Pyoderma gangrenosum and Wegener granulomatosis-like syndrome induced by cocaine

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<ul><li><p>Clinical dermatology Concise report CEDClinical and Experimental Dermatology</p><p>Pyoderma gangrenosum and Wegener granulomatosis-likesyndrome induced by cocaine</p><p>D. Jimenez-Gallo,1 C. Albarran-Planelles,1 M. Linares-Barrios,1 C. Rodrguez-Hernandez,2</p><p>A. Martnez-Rodrguez,1 E. Garca-Moreno2 and R. Bravo-Monge3</p><p>Departments of 1Dermatology and 2Immunology, and 3Emergency Department, Puerta del Mar University Hospital, Cadiz, Spain</p><p>doi:10.1111/ced.12207</p><p>Summary Cocaine abuse is associated with various skin and rheumatological diseases that mimicprimary autoimmune diseases, including retiform purpura with involvement of the</p><p>ears, cocaine-induced midline destructive lesions (CIMDL), and eruptive pyoderma gan-</p><p>grenosum (PG). Previous reports have suggested the use of perinuclear antineutrophil</p><p>cytoplasmic antibodies (pANCA) with specificity against human neutrophil elastase</p><p>(HNE) to differentiate these cocaine-induced diseases from primary autoimmune dis-</p><p>eases. We describe a case of a 54-year-old woman with a history of cocaine abuse, who</p><p>had PG lesions on her legs with accompanying CIMDL and lung lesions similar to those</p><p>seen in Wegener granulomatosis. Detection of HNE-positive pANCA, and improvement</p><p>or clinical recurrence after cessation or consumption of cocaine, respectively, were key</p><p>to differentiating this presentation from primary autoimmune disease.</p><p>Cocaine consumption has been related to a wide vari-</p><p>ety of clinical conditions, including cocaine-induced</p><p>midline destructive lesions (CIMDL),1 cutaneous vascu-</p><p>litis induced by cocaine contaminated with levamisol,2</p><p>and eruptive pyoderma gangrenosum (PG).3 Some of</p><p>these pathologies have been related to the presence of</p><p>peri-nuclear antineutrophil cytoplasmic antibodies</p><p>(pANCA) with specificity against human neutrophil</p><p>elastase (HNE).46 We describe a case of autoimmunity</p><p>due to cocaine, with cutaneous, pulmonary, and ear,</p><p>nose and throat involvement. The primary key for the</p><p>aetiological diagnosis was the detection of HNE-posi-</p><p>tive pANCA.</p><p>Report</p><p>A 54-year-old woman presented with a 2-month</p><p>history of multiple painful ulcers on both legs. During</p><p>this period, she had been treated with topical and oral</p><p>antibiotics with no improvement. Her general health</p><p>was otherwise good, but she reported occasional</p><p>episodes of dry cough and bloody sputum. She had</p><p>been a user of cocaine by inhalation (approximately</p><p>3.5 g/week) for 5 years.</p><p>On physical examination, multiple painful ulcers</p><p>were seen on the patients legs. These were purplish</p><p>in colour, had a cribriform morphology with a</p><p>slightly raised edge, and varied between 10 and</p><p>50 mm in size (Fig. 1a). Each ulcer first developed as</p><p>a pustule, which then developed into an ulcer within</p><p>about 3 days (Fig. 1b). The patient also had a saddle-</p><p>nose nasal deformity, associated with extensive</p><p>oronasal fistula in the palate (Fig. 1c), due to the</p><p>cocaine abuse.</p><p>On histological examination of a biopsy taken from</p><p>the edge of a skin ulcer, a dense inflammatory infil-</p><p>trate was seen in the dermis, with neutrophils and</p><p>fibrin deposits in the vessels (Fig. 2). No granulomas</p><p>or vasculitis were present. Direct immunofluorescence</p><p>gave negative results, as did stains and cultures for</p><p>bacteria, fungi and alcohol-resistant acid bacilli.</p><p>Based on the clinical and histological findings, the</p><p>patient was diagnosed as having PG, and further</p><p>Correspondence: Dr David Jimenez-Gallo, Department of Dermatology,</p><p>Puerta del Mar University Hospital, 21 Ana de Viya Avenue, Cadiz, 11009,</p><p>Spain</p><p>E-mail: davidjimenezgallo@gmail.com</p><p>Conflict of interest: none declared.