Levamisole-induced vasculitis is a characteristic cutaneous vasculitis syndrome associated with the use of levamisole-adulterated cocaine. Patients will typically present with a painful, purpuric rash in a retiform or stellate pattern with or without central necrosis involving the extremities, trunk, nasal tip, digits, cheeks, and/or ears. A history of cocaine abuse can be elicited. Histologic features include microvascular thrombi and/or leukocytoclastic vasculitis involving small vessels of the superficial and deep dermis. Epidermal involvement is variably seen. Laboratory findings include leukopenia, neutropenia (including agranulocytosis), elevated erythrocyte sedimentation rate, normal coagulation studies, and positive autoantibodies including perinuclear and cytoplasmic antineutrophil cytoplasmic antibodies, antinuclear antibody, and lupus anticoagulant. Differential diagnosis includes other microscopic vasculitides, and clinical and laboratory correlation with histologic findings is essential. Lesions typically resolve with the cessation of cocaine use. Because of the treatment implications and rising incidence of this entity, rapid and accurate diagnosis is essential.
Levamisole is a veterinary antihelminthic drug that, in the past, was a US Food and Drug Administration–approved drug in humans used to treat various cancers and rheumatoid arthritis because of its immunomodulating effects.1,2 The Food and Drug Administration banned the use of levamisole in the United States in 2000 because of adverse side effects including agranulocytosis and vasculitis.3,4 However, reports began surfacing around late 2009 and early 2010 about a characteristic cutaneous vasculitis found in cocaine users associated with neutropenia and positive antineutrophil cytoplasmic antibodies (ANCAs).5–10 Soon after, researchers isolated levamisole using urine toxicology and gas chromatography–mass spectrometry studies in patients with suspected levamisole-induced vasculitis, confirming prior suspicions that it was in fact the etiologic agent.11,12 Approximately 70% of the cocaine in the United States contains levamisole, which is used to add volume and weight to the drug and possibly to potentiate the psychotropic effects of cocaine.3,13,14 Levamisole has been detected in cocaine since 2003, and detection has only increased in recent years.14,15 Levamisole-induced vasculitis was originally described in 1978 in a patient being treated for rheumatoid arthritis and has been described in children receiving treatment for nephrotic syndrome.2,4 However, because levamisole is no longer in clinical use, the reported cases today are exclusively from users of levamisole-adulterated cocaine. Because of the unique clinical picture and treatment implications, pathologists should be aware of this diagnostic entity.
Levamisole-induced vasculitis has predilection for women (male to female ratio, 1:3) with mean age of presentation of 44 years.12 Patients typically present with a tender, purpuric rash in a retiform or stellate pattern with or without central necrosis involving the extremities, trunk, nasal tip, digits, cheeks, and/or ears (Figure 1).7,16 Bulla formation is not uncommon and, with subsequent skin sloughing, bacterial superinfection can increase morbidity.12 Lesions of the ear and digits have been reported to self-amputate.12 In addition to the cutaneous manifestations, laboratory findings include leukopenia, neutropenia (including agranulocytosis), elevated erythrocyte sedimentation rate, normal coagulation studies, and positive autoantibodies including perinuclear and cytoplasmic ANCAs (p- and c-ANCAs), antinuclear antibody, and lupus anticoagulant.7,11,17
The two classic pathologic findings include (1) leukocytoclastic vasculitis of small vessels consisting of fibrinoid necrosis of the vessel wall, extravasated erythrocytes, karyorrhectic debris, and angiocentric inflammation and (2) multiple fibrin thrombi within small vessels in the superficial and deep dermis (Figures 2 through 5). Classically, both of these histologic findings are present; however, it is not uncommon to have only one or the other present. The presence of microvascular fibrin thrombi appears to be the most consistent histologic feature.7,12 Some authors have purported that the presence of both microvascular fibrin thrombi and leukocytoclastic vasculitis may be relatively specific for levamisole-induced vasculitis.11 Fibrin thrombi may show a spectrum of early fibrinous plugs to well-organized fibrous thrombi, reflecting the repeated insults from chronic levamisole-adulterated cocaine use.11 The epidermis may or may not show changes depending on the location of the biopsy. Epidermal changes, if present, include suprabasilar bulla formation, full-thickness epidermal necrosis, and ulceration.6,11,16,18 Some authors have described extensive interstitial and perivascular neovascularization; however, this finding is rarely seen.18 Bone marrow biopsies for patients with the additional clinical finding of agranulocytosis show myeloid hypoplasia, mild megakaryocyte hyperplasia, and increased bone marrow plasma cells with circulating plasmacytoid lymphocytes in the peripheral blood, all of which can be helpful in distinguishing cocaine-related versus non–cocaine-related causes of agranulocytosis.17,19
The exact pathogenesis of levamisole-induced vasculitis is currently uncertain.7,12,20 An immune complex–mediated process is the favored hypothesis based on immunofluorescence studies in the skin.6,7 For the agranulocytosis, studies have suggested that levamisole may act as a hapten causing formation of antibodies to various leukocyte antigens, leading to opsonization and subsequent destruction of neutrophils, and may also account for the development of autoantibodies.19,21
