pyoderma gangrenosum and wegener granulomatosis-like syndrome induced by cocaine

Clinical dermatology • Concise report CEDClinical and Experimental Dermatology

Pyoderma gangrenosum and Wegener granulomatosis-likesyndrome induced by cocaine

D. Jim�enez-Gallo,1 C. Albarr�an-Planelles,1 M. Linares-Barrios,1 C. Rodr�ıguez-Hern�andez,2

A. Mart�ınez-Rodr�ıguez,1 E. Garc�ıa-Moreno2 and R. Bravo-Monge3

Departments of 1Dermatology and 2Immunology, and 3Emergency Department, Puerta del Mar University Hospital, Cadiz, Spain

doi:10.1111/ced.12207

Summary Cocaine abuse is associated with various skin and rheumatological diseases that mimic

primary autoimmune diseases, including retiform purpura with involvement of the

ears, cocaine-induced midline destructive lesions (CIMDL), and eruptive pyoderma gan-

grenosum (PG). Previous reports have suggested the use of perinuclear antineutrophil

cytoplasmic antibodies (pANCA) with specificity against human neutrophil elastase

(HNE) to differentiate these cocaine-induced diseases from primary autoimmune dis-

eases. We describe a case of a 54-year-old woman with a history of cocaine abuse, who

had PG lesions on her legs with accompanying CIMDL and lung lesions similar to those

seen in Wegener granulomatosis. Detection of HNE-positive pANCA, and improvement

or clinical recurrence after cessation or consumption of cocaine, respectively, were key

to differentiating this presentation from primary autoimmune disease.

Cocaine consumption has been related to a wide vari-

ety of clinical conditions, including cocaine-induced

midline destructive lesions (CIMDL),1 cutaneous vascu-

litis induced by cocaine contaminated with levamisol,2

and eruptive pyoderma gangrenosum (PG).3 Some of

these pathologies have been related to the presence of

peri-nuclear antineutrophil cytoplasmic antibodies

(pANCA) with specificity against human neutrophil

elastase (HNE).4–6 We describe a case of autoimmunity

due to cocaine, with cutaneous, pulmonary, and ear,

nose and throat involvement. The primary key for the

aetiological diagnosis was the detection of HNE-posi-

tive pANCA.

Report

A 54-year-old woman presented with a 2-month

history of multiple painful ulcers on both legs. During

this period, she had been treated with topical and oral

antibiotics with no improvement. Her general health

was otherwise good, but she reported occasional

episodes of dry cough and bloody sputum. She had

been a user of cocaine by inhalation (approximately

3.5 g/week) for 5 years.

On physical examination, multiple painful ulcers

were seen on the patient’s legs. These were purplish

in colour, had a cribriform morphology with a

slightly raised edge, and varied between 10 and

50 mm in size (Fig. 1a). Each ulcer first developed as

a pustule, which then developed into an ulcer within

about 3 days (Fig. 1b). The patient also had a saddle-

nose nasal deformity, associated with extensive

oronasal fistula in the palate (Fig. 1c), due to the

cocaine abuse.

On histological examination of a biopsy taken from

the edge of a skin ulcer, a dense inflammatory infil-

trate was seen in the dermis, with neutrophils and

fibrin deposits in the vessels (Fig. 2). No granulomas

or vasculitis were present. Direct immunofluorescence

gave negative results, as did stains and cultures for

bacteria, fungi and alcohol-resistant acid bacilli.

Based on the clinical and histological findings, the

patient was diagnosed as having PG, and further

Correspondence: Dr David Jim�enez-Gallo, Department of Dermatology,

Puerta del Mar University Hospital, 21 Ana de Viya Avenue, Cadiz, 11009,

Spain

E-mail: [email protected]

Conflict of interest: none declared.

Accepted for publication 27 March 2013

ª 2013 British Association of Dermatologists878 Clinical and Experimental Dermatology (2013) 38, pp878–882

investigations were performed. Chest radiography

showed pulmonary infiltrates in the middle and lower

lobes of the right lung, accompanied by an interstitial

lung pattern (Fig. 3a). Computed tomography (CT) of

the chest identified bilateral pulmonary nodules and

cavitation (Fig. 3b), and a facial CT scan showed

extensive midline destruction associated with the

oronasal fistula (Fig. 3c).

Full blood count, coagulation and biochemistry tests

were normal. Results for the following were negative

or within normal limits: anti-Sm, anti-RNP, anti-Ro,

anti-La, anti-Scl70, anticentromere, anti-b2-glycopro-tein, anticardiolipin and antihistone antibodies, anti-

double-stranded DNA, cryoglobulins, complement lev-

els, rheumatoid factor, and urine sedimentation tests.

Investigations for syphilis, hepatitis B and C, human

immunodeficiency virus and tuberculosis (TB) were

also negative. Circulating pANCA without specificity

for myeloperoxidase (MPO) or proteinase (PR)3 was

found, at a titre of 1 : 80 (Fig. 3d). Because of the

patient’s history of cocaine abuse, a specific search

was performed for atypical ANCAs that were positive

for elastase. The patient was also positive for antinu-

clear antibodies, at a titre of 1 : 40.

