence of immobility or smoking, + OCP which was discontinued • Warfarin for 3 months and then stopped

• 4/2014 pt has similar episode and found to have L leg DVT • Warfarin restarted • Normal workup per patient

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. • Concern for thrombophlebitis, DVT •No personal or family h/o miscarriages, PE, clotting disorders • Repeat U/S, coagulopathy workup, ANA, dsDNA, anti‐Ro and La, and anti‐Smith •ROS negative for weight loss, fatigue, malaise, fever, chills • More detailed history: photosensitivity but no malar or discoid rash, , serositis, kidney disease, neurologic •Afebrile, HR 128, SO2 100% on room air symptoms

•Pertinent Labs: WBC 3.7, Hct 35, ESR 85, INR 3

Course •Hypercoagulability workup: •10/2013: Normal Factor V Leiden, Prothrombin •U/S demonstrates left popliteal vein thrombosis gene mutation, Protein C & S levels •Hematology increases INR goal to 3‐4, monitor

•4/2014: +anticardiolipin Ab, lupus anticoagulant, •Repeat aCL IgG 38 and B2GP1 9934 beta‐2 glycoprotein, normal antithrombin III •ANA 1:5120, dsDNA 1:80, Anti‐Sm and Anti‐RNP positive

•Diagnosis: Systemic Lupus Erythematosus with secondary : Antiphospholipid Antibody Syndrome •Hydroxychloroquine 200 mg BID

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Pseudocellulitis

•Dozens of clinical mimickers of cellulitis: ‘pseudocellulitis’, no ‘gold standard’ diagnostic tool

•Estimated misdiagnosis rate as high as 30% • Most common mimicker: stasis dermatitis

•Empiric use of aggressive antibiotics  rising rates of resistance in soft tissue infections • ‘98 –’04: MRSA soft tissue infections 26.2  47.4%

‐ Moet GJ et al. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: report fromthe SENTRY Antimicrobial Surveillance Program (1998‐2004). Diagn Microbiol Infect Dis 2007;57:7‐13. ‐ David, C.V., et al., Diagnostic accuracy in patients admitted to hospitals with cellulitis. Dermatol Online J. 2011 Mar 15:17(3):1.

32 year old W admitted for diarrhea and weight loss with itchy plaques on the legs

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Localized (Pretibial) Myxedema

• TSH <0.01, T4 = 25 • Graves disease

• A/w hyperthyroidism (usually Graves), may appear w/ hypothyroidism that follows treatment • Found in 1–5% of patients with Graves, but up to 25% of those with exophthalmos • Rarely, in Hashimoto’s thyroiditis without thyrotoxicosis, and euthyroid patients • Rarely, face, shoulders, upper extremities, lower abdomen, scars or donor graft sites

Cutaneous manifestations of hyperthyroidism

• Warm, moist skin, with increased temperature • Diffuse non‐scarring alopecia 56 yo M admitted for pancytopenia, • Palmoplantar found to have leg rash • Facial flushing • Increased skin pigmentation • (aka Plummers nails)

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. DDx

• Pruritic Infectious • Dermatophyte • Present for 6 weeks • Subcutaneous mycoses (chromoblastomycosis) • Atypical mycobacteria • Noticed after leg • Less likely bacterial, sporothrix or systemic scratched on a bush mycoses Inflammatory • Not improved with • Contact dermatitis triamcinolone cream • Eczema • Reactive phenomena

Diagnostic Studies

KOH negative

Tissue culture • Gram stain (-) • Culture grew CoNS • Acid fast smear (-) • Mycobacterial culture (-) • Fungal culture (-)

Punch biopsy

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Necrolytic Acral Erythema Necrolytic Acral Erythema • Type of necrolytic erythema • Necrolytic Migratory Erythema (glucagonoma) • Nutritional Deficiency (zinc/acrodermatitis enteropathica, niacin/pellagra, biotin, essential fatty acids)

• In chronic hepatitis, prevalence is 1.7%

• Predilection for dorsal feet and lower extremities • First described in 1996 • Treatment • Case series of 7 patients from Egypt with hepatitis C • Oral zinc supplementation 440 mg/day, divided BID • Hepatitis C treatment • Patient’s Hepatitis Viral Load: 748,000 • Topical corticosteroids are NOT effective

HCV & Necrolytic Migratory Erythema • Up to 38% of patients with LP, especially associated with oral form • Glucagonoma • Inquire esophageal ROS, genital involvement • Analogous to acrodermatitis enteropathica