</p><p>Accepted for publication 27 March 2013</p><p> 2013 British Association of Dermatologists878 Clinical and Experimental Dermatology (2013) 38, pp878882</p></li><li><p>investigations were performed. Chest radiography</p><p>showed pulmonary infiltrates in the middle and lower</p><p>lobes of the right lung, accompanied by an interstitial</p><p>lung pattern (Fig. 3a). Computed tomography (CT) of</p><p>the chest identified bilateral pulmonary nodules and</p><p>cavitation (Fig. 3b), and a facial CT scan showed</p><p>extensive midline destruction associated with the</p><p>oronasal fistula (Fig. 3c).</p><p>Full blood count, coagulation and biochemistry tests</p><p>were normal. Results for the following were negative</p><p>or within normal limits: anti-Sm, anti-RNP, anti-Ro,</p><p>anti-La, anti-Scl70, anticentromere, anti-b2-glycopro-tein, anticardiolipin and antihistone antibodies, anti-</p><p>double-stranded DNA, cryoglobulins, complement lev-</p><p>els, rheumatoid factor, and urine sedimentation tests.</p><p>Investigations for syphilis, hepatitis B and C, human</p><p>immunodeficiency virus and tuberculosis (TB) were</p><p>also negative. Circulating pANCA without specificity</p><p>for myeloperoxidase (MPO) or proteinase (PR)3 was</p><p>found, at a titre of 1 : 80 (Fig. 3d). Because of the</p><p>patients history of cocaine abuse, a specific search</p><p>was performed for atypical ANCAs that were positive</p><p>for elastase. The patient was also positive for antinu-</p><p>clear antibodies, at a titre of 1 : 40.</p><p>Given the pulmonary findings, we conducted fibro-</p><p>bronchoscopy, which did not indicate malignant</p><p>disease, and tested for bacteria, fungi and acid-alcohol</p><p>resistant bacilli. Histology of a lung biopsy showed</p><p>nonspecific interstitial pulmonary disease.</p><p>The final diagnosis was PG and Wegener granulo-</p><p>matosis (WG)-like syndrome induced by cocaine, based</p><p>on destruction of the midline of the nose and palate,</p><p>(a)</p><p>(b) (c)</p><p>Figure 1 Clinical images. (a) Painful violet-edged ulcers on the</p><p>legs; (b) pustule with violet-coloured halo on the leg; (c) saddle-</p><p>nose deformity with palatal oronasal fistula.</p><p>(a) (b)</p><p>Figure 2 (a) Ulceration and deep and dense inflammatory infiltrate; (b) neutrophils in the inflammatory infiltrate associated with fibrin</p><p>deposits in the vessels. Haematoxylin and eosin, original magnification (a) 940 (b) 9200.</p><p> 2013 British Association of Dermatologists Clinical and Experimental Dermatology (2013) 38, pp878882 879</p><p>PG and WG-like syndrome induced by cocaine D. Jimenez-Gallo et al.</p></li><li><p>accompanied by the fixed pulmonary infiltrates and</p><p>bilateral cavitary pulmonary nodules. Cocaine was fur-</p><p>ther implicated as the cause of the illness because of</p><p>the patients clinical improvement or relapse after</p><p>cessation or consumption, respectively, along with an</p><p>increase in pANCA titres to 1 : 160 after cocaine</p><p>abuse and the detection of HNE-specific ANCAs.</p><p>Since the initial presentation, our patient has had</p><p>further and increasingly severe episodes of PG,</p><p>associated with resumption of cocaine abuse. The most</p><p>recent flare was accompanied by significant retiform</p><p>purpura and involvement of the legs and ears. Currently</p><p>the disease is stable with bolus administration of cyclo-</p><p>phosphamide, despite continued cocaine consumption,</p><p>verified by drug-testing of the patients urine.</p><p>An increase in cocaine abuse worldwide is leading</p><p>to a rise in associated pathology.7 Inhalation of</p><p>cocaine can result in nasal inflammation and necrosis</p><p>because of its vasoconstrictor effect, microtraumas</p><p>caused by the cocaine itself and accompanying sub-</p><p>stances, and an increased incidence of infections</p><p>caused by Staphylococcus aureus.1,4 These factors are</p><p>known to cause CIMDL. The main problem arises in</p><p>differentiating CIMDL from primary WG.