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Levamisole-induced vasculitis develops in patients exposed to cocaine that has been adulterated or “cut” with levamisole. Characteristic physical exam findings, history, and laboratory data may help clinicians differentiate this entity from other vasculitides and therefore help with long-term management of this potentially recurrent problem.

Patients who develop levamisole-induced vasculitis present with purpuric macules and papules, retiform purpura, and skin necrosis characteristically localized to the helices and lobes of the ears, the nasal tip, the digits, and the cheeks (See Figure 1). Patients may also have evidence of systemic autoimmunity and may complain of constitutional symptoms such as night sweats, fevers, malaise, and arthralgias.

Figure 1.

Purpura and necrosis of the cheeks, ears, and nose in a patient with levamisole vasculitis/vasculopathy.


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Histopathology is paramount to the diagnosis of any type of vasculitis. In levamisole-induced vasculitis, biopsy specimens may demonstrate necrosis and inflammation of vessel walls, with red blood cell extravasation, karyorrhexis, and fibrin microthrombi within small vessels in the superficial and deep dermis.

Basic laboratory testing to evaluate vasculitis should be sent, including a complete blood count, a complete metabolic panel, and a urinalysis. Patients may have anemia, leukopenia, and neutropenia. Urinalysis may demonstrate proteinuria and hematuria. Depending on the clinical situation, clinicians may choose to broaden the workup for vasculitis, especially since levamisole-induced vasculitis should be a diagnosis of exclusion.

Urine drug testing is recommended for any patient presenting with clinical findings concerning for levamisole-induced vasculitis. Clinicians should obtain a urine specimen as soon as possible to test for the presence of cocaine. Testing for urine levamisole is not recommended; such testing requires specialized equipment, and the drug has a short half-life (5-6 hours), with only a small amount excreted in the urine. Of note, the presence or absence of cocaine in the urine does not definitively confirm or exclude the diagnosis of levamisole-induced vasculitis.

Autoantibody testing in levamisole-induced vasculitis is often positive for myeloperoxidase (MPO)-antineutrophilic cytoplasmic antibody (ANCA) and proteinase 3-ANCA. This double positivity for MPO and PR3 in a patient with typical cutaneous findings suggests levamisole-induced vasculitis, whereas single positive results and clinical history may suggest alternate diagnoses such as granulomatosis with polyangiitis or microscopic polyangiitis. Patients who develop skin complications of levamisole may also have higher rates of positive results when testing for anti-phospholipid antibodies.

In summary, patients who present with characteristic cutaneous findings, with or without constitutional symptoms and neutropenia, should prompt suspicion and workup for levamisole-induced vasculitis.

Who is at Risk for Developing this Disease?

Any person who uses cocaine is at risk for developing levamisole-induced vasculitis. Since its presence in cocaine was first documented in the United States in 2003, and soon thereafter in Europe and Canada, the percent of cocaine cut with levamisole has steadily increased. According to the United States Drug Enforcement Agency, before 2008 less than 10% of tested, wholesale-level cocaine contained levamisole, whereas by 2009 approximately 71% of tested cocaine samples were positive for the drug. Although the numbers reported in European countries vary, the trend is similar.

Levamisole is an antihelminthic drug with anti-inflammatory and immunomodulatory properties used primarily in veterinary medicine. It has been used for cancer therapy in humans, and in dermatology it has been used for leprosy, collagen vascular disease, recalcitrant warts, and lichen planus, among other conditions. Complications such as agranulocytosis and vasculitis were reported in the 1970s among patients taking levamisole for inflammatory conditions. It was removed from markets in the United States in 1999 but remains widely available, even without a prescription, in some countries (See Figure 2).

The reason levamisole is added to cocaine is unclear, but it may be related to an amphetamine-like substance called aminorex, which is a metabolite of levamisole. Aminorex has activity on serotonin, norepinephrine, and dopamine transporters, with a half-life greater than that of cocaine. This metabolite may potentiate the effect of cocaine. Other research suggests that levamisole may increase endogenous opioid release or act through nicotinic receptors to increase the release of norepinephrine.

Epidemiologic studies suggest that women who use cocaine may be more susceptible to developing levamisole-induced vasculitis. However, both men and women are at risk, and ages ranging from 18-64 are noted in case series.

What is the Cause of the Disease?

The pathophysiology of levamisole-induced autoimmunity is incompletely characterized. Recent work suggests that levamisole promotes neutrophils to undergo a specific type of cell death characterized by extrusion of granule proteins bound to chromatin and other nuclear materials. These complexes contain the major antigenic targets of autoantibodies and may be triggered by the interaction of levamisole with a muscarinic receptor on neutrophils. It is thought that these complexes may be directly toxic to vascular endothelium and contribute to the vascular pathology seen in levamisole-induced vasculitis.

Systemic Implications and Complications

Patients with levamisole-induced vasculitis may demonstrate symptoms of systemic autoimmunity. These patients may present with fever, weight loss, fatigue, and arthralgias. They may be profoundly neutropenic or anemic. An abnormal urinalysis can be indicative of renal complications. This possibility must be evaluated thoroughly, as renal abnormalities, including glomerulonephritis progressing to end stage renal disease, are reported among patients with levamisole-induced vasculitis.

Treatment Options

Treatment options include:

  • In the acute setting, primary management consists of supportive care, including wound care, fluid resuscitation, and antibiotics, if indicated. Affected patients can be profoundly immunosuppressed and may have extensive skin complications, with ulceration.

  • The use of systemic corticosteroids is not well established but can be considered, particularly in the setting of systemic manifestations or progressive cutaneous disease.

  • Surgical consultation may be necessary in cases of extensive skin ulceration.

  • The role of filgrastim in the management of levamisole-induced neutropenia is unknown; patients tend to have count recovery within five to ten days regardless of treatment.

  • Successful long-term therapy includes cessation of cocaine abuse. Patients should be counseled about the risk for recurrent symptoms upon re-exposure and should avoid any product that might contain levamisole.

Optimal Therapeutic Approach for this Disease

The first step in managing a patient with levamisole-induced vasculitis is to establish a working diagnosis. Because this entity may overlap in clinical presentation and laboratory findings with other types of vasculitis, it is imperative to suspect and establish the diagnosis, when appropriate, in order to spare patients exposure to systemic immune suppression necessitated by other diseases (e.g., granulomatosis with polyangiitis). The single most important long-term therapeutic intervention is to help patients strictly avoid all products that may be adulterated with levamisole. Otherwise, no therapeutic intervention is clearly established. Systemic therapy with corticosteroids might be considered for systemic or progressive cutaneous disease. Supportive care is a cornerstone of therapy. For more extensive cutaneous disease, surgical intervention may be required.

Patient Management

Patients should be clearly instructed to stop all products, including cocaine, that might be contaminated with levamisole. A drug recovery program may be beneficial. There is no specific maintenance therapy other than strategies to support patients while they recover from drug abuse.

Unusual Clinical Scenarios to Consider in Patient Management

Patients might expressly deny the use of cocaine. Nevertheless, a urine drug screen should be performed whenever the diagnosis is suspected. Physical exam and laboratory findings can be non-specific, but the clinical presentation of purpura and necrosis of the ears, cheeks, and nose is characteristic. While it is critical to evaluate for and rule out other important types of systemic vasculitis, levamisole-induced vasculitis should be considered in the appropriate clinical context.

This article originally appeared on Dermatology Advisor