Nejm.org Dermnz.net

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Necrobiosis Lipoidica Diabeticorum Necrobiosis Lipoidica Diabeticorum

• Associated with diabetes, glucose intolerance

• Decreased sensation to pinprick and fine touch, and partial alopecia

• Usually follows trauma

• 82 yo M presented to OSH for evaluation of left hand lesion s/p dog bite 82 yo M with “Resistant Hand Lesions”

• Started on vancomycin, piperacillin-tazobactam

• Developed painful, hemorrhagic bullae over wound

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. History:

• Biopsy at OSH: “acute inflammatory cellular • PMH: Suppurativa, COPD, HTN, exudate and granulation tissue” DM2, sinus bradycardia s/p PPM, MM

• Debrided at OSH for presumptive necrotizing • SHx: Married, 60 pack year smoker, dog cellulitis • ROS: 5 lb unintentional wt loss/ 1 week, +Diarrhea • Left hand wound expands

• Similar wound appears on right hand

DDx:

• Neutrophilic Dermatosis: • Pyoderma Gangrenosum, Sweet’s syndrome • Infectious: • Bacterial, mycobacterial, protozoal, fungal, viral • Vasculitis: • ANCA-associated or medium vessel vasculitis • Malignancy: • Lymphomatoid granulomatosis

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Pyoderma Gangrenosum Exam and Tests: • Classic: inflammatory pustule  rapidly enlarging ulcer w/ undermined, “gun metal gray” borders and • PE: Afebrile, VSS cribiform scarring; legs

• Labs: •WBC 9.1 • 91% Polys, 1% Bands • CBC, CMP otherwise WNL

• Tissue cultures, ANCAs negative

• Path: Re-reviewed  pyoderma gangrenosum

Peristomal PG Atypical Pyoderma Gangrenosum

• More superficial ulcers or deep erosions with blue-gray, bullous border

• Usually on the hands, arms or face • aka neutrophilic dermatosis of the hands

• Can be very delayed Callen JP, Jackson MJ. Pyoderma gangrenosum: an update. Rheum Dis Clin N Am. 33(2007): 787‐802.

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Associated Diseases Chronic Atypical PG • 50-70% have an antecedent, coincident or subsequent associated disease • Most common associations: • 20-30% inflammatory bowel disease • Myelogenous leukemia • 20% arthritis • Myelodysplastic disorders • Seronegative arthritis, spondylitis of IBD, RA • Refractory anemias • 15-25% hematologic disease • IgA paraproteinemia • AML, CML, hairy cell leukemia, myelodysplasia, monoclonal gammopathy • More likely in atypical cases

• Course: acute, relapsing, chronic • Relapsing or chronic more likely associated with underlying disease Callen JP, Jackson MJ. Pyoderma gangrenosum: an update. Rheum Dis Clin N Am. 33(2007): 787‐802

Hospital Course

• Labs: WBC 9.7/ Hb 9.1 ↓ / PLT 78 ↓

• Systemic w/u for underlying disease initiated

• Disease continues to rapidly progress despite IV steroids

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Pathergy DDx Pathergy • Behcet’s Disease • Non-specific inflammatory response to intradermal trauma • Acute Febrile Neutrophilic Dermatosis • Papules, plaques, pustules, ulceration • Pyoderma gangrenosum • Used as a diagnostic test for Behcet’s Disease • 18g needle inserted at an angle through the dermis of • Bowel-associated dermatosis-arthritis the skin syndrome • Lesions within 48 hours • Elicited in a minority of cases • Rheumatoid arthritis

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Systemic Workup for PG Systemic Workup • CBC, CMP, hepatitis panel, U/A • GI workup refused by primary team • ANA, ANCA, RF, ACL Ab/LAC • SPEP reveals abnormal banding pattern • SPEP, UPEP • Hematology Consultation •CXR

•GI workup

Treatment of PG

AGENT DOSE PROS CLINICAL CONS Diagnostic Procedure Prednisone 0.5-1mg/kg/day Rapid onset Short term 2/2 SE Cyclosporine 4-5 mg/kg/day Rapid onset • Bone marrow bx Azathioprine 100-300mg/day Easy long term use Dapsone 50-200 mg/day Long term safety Slow onset Methotrexate 10-30 mg/week Well-tolerated • Complicated myelodysplastic syndrome Mycophenolate 2-3 g/day Long term safety Slow onset Mofetil • 5qdel but pancytopenia, advanced age  poor prognosis Thalidomide 50-200 mg/day Colchicine 1.5-3 mg/kg/day Minocycline, 100 mg BID-TID Well-tolerated Often ineffective doxycycline Infliximab 5mg/kg/wk IV at 0, Rapid onset Not FDA approved 2,6 wks q 6-8 wk Well-tolerated

