58 yowoman referred for unresponsive drug rash

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

12:50 - 1:50pm

Can't Miss Dermatology Diagnoses: Cutaneous Manifestations of Systemic DiseaseSPEAKERDaniela Kroshinsky, MD MPH

Disclosures

►Daniela Kroshinsky, MD MPH: No financial relationships to disclose.

The following relationships exist related to this presentation:

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

• Review treatment options

• Learn other mimicking cutaneous conditions

58 yo woman referred for unresponsive drug rash


Dermatomyositis

• Ragged cuticles, nail 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


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• Pulmonary disease occurs in approximately 15–30%

• Generally presents as a diffuse interstitial fibrosis

• Cardiac disease is not commonly symptomatic• Usually presents as arrhythmias or as conduction defects

Malignancy Association• Estimated 10% to over 50% of patients

• Genitourinary (esp ovarian) and colon malignancies may be overrepresented, nasopharyngeal in some SE Asian populations

• Common others: breast, lung, gastric, pancreatic, lymphomas (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


Malignancy Screening • 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

Mimickers

31 yo W with anxiety, palpitations, and recurrent cellulitis


• 31yo W h/o bipolar disorder, anxiety, hypothyroidism and deep vein thrombosis on warfarin

• Presents to ED with anxiety, palpitations, and left calf edema, pain, and erythema

•Three weeks prior to presentation, she developed redness, pain and swelling of her left leg•U/S negative, pelvic MRI negative•Course of clindamycin

•Two weeks later, develops same symptoms on 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


•No personal or family h/o miscarriages, PE, clotting disorders

•ROS negative for weight loss, fatigue, malaise, fever, chills

•Afebrile, HR 128, SO2 100% on room air

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

• Concern for thrombophlebitis, DVT

• Repeat U/S, coagulopathy workup, ANA, dsDNA, anti‐Ro and La, and anti‐Smith

• More detailed history: photosensitivity but no malar or discoid rash, arthritis, serositis, kidney disease, neurologic symptoms

•Hypercoagulability workup:•10/2013: Normal Factor V Leiden, Prothrombin gene mutation, Protein C & S levels

•4/2014: +anticardiolipin Ab, lupus anticoagulant, beta‐2 glycoprotein, normal antithrombin III

Course

•U/S demonstrates left popliteal vein thrombosis•Hematology increases INR goal to 3‐4, monitor

•Repeat aCL IgG 38 and B2GP1 9934•ANA 1:5120, dsDNA 1:80, Anti‐Sm and Anti‐RNPpositive

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


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 from the 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


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 • Palmoplantar hyperhidrosis • Facial flushing • Increased skin pigmentation • Onycholysis (aka Plummers nails)

56 yo M admitted for pancytopenia, found to have leg rash


• Pruritic

• Present for 6 weeks

• Noticed after leg scratched on a bush

• Not improved with triamcinolone cream

DDx

Infectious

• Dermatophyte

• Subcutaneous mycoses (chromoblastomycosis)

• Atypical mycobacteria

• Less likely bacterial, sporothrix or systemic mycoses

Inflammatory

• Contact dermatitis

• Eczema

• Reactive phenomena

Diagnostic Studies

KOH negative

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

Punch biopsy


Necrolytic Acral Erythema

• First described in 1996

• Case series of 7 patients from Egypt with hepatitis C

• Patient’s Hepatitis Viral Load: 748,000

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

• Treatment• Oral zinc supplementation 440 mg/day, divided BID• Hepatitis C treatment• Topical corticosteroids are NOT effective

Necrolytic Migratory Erythema

• Glucagonoma• Analogous to acrodermatitis enteropathica

Nejm.orgDermnz.net

• Up to 38% of patients with LP, especially associated with oral form

• Inquire esophageal ROS, genital involvement

HCV & Lichen Planus


Necrobiosis Lipoidica Diabeticorum Necrobiosis Lipoidica Diabeticorum

• Associated with diabetes, glucose intolerance

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

• Usually follows trauma

82 yo M with “Resistant Hand Lesions”• 82 yo M presented to OSH for evaluation of left

hand lesion s/p dog bite

• Started on vancomycin, piperacillin-tazobactam

• Developed painful, hemorrhagic bullae over wound


• Biopsy at OSH: “acute inflammatory cellular exudate and granulation tissue”

• Debrided at OSH for presumptive necrotizing cellulitis

• Left hand wound expands

• Similar wound appears on right hand

History:

• PMH: Hidradenitis Suppurativa, COPD, HTN, DM2, sinus bradycardia s/p PPM, MM

• SHx: Married, 60 pack year smoker, dog

• ROS: 5 lb unintentional wt loss/ 1 week, +Diarrhea

DDx:

