530 Letters. Fig 3. DNA sequence of the DSRAD gene shows a 767 dela mutation in exon 2 of DSRAD gene in the affected family.

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1 530 Letters SEPTEMBER 2010 Fig 2. Clinical photographs of the proband s skin eruption. A, Freckle-like pigmented macules on the face. B, Hypopigmented and hyperpigmented macules on the dorsal aspects of the extremities and hands. Fig 3. DNA sequence of the DSRAD gene shows a 767 dela mutation in exon 2 of DSRAD gene in the affected family. REFERENCES 1. Miyamura Y, Suzuki T, Kono M, Inagaki K, Ito S, Suzuki N, et al. Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet 2003;73: Rongioletti F, Rebora A. Acquired brachial cutaneous dyschromatosis: a common pigmentary disorder of the arm in middleaged women. J Am Acad Dermatol 2000;42: Li M, Li C, Hua H, Zhu W, Lu Y, Yang L. Identification of two novel mutations in Chinese patients with dyschromatosis symmetrica hereditaria. Arch Dermatol Res 2005;297: doi: /j.jaad Cocaine-associated retiform purpura and neutropenia: Is levamisole the culprit? To the Editor: We describe two patients with neutropenia and retiform purpura associated with cocaine use and alert clinicians to the possible emerging public health threat of levamisole-contaminated cocaine. Case 1 was a 38-year-old woman with hepatitis C, remote miscarriage, and active polysubstance abuse who was admitted for methicillin-resistant Staphylococcus aureus endocarditis. A toxicology screen performed on admission was positive for cocaine, opiates, and benzodiazepines. She developed a deep venous thrombosis on her right lower extremity that was initially treated with heparin and an appropriate bridge to warfarin. On day 27 (day 12 of warfarin), she developed multiple discrete, stellate, purpuric macules, papules, and plaques with a bright erythematous border on her pinna, earlobes, cheeks, right breast, and bilateral proximal upper and lower extremities (Fig 1, A-C ). Concomitant unexplained episodic tachycardia and neutropenia were noted. Skin biopsy specimens revealed leukocytoclastic vasculitis with mural fibrin deposition, neutrophilic infiltrate, nuclear dust, and extravasated erythrocytes involving superficial small vessels with pauciinflammatory luminal thrombosis in a few vessels (Fig 1, G and H ). Synchronous tests revealed positive platelet factor IV antibody (but negative serotonin release assay), mixing studies (noncorrecting), lupus

2 VOLUME 63, NUMBER 3 Letters 531 Fig 1. Retiform purpura in two patients (A-C, case 1; D-F, case 2). Each patient had scattered, stellate-shaped purpuric patches with brightly erythematous borders and pending central necrosis symmetrically distributed over the ears, face, and extremities. Histopathologic images of both patients (G and H, case 1; I, case 2). In case 1, both leukocytoclastic vasculitis (G) and bland thrombosis (H) were present. In case 2, thrombotic vasculopathy with only sparse inflammation (I) was present. anticoagulant, and Russell viper venom time. Antineutrophil cytoplasmic antibodies (ANCAs) directed against proteinase-3 (PR-3) were 39.2 EU/mL (normal,\4.0 EU/mL). Her absolute neutrophil count nadir was /L. A subsequent urine toxicology screen on hospital day 33 was positive for cocaine, confirming in-hospital cocaine use. Case 2 was a 43-year old female with no medical history who presented with a 2-month history of tender, stellate, purpuric patches and plaques on the bilateral lower extremities and pinna, fixed livedo racemosa on the bilateral posterior upper arms and thighs, and fingernail splinter hemorrhages (Fig 1, D-F ). She used cocaine on a daily basis beginning 1 month before the onset of the skin lesions. Skin biopsy specimens revealed extensive occlusion of small superficial and deeper dermal blood vessels by fibrin thrombi without vasculitis (Fig 1, I ). An absolute neutrophil count was /L. The partial thromboplastin time was elevated at 38.3 seconds. The dsdna, lupus anticoagulant, and anticardiolipin immunoglobulin M tests were positive. An antinuclear antibody titer was negative. ANCAs directed against myeloperoxidase (MPO) were 15.4 EU/mL (negative, \4.0 EU/mL). A urine toxicology