</p><p>For this purpose, Trimarchi et al.5 evaluated clinical,</p><p>radiological, histopathological and serological findings</p><p>in patients with a diagnosis of WG, and compared</p><p>them with cases of CIMDL. The degree of nasal and</p><p>paranasal destruction was more severe in patients</p><p>with CIMDL; however, lung and kidney involvement</p><p>and destruction of the ears and orbit were more</p><p>common in WG. Compared with CIMDL, WG was</p><p>associated with a higher frequency of fever, malaise,</p><p>arthralgias and myalgias, and also of laboratory</p><p>abnormalities such as increased incidence of acute-</p><p>phase reactants, microhaematuria, proteinuria and</p><p>renal damage. Radiologically, nasal-septum perforation</p><p>and involvement of other nasal structures was more</p><p>frequent in patients with CIMDL. Histologically, the</p><p>presence of nonspecific changes in the biopsies was</p><p>also greater in CIMDL. Biopsies from patients with WG</p><p>showed findings such as microabscesses, granulomas</p><p>or multinucleated giant cells at the extravascular level,</p><p>with deep and localized necrosis.</p><p>An important finding to aid in the differential diagno-</p><p>sis of WG and CIMDL is the presence of ANCAs. The</p><p>antigens of classic ANCA-associated vasculitis are PR3</p><p>and MPO. The presence of PR3 supports the diagnosis of</p><p>(a) (b)</p><p>(c) (d)Figure 3 (a) Radiograph showing the</p><p>presence of pulmonary infiltrates in the</p><p>middle and lower lobes of the right lung.</p><p>(b,c) Computed tomograph scan scan</p><p>showing (b) pulmonary infiltrates in the</p><p>right lung accompanied by a cavitated</p><p>nodule at the lingula of the left lung, and</p><p>(c) extensive destruction of the midline of</p><p>the upper respiratory tract associated</p><p>with an oronasal fistula. (d) Granulocyte</p><p>immunofluorescence fixed in ethanol</p><p>showing a perinuclear pattern of antinu-</p><p>clear cytoplasmic antibodies to elastase</p><p>(original magnification 9600).</p><p> 2013 British Association of Dermatologists880 Clinical and Experimental Dermatology (2013) 38, pp878882</p><p>PG and WG-like syndrome induced by cocaine D. Jimenez-Gallo et al.</p></li><li><p>WG, while MPO is associated with ChurgStrauss gran-ulomatosis and microscopic polyangiitis. pANCA is</p><p>almost always associated with MPO, and cytoplasmic</p><p>ANCA is typically associated with PR3.8 However, there</p><p>are other atypical ANCAs that are also normally associ-</p><p>ated with a perinuclear pattern (i.e. pANCA), for which</p><p>are not performed in routine laboratory immunology.</p><p>Their investigation requires specific suspicion by the cli-</p><p>nician. These atypical ANCAs include HNE, lactoferrin,</p><p>azuricidin, catalase K, bactericidal/permeability-increas-</p><p>ing (BPI) protein, cathepsin G, defensin and lyso-</p><p>zyme.1,5,6 HNE is an atypical ANCA that has been</p><p>structurally and functionally related with PR3 ANCA,</p><p>and for this reason could favour the simulation of WG</p><p>in our patient. HNE ANCA was recently described as a</p><p>marker of CIMDL; however, it is rarely detected in</p><p>patients with WG.46</p><p>The differential diagnosis for midline destructive</p><p>lesions includes, among others, CIMDL, WG, extranodal</p><p>lymphoma, squamous cell carcinoma, midline malig-</p><p>nant reticulosis, TB, syphilis, leishmaniasis, blasto-</p><p>mycosis and actinomycosis.1,9 Another interesting</p><p>detail of this case is the relationship between cocaine</p><p>abuse and development of PG. The two cases described</p><p>by Roche et al.3 in 2008 are the only similar cases</p><p>published to date (Table 1).</p><p>In conclusion, we report a case in which the</p><p>clinical features were triggered by cocaine abuse</p><p>accompanied by a raised titre of HNE ANCA. The</p><p>similarity of these autoantibodies to PR3 ANCA,</p><p>together with the toxic effects of cocaine, could</p><p>explain the destruction of the midline and lung</p><p>lesions simulating WG. The lesions of PG, a neutro-</p><p>philic dermatosis, could also be related to the</p><p>presence of these antibodies. To our knowledge, this</p><p>is only the third case of PG reported, and the first to</p><p>include pulmonary involvement mimicking cocaine-</p><p>induced WG, illustrating the various clinical features</p><p>that produce autoimmunity related to this drug. The</p><p>raised titre of elastase ANCAs seemed to be related to</p><p>the cocaine abuse and worsening of the PG in this</p><p>case. This case highlights the importance of HNE</p><p>ANCA for diagnosis, and the incorporation of cocaine</p><p>abuse in the aetiology of PG.