Given the pulmonary findings, we conducted fibro-

bronchoscopy, which did not indicate malignant

disease, and tested for bacteria, fungi and acid-alcohol

resistant bacilli. Histology of a lung biopsy showed

nonspecific interstitial pulmonary disease.

The final diagnosis was PG and Wegener granulo-

matosis (WG)-like syndrome induced by cocaine, based

on destruction of the midline of the nose and palate,

(a)

(b) (c)

Figure 1 Clinical images. (a) Painful violet-edged ulcers on the

legs; (b) pustule with violet-coloured halo on the leg; (c) saddle-

nose deformity with palatal oronasal fistula.

(a) (b)

Figure 2 (a) Ulceration and deep and dense inflammatory infiltrate; (b) neutrophils in the inflammatory infiltrate associated with fibrin

deposits in the vessels. Haematoxylin and eosin, original magnification (a) 940 (b) 9200.

ª 2013 British Association of Dermatologists Clinical and Experimental Dermatology (2013) 38, pp878–882 879

PG and WG-like syndrome induced by cocaine � D. Jim�enez-Gallo et al.

accompanied by the fixed pulmonary infiltrates and

bilateral cavitary pulmonary nodules. Cocaine was fur-

ther implicated as the cause of the illness because of

the patient’s clinical improvement or relapse after

cessation or consumption, respectively, along with an

increase in pANCA titres to 1 : 160 after cocaine

abuse and the detection of HNE-specific ANCAs.

Since the initial presentation, our patient has had

further and increasingly severe episodes of PG,

associated with resumption of cocaine abuse. The most

recent flare was accompanied by significant retiform

purpura and involvement of the legs and ears. Currently

the disease is stable with bolus administration of cyclo-

phosphamide, despite continued cocaine consumption,

verified by drug-testing of the patient’s urine.

An increase in cocaine abuse worldwide is leading

to a rise in associated pathology.7 Inhalation of

cocaine can result in nasal inflammation and necrosis

because of its vasoconstrictor effect, microtraumas

caused by the cocaine itself and accompanying sub-

stances, and an increased incidence of infections

caused by Staphylococcus aureus.1,4 These factors are

known to cause CIMDL. The main problem arises in

differentiating CIMDL from primary WG.

For this purpose, Trimarchi et al.5 evaluated clinical,

radiological, histopathological and serological findings

in patients with a diagnosis of WG, and compared

them with cases of CIMDL. The degree of nasal and

paranasal destruction was more severe in patients

with CIMDL; however, lung and kidney involvement

and destruction of the ears and orbit were more

common in WG. Compared with CIMDL, WG was

associated with a higher frequency of fever, malaise,

arthralgias and myalgias, and also of laboratory

abnormalities such as increased incidence of acute-

phase reactants, microhaematuria, proteinuria and

renal damage. Radiologically, nasal-septum perforation

and involvement of other nasal structures was more

frequent in patients with CIMDL. Histologically, the

presence of nonspecific changes in the biopsies was

also greater in CIMDL. Biopsies from patients with WG

showed findings such as microabscesses, granulomas

or multinucleated giant cells at the extravascular level,

with deep and localized necrosis.

An important finding to aid in the differential diagno-

sis of WG and CIMDL is the presence of ANCAs. The

antigens of classic ANCA-associated vasculitis are PR3

and MPO. The presence of PR3 supports the diagnosis of

(a) (b)

(c) (d)Figure 3 (a) Radiograph showing the

presence of pulmonary infiltrates in the

middle and lower lobes of the right lung.

(b,c) Computed tomograph scan scan

showing (b) pulmonary infiltrates in the

right lung accompanied by a cavitated

nodule at the lingula of the left lung, and

(c) extensive destruction of the midline of

the upper respiratory tract associated

with an oronasal fistula. (d) Granulocyte

immunofluorescence fixed in ethanol

showing a perinuclear pattern of antinu-

clear cytoplasmic antibodies to elastase

(original magnification 9600).



WG, while MPO is associated with Churg–Strauss gran-ulomatosis and microscopic polyangiitis. pANCA is

almost always associated with MPO, and cytoplasmic

ANCA is typically associated with PR3.8 However, there

are other atypical ANCAs that are also normally associ-

ated with a perinuclear pattern (i.e. pANCA), for which

are not performed in routine laboratory immunology.