• Neutrophilic Dermatosis: • Pyoderma Gangrenosum, Sweet’s syndrome

• Infectious: • Bacterial, mycobacterial, protozoal, fungal, viral

• Vasculitis: • ANCA-associated or medium vessel vasculitis

• Malignancy: • Lymphomatoid granulomatosis


Exam and Tests:

• PE: Afebrile, VSS

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

• Tissue cultures, ANCAs negative

• Path: Re-reviewed pyoderma gangrenosum

Pyoderma Gangrenosum• Classic: inflammatory pustule rapidly enlarging ulcer w/ undermined, “gun metal gray” borders and cribiform scarring; legs

Peristomal PG

• Can be very delayed

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

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


Associated Diseases• 50-70% have an antecedent, coincident or

subsequent associated disease

• 20-30% inflammatory bowel disease

• 20% arthritis • Seronegative arthritis, spondylitis of IBD, RA

• 15-25% hematologic disease • 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

Chronic Atypical PG• Most common associations:

• Myelogenous leukemia• Myelodysplastic disorders• Refractory anemias• IgA paraproteinemia

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


Pathergy• Non-specific inflammatory response to

intradermal trauma

• Papules, plaques, pustules, ulceration

• Used as a diagnostic test for Behcet’s Disease• 18g needle inserted at an angle through the dermis of

the skin• Lesions within 48 hours• Elicited in a minority of cases

DDx Pathergy• Behcet’s Disease

• Acute Febrile Neutrophilic Dermatosis

• Pyoderma gangrenosum

• Bowel-associated dermatosis-arthritis syndrome

• Rheumatoid arthritis


Systemic Workup for PG• CBC, CMP, hepatitis panel, U/A

• ANA, ANCA, RF, ACL Ab/LAC

• SPEP, UPEP

• CXR

• GI workup

Systemic Workup

• GI workup refused by primary team

• SPEP reveals abnormal banding pattern

• Hematology Consultation

Treatment of PGAGENT DOSE PROS CLINICAL CONSPrednisone 0.5-1mg/kg/day Rapid onset Short term 2/2 SECyclosporine 4-5 mg/kg/day Rapid onsetAzathioprine 100-300mg/day Easy long term useDapsone 50-200 mg/day Long term safety Slow onsetMethotrexate 10-30 mg/week Well-toleratedMycophenolate Mofetil

2-3 g/day Long term safety Slow onset

Thalidomide 50-200 mg/dayColchicine 1.5-3 mg/kg/dayMinocycline, doxycycline

100 mg BID-TID Well-tolerated Often ineffective

Infliximab 5mg/kg/wk IV at 0, 2,6 wks q 6-8 wk

Rapid onsetWell-tolerated

Not FDA approved

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

Diagnostic Procedure• Bone marrow bx

• Complicated myelodysplastic syndrome

• 5qdel but pancytopenia, advanced age poor prognosis


Autoimmune Manifestations of MDS• Isolated autoimmune phenomenon

• 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.

One week s/p first infusion of Infliximab 5mg/kg IV

• 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


Cutaneous Signs of IBD• Prevalence of cutaneous manifestations of Crohns disease and Ulcerative Colitis ~ 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 inflammation


Specific Lesions of Crohns Disease• Fissures, fistulas

• Often contiguous with external mucous membranes

• Up to 36% of cases • 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 CD• Oral disease:

• 8% to 9% of CD• Swelling of the labia, gingiva, or mucosa; painful • Mucosal and gingival cobblestoning• Mucosal ulcerations and nodules

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


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


Associated Conditions• Psoriasis • Alopecia areata• Vitiligo• Reactive arthritis• Eczema•Nail clubbing • Acrodermatitis enteropathica•Hidradenitis suppurativa•Nodulocystic Acne

34 yo woman presents for cellulitis unresponsive to antibiotics s/p attempted I&D for possible abscess

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

Diagnosis of AML confirmed after bone marrow biopsy

Initiated on hydroxyurea with cytarabine/ idarubicin7+3 induction

Biopsy performed for histology and culture


Left lateral lower leg

Leukemia cutis

Carcinoma Erysipeloides

• Well-circumscribed, erythematous, warm, firm plaques

• Underlying malignancy

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


Breast Carcinoma Erysipeloides

A.Marneros

Carcinoma en cuirasse

• Fibrosis

• Induration

• Peau d’orange

• H/o nearby cancer (breast)Bolognia Dermatology Fig 122.3


Breast Carcinoma Telangiectoides

Marneros A et al. JAAD 2009

Conclusions• Identify and differentiate cutaneous manifestations

of systemic disease

• Learn systematic work-up for specific cutaneous findings

• Review treatment options

58 yowoman referred for unresponsive drug rash

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