Laboratory findings in patients with levamisole-induced vasculitis include leukopenia (leukocyte count <4000/μL), neutropenia (neutrophil count <1500/μL), agranulocytosis (neutrophil count <500/μL), elevated erythrocyte sedimentation rate, normal coagulation studies, and positive autoantibodies including p- and c-ANCAs, anti-nuclear antibody, and lupus anticoagulant. The specificity of the ANCA involved can be useful in differentiating among other vasculitides such as granulomatous polyangiitis (formerly Wegener granulomatosis), microscopic polyangiitis, and Churg-Strauss granulomatosis. By indirect immunofluorescence, two classic patterns are seen on cytospin-prepared, ethanol-fixed neutrophils.22 Anti-neutrophil cytoplasmic antibodies directed against proteinase 3 produce a cytoplasmic pattern reflected in the term c-ANCA. Anti-neutrophil cytoplasmic antibodies directed against myeloperoxidase typically produce a perinuclear pattern (p-ANCA).23 Results of indirect immunofluorescence are confirmed by the performance of antigen-specific immunoassays for proteinase 3 and myeloperoxidase ANCAs.23 The presence of c-ANCA is usually seen in granulomatous polyangiitis, and p-ANCA is usually seen in microscopic polyangiitis. However, so-called atypical ANCAs exist because of other neutrophil granule constituents (including human neutrophil elastase, azurocidin, lactoferrin, and lysozyme), which cause inconsistent fluorescence patterns.24 Elevated levels of antibodies against human neutrophil elastase have been strongly associated with cocaine-induced lesions.25 Thus, antibody specificities of ANCAs may play a discriminatory role in the diagnosis of levamisole-induced vasculitis.11,25 Lastly, the half-life of levamisole is 5.6 hours, and it can be detected by gas chromatography–mass spectrometry, although this is not necessary for diagnosis.26 Screening for cocaine use can be accomplished through a urine enzyme immunoassay, which typically detects cocaine metabolites benzoylecgonine and m-hydroxybenzoylecgonine. Confirmation of cocaine use is typically performed using a quantitative gas chromatography–mass spectrometry or quantitative liquid chromatography–tandem mass spectrometry test to quantify the cocaine metabolite benzoylecgonine in samples of urine, serum, or plasma. Testing for levamisole has been performed using mass spectrometry,13 but is not required because of the high prevalence of levamisole in cocaine and the fact that the diagnosis can be made in the context of the other clinical, pathologic, and laboratory findings.
The differential diagnosis includes ANCA-associated vasculitides (granulomatous polyangiitis, microscopic polyangiitis, Churg-Strauss syndrome), septic vasculitis, disseminated intravascular coagulation, cryoglobulinemia, warfarin-induced skin necrosis, and heparin-induced thrombocytopenia.6,7 All of these can present clinically with palpable, retiform purpura similar to that seen in levamisole-induced vasculitis. Granulomatous polyangiitis typically shows small vessel vasculitis with poorly formed granulomatous inflammation. Microvascular fibrin thrombi can also be seen. Clinically, patients will often have lung and/or kidney involvement. Antibodies against c-ANCA with anti–proteinase 3 specificity are usually seen. Microscopic polyangiitis will show small vessel leukocytoclastic vasculitis, and patients usually have renal involvement, with p-ANCA antibodies (with antimyeloperoxidase specificity) identified. Churg-Strauss usually presents in young adults and shows a mixed inflammatory small vessel vasculitis with numerous eosinophils, neutrophils, and granulomatous inflammation. It is strongly associated with asthma and peripheral eosinophilia. It is important to recognize that there is a great deal of histologic overlap between the microscopic vasculitides and clinical correlation is essential for accurate diagnosis.
CURRENT TREATMENT AND PROGNOSIS
The ideal treatment for levamisole-induced vasculitis has not been determined; however, nearly all cases resolve upon the cessation of cocaine use.7,11,12 The role of corticosteroids is not well defined; these have not definitively been shown to improve or accelerate healing.7,11,27 Use of plasmapheresis has been investigated but only in case reports.27 Some patients develop bacterial superinfection of the lesions after rupture of bullae, leading to complications such as extensive wound infections requiring surgical debridement and subsequent skin grafting.12,27 This is further exacerbated by the fact that neutropenia and leukopenia is common in these patients, causing an induced immune-suppressed state. There are some reports of patients with such severe wounds that they necessitate amputation.9,12 Because of the strong association with neutropenia and risk of bacterial infections of wounds, it may be prudent to avoid corticosteroids because of the immunosuppressive effects and the paucity of data related to their effectiveness. This is where it is critical for pathologists to be aware of this entity so that the correct treatment regimen can be started earlier rather than later in an effort to avoid the aforementioned morbid sequelae. This is especially true considering entities in the differential diagnosis are generally treated with corticosteroids.
In summary, levamisole-induced vasculitis is a cutaneous vasculitis syndrome associated with the use of levamisole-adulterated cocaine. Patients will typically present with a painful, purpuric rash in a retiform or stellate pattern with or without central necrosis involving the extremities, trunk, nasal tip, digits, cheeks, and/or ears. A history of cocaine abuse can be elicited. Characteristic histologic features include microvascular thrombi and/or leukocytoclastic vasculitis involving small vessels of the superficial and deep dermis, with fibrin thrombi the most consistent finding. Epidermal involvement is variably seen depending on the location of the biopsy. Laboratory studies can show leukopenia, neutropenia (including agranulocytosis), elevated erythrocyte sedimentation rate, normal coagulation studies, and positive autoantibodies including p- and c-ANCA, anti-nuclear antibody, and lupus anticoagulant. The differential diagnosis encompasses other microscopic vasculitides including granulomatous polyangiitis (formerly known as Wegener granulomatosis), microscopic polyangiitis, and Churg-Strauss syndrome. Therefore, clinical and laboratory correlation with histologic findings is essential for diagnosis and treatment (Table). Resolution of symptoms is seen with the cessation of cocaine use. Because of the treatment implications and increasing incidence of this entity, rapid and accurate diagnosis is essential.
The authors have no relevant financial interest in the products or companies described in this article.