Their investigation requires specific suspicion by the cli-

nician. These atypical ANCAs include HNE, lactoferrin,

azuricidin, catalase K, bactericidal/permeability-increas-

ing (BPI) protein, cathepsin G, defensin and lyso-

zyme.1,5,6 HNE is an atypical ANCA that has been

structurally and functionally related with PR3 ANCA,

and for this reason could favour the simulation of WG

in our patient. HNE ANCA was recently described as a

marker of CIMDL; however, it is rarely detected in

patients with WG.4–6

The differential diagnosis for midline destructive

lesions includes, among others, CIMDL, WG, extranodal

lymphoma, squamous cell carcinoma, midline malig-

nant reticulosis, TB, syphilis, leishmaniasis, blasto-

mycosis and actinomycosis.1,9 Another interesting

detail of this case is the relationship between cocaine

abuse and development of PG. The two cases described

by Roche et al.3 in 2008 are the only similar cases

published to date (Table 1).

In conclusion, we report a case in which the

clinical features were triggered by cocaine abuse

accompanied by a raised titre of HNE ANCA. The

similarity of these autoantibodies to PR3 ANCA,

together with the toxic effects of cocaine, could

explain the destruction of the midline and lung

lesions simulating WG. The lesions of PG, a neutro-

philic dermatosis, could also be related to the

presence of these antibodies. To our knowledge, this

is only the third case of PG reported, and the first to

include pulmonary involvement mimicking cocaine-

induced WG, illustrating the various clinical features

that produce autoimmunity related to this drug. The

raised titre of elastase ANCAs seemed to be related to

the cocaine abuse and worsening of the PG in this

case. This case highlights the importance of HNE

ANCA for diagnosis, and the incorporation of cocaine

abuse in the aetiology of PG.

Learning points

● Retiform purpura, destruction of the midline,

and PG are syndromes associated with cocaine

consumption.

● pANCA with specificity against HNE is a mar-

ker of dermatological and rheumatic diseases

induced by cocaine.

● Clinicoimmunological correlation allows differ-

entiation of WG from the clinical syndrome

induced by cocaine.

● Cocaine should be considered in the list of

causes of PG.

● Cessation of cocaine abuse is the most effective

treatment, but cyclophosphamide may be useful

if the patient continues to use the drug.

References

1 Stahelin L, Fialho SC, Neves FS et al. Cocaine-induced

midline destruction lesions with positive ANCA test

mimicking Wegener’s granulomatosis. Rev Bras Reumatol

2012; 52: 434–7.

Table 1 Features of documented cases of pyoderma gangrenosum (PG) associated with cocaine use.

Source

Gender/age,

years

Cocaine

consumption,

years

Predominant

location of PG ANCA Effective treatment

Accompanying

symptoms

Roche et al.,

20083M/30 2 Back Negative Infliximab 5 mg/kg at weeks 0, 2, and 6

followed by infusion every 8 weeks,

accompanied by methotrexate

15 mg/week

None

M/38 10 Back Negative Infliximab 5 mg/kg at weeks 0, 2, and 6

followed by infusion every 8 weeks,

accompanied by topical tacrolimus.

None

Present case F/54 5 Legs HNE ANCA

positive

Cyclophosphamide bolus of 15 mg/kg

every 2 weeks (3 pulses) followed by

15 mg/kg every 3 weeks (6 pulses)

Destruction of midline,

presence of retiform

purpura and lung

involvement

ANCA, antineutrophil cytoplasmic antibodies; HNE, human neutrophil elastase.

ª 2013 British Association of Dermatologists Clinical and Experimental Dermatology (2013) 38, pp878–882 881


2 Ullrich K, Koval R, Koval E et al. Five consecutive cases of a

cutaneous vasculopathy in users of levamisole-adulterated

cocaine. J Clin Rheumatol 2011; 17: 193–6.3 Roche E, Mart�ınez-Mench�on T, S�anchez-Carazo JL et al.

Two cases of eruptive pyoderma gangrenosum associated

with cocaine use. Actas Dermosifiliogr 2008; 99: 727–30.

4 Rachapalli SM, Kiely PD. Cocaine-induced midline

destructive lesions mimicking ENT-limited Wegener’s

granulomatosis. Scand J Rheumatol 2008; 37: 477–80.

5 Trimarchi M, Gregorini G, Facchetti F et al.

Cocaine-induced midline destructive lesions: clinical,

radiographic, histopathologic, and serologic features and

their differentiation from Wegener granulomatosis.

Medicine (Baltimore) 2001; 80: 391–404.

6 Wiesner O, Russell KA, Lee AS 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: 2954–65.7 Salas-Esp�ındola Y, Peniche-Castellanos A, L�opez-Gehrke

I, Mercadillo-P�erez P. Leukocytoclastic vasculitis related

to cocaine use. Actas Dermosifiliogr 2011; 102: 825–7.8 Walsh NM, Green PJ, Burlingame RW et al. Cocaine-related

retiform purpura: evidence to incriminate the adulterant,

levamisole. J Cutan Pathol 2010; 37: 1212–19.9 Daggett RB, Haghighi P, Terkeltaub RA. Nasal cocaine

abuse causing an aggressive midline intranasal and

pharyngeal destructive process mimicking midline

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pyoderma gangrenosum and wegener granulomatosis-like syndrome induced by cocaine

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