</p><p>Learning points</p><p> Retiform purpura, destruction of the midline,and PG are syndromes associated with cocaine</p><p>consumption.</p><p> pANCA with specificity against HNE is a mar-ker of dermatological and rheumatic diseases</p><p>induced by cocaine.</p><p> Clinicoimmunological correlation allows differ-entiation of WG from the clinical syndrome</p><p>induced by cocaine.</p><p> Cocaine should be considered in the list ofcauses of PG.</p><p> Cessation of cocaine abuse is the most effectivetreatment, but cyclophosphamide may be useful</p><p>if the patient continues to use the drug.</p><p>References</p><p>1 Stahelin L, Fialho SC, Neves FS et al. Cocaine-induced</p><p>midline destruction lesions with positive ANCA test</p><p>mimicking Wegeners granulomatosis. Rev Bras Reumatol</p><p>2012; 52: 4347.</p><p>Table 1 Features of documented cases of pyoderma gangrenosum (PG) associated with cocaine use.</p><p>Source</p><p>Gender/age,</p><p>years</p><p>Cocaine</p><p>consumption,</p><p>years</p><p>Predominant</p><p>location of PG ANCA Effective treatment</p><p>Accompanying</p><p>symptoms</p><p>Roche et al.,</p><p>20083M/30 2 Back Negative Infliximab 5 mg/kg at weeks 0, 2, and 6</p><p>followed by infusion every 8 weeks,</p><p>accompanied by methotrexate</p><p>15 mg/week</p><p>None</p><p>M/38 10 Back Negative Infliximab 5 mg/kg at weeks 0, 2, and 6</p><p>followed by infusion every 8 weeks,</p><p>accompanied by topical tacrolimus.</p><p>None</p><p>Present case F/54 5 Legs HNE ANCA</p><p>positive</p><p>Cyclophosphamide bolus of 15 mg/kg</p><p>every 2 weeks (3 pulses) followed by</p><p>15 mg/kg every 3 weeks (6 pulses)</p><p>Destruction of midline,</p><p>presence of retiform</p><p>purpura and lung</p><p>involvement</p><p>ANCA, antineutrophil cytoplasmic antibodies; HNE, human neutrophil elastase.</p><p> 2013 British Association of Dermatologists Clinical and Experimental Dermatology (2013) 38, pp878882 881</p><p>PG and WG-like syndrome induced by cocaine D. Jimenez-Gallo et al.</p></li><li><p>2 Ullrich K, Koval R, Koval E et al. Five consecutive cases of a</p><p>cutaneous vasculopathy in users of levamisole-adulterated</p><p>cocaine. J Clin Rheumatol 2011; 17: 1936.3 Roche E, Martnez-Menchon T, Sanchez-Carazo JL et al.</p><p>Two cases of eruptive pyoderma gangrenosum associated</p><p>with cocaine use. Actas Dermosifiliogr 2008; 99: 72730.</p><p>4 Rachapalli SM, Kiely PD. Cocaine-induced midline</p><p>destructive lesions mimicking ENT-limited Wegeners</p><p>granulomatosis. Scand J Rheumatol 2008; 37: 47780.</p><p>5 Trimarchi M, Gregorini G, Facchetti F et al.</p><p>Cocaine-induced midline destructive lesions: clinical,</p><p>radiographic, histopathologic, and serologic features and</p><p>their differentiation from Wegener granulomatosis.</p><p>Medicine (Baltimore) 2001; 80: 391404.</p><p>6 Wiesner O, Russell KA, Lee AS et al. Antineutrophil</p><p>cytoplasmic antibodies reacting with human neutrophil</p><p>elastase as a diagnostic marker for cocaine-induced</p><p>midline destructive lesions but not autoimmune vasculitis.</p><p>Arthritis Rheum 2004; 50: 295465.7 Salas-Espndola Y, Peniche-Castellanos A, Lopez-Gehrke</p><p>I, Mercadillo-Perez P. Leukocytoclastic vasculitis related</p><p>to cocaine use. Actas Dermosifiliogr 2011; 102: 8257.8 Walsh NM, Green PJ, Burlingame RW et al. Cocaine-related</p><p>retiform purpura: evidence to incriminate the adulterant,</p><p>levamisole. J Cutan Pathol 2010; 37: 121219.9 Daggett RB, Haghighi P, Terkeltaub RA. Nasal cocaine</p><p>abuse causing an aggressive midline intranasal and</p><p>pharyngeal destructive process mimicking midline</p><p>reticulosis and limited Wegeners granulomatosis. J</p><p>Rheumatol 1990; 17: 83840.</p><p> 2013 British Association of Dermatologists882 Clinical and Experimental Dermatology (2013) 38, pp878882</p><p>PG and WG-like syndrome induced by cocaine D. Jimenez-Gallo et al.</p></li></ul>

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