3 Table I. Narrowed differential diagnosis for our patients with description of differentiating clinical and pathologic features Clinical Condition Morphology Timing Distribution Pathologic features Laboratory values Antineutrophil cytoplasmic (ANCA) associated vasculitides Antiphospholipid antibody syndrome Cocaine-induced purpura Palpable purpura, retiform purpura, nodules, ulcers, papulonecrotic lesions, and oral ulcers Variable; livedo 6 retiform purpura, atrophie blanche, leg ulcers, digital gangrene, cutaneous necrosis, splinter hemorrhages, and anetoderma Retiform purpura (current case); ulcers 8 ; persistent erythematous, partially hemorrhagic, infiltrated, confluent wheals 10 ; and palpable purpura 19 MPA can be acutely triggered by drugs/infection WG relapses can be triggered by Staphylococcus aureus carriage CSS skin findings typically not seen until the third phase of the disease and are chronic; can be triggered by infection and leukotriene inhibitors Acute and chronic forms exist Acute in onset Face, extremities, scalp, and oral/nasal mucosa (WG); many systemic associations, predominantly in the lungs and kidneys Livedo reticularis is widespread; atrophie blanche around malleoli; retiform purpura on the upper and lower extremities, ear helices, cheeks, trunk, and forehead; anetoderma on the proximal extremities and trunk Diffuse; face, scalp, trunk, extremities MPA: segmental necrotizing vasculitis of capillaries/venules/ medium-sized vessels; LCV WG: necrotizing granulomatous vasculitis; LCV CSS: eosinophils, extravascular granulomatous inflammation, and necrotizing vasculitis of small- and mediumsized vessels Early lesions show thrombosis of small- and mediumsized dermal vessels LCV and bland thrombosis; diffuse neutrophilic infiltrate; LCV of small vessels only or small- and medium-sized vessels p-anca (anti-mpo, 60%); c-anca (anti-pr3; 30%); check urinalysis for glomerulonephritis c-anca (anti-pr3, 80%); p-anca (anti-mpo, 10%); check urinalysis for glomerulonephritis; 50% have positive rheumatoid factor p-anca (anti-mpo, 55-60%); c-anca (anti-pr3, 10-15%); eosinophilia Positive lupus anticoagulant, anticardiolipin antibody, or anti-b 2 glycoprotein antibody on 2 occasions at least 12 wks apart Urine toxicology; ANCA (anti-pr3; anti-mpo) 532 Letters SEPTEMBER 2010

4 Cryoglobulinemias Mixed (Types II/III) Type I Predominantly palpable purpura Raynaud phenomenon, retiform purpura, livedo, and gangrene DIC Petechiae / ecchymoses / hemorrhagic bullae / gangrene Heparin-induced thrombocytopenia Tender, sharply demarcated retiform purpura Chronic Can be cold-induced, acute Acute and chronic forms exist Typically 5-10 days after starting heparin Lower extremities; also associated with peripheral neuropathy, arthralgias, hepatic disease, and membranoproliferative glomerulonephritis Acral sites ( fingers, toes, and ears) predominate Usually symmetrical on extremities, often distal (ie, lips, ears, nose, and genitals), and on sites of venipuncture/surgery Injection sites or sites distal to infusions, especially lower extremities LCV; direct immunofluorescence shows IgM and/or C3 in vascular pattern in papillary dermis Bland hyaline or red-cell occlusion of vessels, eosinophilic thrombi within small dermal vessels 6 necrosis Fibrin deposits ( red ) clots in dermal vessels; sparse inflammatory infiltrates Platelet deposits ( white ) clots in dermal vessels; Positive for type II/III (mixed) cryoglobulins; association with hepatitis C [[ hepatitis B, HIV; positive rheumatoid factor (70%) Association with underlying plasma cell dyscrasia or lymphoproliferative disorder Elevated prothrombin time/partial thromboplastin time/international Normalized Ratio; low fibrinogen; low platelets; increased fibrin degradation products; schistocytes on peripheral blood smear Thrombocytopenia variable, may be late, NOT necessary for diagnosis; positive platelet factor IV antibody and serotonin release assay Continued VOLUME 63, NUMBER 3 Letters 533

5 Table I. Cont d Clinical Condition Morphology Timing Distribution Pathologic features Laboratory values Septic vasculitis Warfarin skin necrosis Retiform purpura or palpable purpura Erythematous and retiform purpura plaques, hemorrhagic bullae, full-thickness necrosis Typically acute onset Usually predominantly acral Severe pandermal vasculitis (smalland/or medium-sized vessels) with neutrophil and bacteria-containing thrombi, extravascular neutophilia, neutrophilic exocytosis, and papillary dermal edema; may show organism in vessel; may only show thrombotic purpura 3-6 days after starting warfarin Breast, buttocks, and thighs ( favors fatty areas) Fibrin deposits ( red ) clots in dermal vessels; arterial thrombi common Workup for systemic infection Protein C may be relatively low (temporary hypercoagulable state); risk factors include proteins C or S or antithrombin III deficiency 534 Letters ANCA, Antineutrophil cytoplasmic antibody; CSS, Churg-Strauss syndrome; c-anca, cytoplasmic ANCA; DIC, disseminated intravascular coagulation; LCV, leukocytoclastic vasculitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; p-anca, perinuclear ANCA; PR3, proteinase 3; WG, Wegner granulomatosis. SEPTEMBER 2010