Adapted from: Callen JP, Jackson MJ. Pyoderma gangrenosum: an update. Rheum Dis Clin N Am. 33(2007): 787‐802

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Autoimmune Manifestations of MDS One week s/p first infusion of • Isolated autoimmune phenomenon Infliximab 5mg/kg IV • Pyoderma gangrenosum

• Acute systemic vasculitis

• Classic connective tissue disorder • Rheumatoid arthritis

• Immune mediated hematologic abnormalities • Hemolytic anemia, immune thrombocytopenia

• Asymptomatic serological immunologic abnormalities • Positive RF, ANA

Pinheiro et al. The 5q‐ syndrome and autoimmune phenomena: report of three cases. Leukemia Research 30 (2006) 507‐ 10.

• 23yo F from the Middle East with chronic idiopathic perianal wounds x3 years complicated by fistulas

• Initially presented with abscess, doctors there concerned for Crohns disease

• Started on infliximab, later developed anaphylaxis

• Switched to adalimumab and azathioprine, disease progresses

• Evaluated in London 2013: colonoscopy not c/w Crohns

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Cutaneous Signs of IBD

• Prevalence of cutaneous manifestations of Crohns disease and ~ 9%‐19/23%

• Three types of skin conditions: • Specific: skin lesions have identical pathologic mechanisms to lesions of the GI tract (usually CD) • Reactive: different pathologic features, likely cross antigenicity between skin and gut mucosa (CD,UC) • Associated: likely relate to human leukocyte antigen linkage and chronic

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Specific Lesions of CD Specific Lesions of Crohns Disease • Oral disease: • Fissures, fistulas • 8% to 9% of CD • Often contiguous with external mucous • Swelling of the labia, gingiva, or mucosa; painful membranes • Mucosal and gingival cobblestoning • Up to 36% of cases • Mucosal ulcerations and nodules • Presence of colitis is a positive predictor of perianal disease compared disease confined to the small bowel • Granulomatous edematous inflammation on histology

Specific Lesions of Crohns Disease

• Metastatic CD • Extension of inflammation to uncommonly affected sites • Skin and subcutaneous; plaques, nodules, and ulcerations • Predominantly extremities or intertriginous areas • Histologically identical to CD

• Severity of CD does not necessarily correlate to skin disease • Colon involvement seen more commonly in the setting of Metastatic CD

• Treatment of choice: treatment of underlying CD • Does not guarantee therapeutic improvement of skin

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Reactive Lesions of IBD

• Erythema nodosum (#1)

• Pyoderma gangrenosum, Sweet’s syndrome

• Pyostomatitis vegetans

Pyostomatitis Vegetans • Superficial pustules and ulcerations, predominantly lips and buccal mucosa

• All reported cases associated with IBD

• Antiseptic mouthwashes and topical corticosteroids for temporary relief, treat IBD

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Associated Conditions • Psoriasis 34 yo woman presents for cellulitis unresponsive to antibiotics s/p • attempted I&D for possible abscess • Vitiligo • Reactive arthritis • Eczema • Nail clubbing • Acrodermatitis enteropathica • • Nodulocystic

CBC reveals WBC = 80, smear c/f acute AML

Diagnosis of AML confirmed after bone marrow biopsy

Initiated on hydroxyurea with cytarabine/ idarubicin 7+3 induction

Biopsy performed for histology and culture

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Left lateral lower leg

Carcinoma Erysipeloides

• Well-circumscribed, erythematous, warm, firm plaques

• Underlying malignancy

• Breast*, gastric, uterine, cervical, colon, GU, prostate, nasopharyngeal, , idiopathic

Leukemia cutis

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Breast Carcinoma Erysipeloides

A.Marneros

Carcinoma en cuirasse

• Fibrosis

• Induration

• Peau d’orange

• H/o nearby cancer (breast)

Bolognia Dermatology Fig 122.3

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes. Breast Carcinoma Telangiectoides Conclusions

• Identify and differentiate cutaneous manifestations of systemic disease

• Learn systematic work-up for specific cutaneous findings

• Review treatment options

Marneros A et al. JAAD 2009

Syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes.