Cocaine- and Levamisole-Induced Vasculitis I77.-

With the increasing prevalence of illicit cocaine use, a broad spectrum of local and systemic disorders associated with this drug of abuse is emerging, involving both cocaine and levamisole (Specks U 2011). The spectrum of autoimmune manifestations caused by cocaine and levamisole can be summarized in three overlapping clinical pictures:

• Cocaine-induced destructive midline lesions (CIMDL) (no other organ involvement)
• Levamisole-adulterated cocaine (LAC) vasculopathy/vasculitis and (overlapping clinical symptoms)
• Cocaine-induced vasculitis (CIV)

Levamisole-adulterated cocaine (LAC) vasculopathy/vasculitis is a complex systemic syndrome characterized primarily by skin involvement (95%), of which about 70% is in the head area (Burg ML et al. 2025) face, ears, cheeks, nose. Further involvement can affect organs such as the nose, kidneys, lungs, liver and brain. This disease is more common in middle-aged women.

In 2021, 22 million people worldwide had used cocaine in the previous year, a figure that is increasing year on year (UNODC 2022). In the European Union, cocaine is the second most commonly used drug after cannabis. Sniffing cocaine crystals through the nose is the most common form of consumption.

Cocaine, a highly potent and addictive drug, is the most commonly consumed psychostimulant substance in Europe and is derived from the leaves of the coca plant (Erythroxylum coca). Cocaine increases the amount of dopamine in the synaptic cleft of the central nervous system by inhibiting its presynaptic reuptake and the presynaptic reabsorption of noradrenaline and serotonin. This leads to changes in behavior and mental health.

Levamisole is a synthetic compound derived from imidazothiazole and was originally used as an anthelmintic in veterinary medicine. Due to its immunomodulatory properties, it was also previously used in humans as an oncologic and various autoimmune diseases. In 1999, reports of severe neutropenia led to the withdrawal of the drug from the market. About 70-80% of cocaine is "stretched" with levamisole, which is added to increase volume and stimulant properties. Levamisole is used for this purpose because it has a similar white, powdery consistency to cocaine and cannot be detected in common impurity tests such as the 'bleach test', a popular street test used to check cocaine purity. In addition, levamisole enhances the addictive effects of cocaine by acting as a nicotine antagonist and prolonging and enhancing the release of glutamate.

The mechanisms linking cocaine use to ANCA-positive vasculitis (AAV) are still largely unexplained. Cocaine use leads to nasal mucosal irritation and vascular ischemia. In addition, cocaine induces activation of the immune system through the formation of neutrophil extracellular traps (NETs), leading to increased inflammation and tissue damage. Finally, this process can lead to pronounced autoimmune reactions characterized by the production of ANCAs.

Skin manifestations include painful, saturated red or hemorrhagic, livedoid or stellate, erythema, plaques and bizarre necrosis, sometimes pyoderma gangraenosum-like. The skin lesions are usually bilateral. Constitutional symptoms such as arthralgia, fever, weight loss, myalgia and sweating are very common in LAC vasculopathy/vasculitis, as are nasal destructive lesions due to cocaine insufflation and sinonasal involvement. Furthermore, arthritis occurs in 30 % of cases. Pulmonary involvement, leukoencephalopathy and glomerulonephritis occur less frequently. Leukoencephalopathy, which was first observed in people treated with levamisole, is an autoimmune reaction that leads to a progressive deterioration in mental status, ataxia and other neurological symptoms (Wu VC et al. 2006). Renal involvement occurs in up to 10% of cases, often at the onset of the disease, and may manifest as proteinuria and hematuria with or without renal failure.

Cocaine can be detected in urine by screening for its metabolite benzoylecgonine, which is detectable for 48 to 72 hours after use and can persist for up to two weeks in frequent users. Cocaine is detectable in blood and saliva for less than 48 hours, in sweat for several weeks and in hair for several months.

Levamisole: Its quantification can only be carried out in specialized laboratories using liquid chromatography in conjunction with mass spectrometry on serum and urine samples. In addition, levamisole is difficult to detect due to its limited renal excretion and its relatively short half-life of 5.6 hours (Marquez J et al. 2017).

Hematological abnormalities such as leukopenia, neutropenia, agranulocytosis, hemolytic anemia and thrombocytopenia are common and occur in about 60 % of cases.

ANCA positivity occurs in up to 90 % of cases (McGrath MM et al. 2011). LAC vasculopathy/vasculitis may be associated with p-ANCA and/or c-ANCA or both in conjunction with multiple antigen specificities. High titers of atypical p-ANCA directed against cathepsin G and lactoferrin are the most common pattern. Anti-MPO antibodies are typically detected in lower concentrations than p-ANCA.

Antiphospholipid antibodies, such as lupus anticoagulant, IgM anti-cardiolipin antibodies and IgM anti-β2 glycoprotein 1 antibodies, are also present in almost 70% of cases. In addition, about the same percentage of patients have low complement levels (C3, C4 or both). In some cases, antinuclear antibodies (ANAs), anti-double-stranded DNA antibodies and anti-C1q antibodies are also present (Gómez-Puerta JA et al. 2017).

A thrombotic vasculopathy or a leukocytoclastic vasculitis is proven. A combination of both is rarer. Superficial and deep small skin vessels are affected. They show fibrinoid necrosis of the vessel walls, which often extends to the adjacent perivascular connective tissue. Extravasation of red blood cells and the presence of intravascular thrombi are also common findings. Direct immunofluorescence can detect mixed antibodies (IgM, IgG and IgA) and C3 deposits in the vessel walls (Jacob RS et al. 2012).

Kidney: The most common histologic pattern in the kidney is pauci-immune glomerulonephritis, which may or may not show cellular crescents and fibrinoid necrosis, similar to most primary AAVs. Membranous glomerulonephritis with or without antibodies to the phospholipase A2 receptor is also relatively common (Collister D et al. 2017).

In rare cases, LAC vasculopathy/vasculitis can take a fulminant course and lead to death due to the severity of the skin lesions or the involvement of several organs.

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