6 VOLUME 63, NUMBER 3 Letters 535 screen performed on admission was positive for cocaine, cannabinoids, and opiates. Both patients developed repeated purpuric plaques and persistent neutropenia in the subsequent months coinciding with positive urine toxicology screens, indicating concurrent cocaine use. The differential diagnosis of retiform purpura is broad, but our patients clinical presentations generated a specific differential diagnosis (Table I). Cocaine-induced ANCA-positive vasculitis is typically PR3 (c-anca [ p-anca) positive and most closely resembles Wegener granulomatosis with nasal septal midline destruction and/or acrally distributed palpable purpura with vasculitis of small- and medium-sized dermal vessels. 1-3 Retiform purpura related to cocaine-induced ANCA-positive disease has not been reported. The uniqueness of retiform purpura in the setting of cocaine use insinuated levamisole as a possible culprit, because it is currently a contaminant in more than 70% of the US cocaine supply 4,5 and has been shown to cause agranulocytosis 6 and purpuric eruptions 7,8 in association with lupus anticoagulant positivity and/or c- or p-anca positivity. Complete clinical resolution of skin lesions occurs 2 to 3 weeks after stopping levamisole and serologies normalize within 2 to 14 months. Skin biopsy specimens from purpuric plaques in children given levamisole for nephrotic syndrome reveal thrombotic vasculitis, leukocytoclastic vasculitis, and/or vascular occlusion. 7 The presence of both leukocytoclastic vasculitis and vascular occlusion was noted in case 1 (Fig 1, G and H )and supported the role of levamisole contamination in this case. Life-threatening agranulocytosis and a positive lupus anticoagulant have been recently identified secondary to levamisole adulteration of cocaine. 5,9,10 We acknowledge that our suspicion of levamisole contamination was retrospective. However, detection of levamisole is challenging, because specific testing is necessary but not routinely available; levamisole s half-life is so short (5.6 hours) that only 2% to 5% of the parent drug is detected in urine 9 ; and the sensitivity of available testing is low. Our patients retiform purpura, histopathology, neutropenia, lupus anticoagulant and ANCA positivity, and temporal association with cocaine use are strongly suggestive of exposure to levamisole. Physicians should be aware of the ubiquitous contamination of cocaine with levamisole and the potentially dangerous clinical manifestations of levamisole exposure. Jeanette M. Waller, MD, a Jamison D. Feramisco, MD, PhD, a Lauren Alberta-Wszolek, MD, b Timothy H. McCalmont, MD, a and Lindy P. Fox, MD a Department of Dermatology, a University of California, San Francisco, San Francisco, California, and the Division of Dermatology, b University of Massachusetts Medical School, UMass Memorial Healthcare, Worcester, Massachusetts Drs Waller and Feramisco contributed equally to this work. Funding sources: None. Conflicts of interest: None declared. Published online March 22, Correspondence to: Lindy P. Fox, MD, Department of Dermatology, University of California, San Francisco School of Medicine, 1701 Divisadero St, 3rd Fl, San Francisco, CA foxli@derm.ucsf.edu REFERENCES 1. Trimarchi M, Gregorini G, Facchetti F, Morassi ML, Manfredini C, Maroldi R, et al. Cocaine-induced midline destructive lesions: clinical, radiographic, histopathologic, and serologic features and their differentiation from Wegener granulomatosis. Medicine (Baltimore) 2001;80: Neynaber S, Mistry-Burchardi N, Rust C, Samtleben W, Burgdorf WH, Seitz MA, et al. PR3-ANCA-positive necrotizing multi-organ vasculitis following cocaine abuse. Acta Dermatol Venereol 2008;88: Wiesner O, Russell KA, Lee AS, Jenne DE, Trimarchi M, Gregorini, et al. Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis. Arthritis Rheum 2004;50: US Department of Justice, Drug Enforcement Administration. Cocaine signature program report, January-October Internal document. 5. Hitt E. Cocaine laced with levamisole increasing, poses risk for aganulocytosis. Medscape. Available from: Accessed September 24, Levamisole. In: DRUGDEX system. Greenwood Village, CO: Thomson Healthcare. Available from: com/hcs/librarian. Accessed January 13, Rongioletti F, Ghio L, Ginevri F, Bleidl D, Rinaldi S, Edefonti A, et al. Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol 1999;140: Powell J, Grech H, Holder J. A boy with cutaneous necrosis occurring during treatment with levamisole. Clin Exp Dermatol 2002;27: Zhu NY, Legatt DF, Turner AR. Agranulocytosis after consumption of cocaine adulterated with levamisole. Ann Intern Med 2009;150: King County Web site. Health advisory: agranulocytosis caused by levamisole-contaminated cocaine. July 15, Available from: health/communicable/providers/2009/advisory aspx. Accessed September 24, doi: /j.jaad