The antihelminthic agent levamisole -- no longer available in the U.S. -- is increasingly being found as an adulterant in cocaine and has been associated with potentially severe cases of vasculitis, French researchers reported.
A literature search for the years 1977 to 2016 identified 192 patients with levamisole-associated vasculopathy. Only 13 of these were given the drug as treatment for conditions such as nephrotic syndrome and rheumatoid arthritis (the agent has immunomodulatory effects) before it was withdrawn from the market in 2000 in the U.S. and 2003 in Canada. The drug is still used for parasitic infections in veterinary practice in the U.S. and South America.
The remaining 179 cases found in the literature review were in patients using cocaine recreationally, according to Luc Mouthon, MD, of Hôpital Cochin in Paris, and colleagues.
"Levamisole reduces the cost of cocaine preparation and increases the release of norepinephrine in peripheral tissues and dopamine in the brain, thereby improving neurotransmission in the central nervous system and increasing the effects and duration of cocaine," the researchers explained online in .
In recent years levamisole has been detected in 70% to 85% of cocaine lots and in up to 88% of urine samples from cocaine users in Europe and the U.S. There has also been an increase in the concentration of levamisole in some lots of seized cocaine, heightening the importance of understanding the specifics of the vasculitis associated with exposure.
Among the cases associated with cocaine use, the majority were women whose median age was 45. Almost all (95%) had some skin involvement; these were primarily purpuric skin lesions (68%) that were necrotic or retiform, and some individuals also had ulcerations, blisters, and plaques. The skin lesions most often were seen on the face (71%) or ears (62%), although the cheeks and nose also were sometimes affected. The lower and upper limbs and trunk also were involved in many patients (70% and 52%, respectively).
Other symptoms included arthralgias; arthritis; and ear, nose, and throat lesions including oral and tracheal ulcers.
Renal insufficiency was present in 12.5% of the cases, and pulmonary involvement, including alveolar hemorrhage, in 10.4%.
C-reactive protein was elevated in 84% of patients who were tested for this, while leukopenia was detected in one half of the patients, and neutropenia, in 43%.
Most patients also had autoantibodies, with antineutrophil cytoplasmic antibodies (ANCA) present in 94%. In 118 patients, ANCA specificity was examined with indirect immunofluorescence assay, and in 43% of patients both anti-myeloperoxidase (MPO) and anti-proteinase 3 (PR3) antibodies were present. This observation of MPO plus PR3 positivity was "striking" and "very unusual" in ANCA vasculopathy, the authors noted.
Among the 137 patients who were tested for the presence of antiphospholipid antibodies (APA), 68% had at least one present, including lupus anticoagulant in 42% and anticardiolipin antibodies in 47%. This again was a most unusual finding in ANCA vasculitis, and "double ANCA specificity and/or positivity for APL antibodies in patients with ANCA-associated vasculitis could be considered a 'red flag' for cocaine intake and should lead practitioners to confirm it," Mouthon and colleagues stated.
A total of 77% of patients underwent skin biopsies. Vasculitis, either leukocytoclastic or necrotizing, was present in 49% of patients, and thrombotic vasculopathy was identified in 42%.
More than half of patients received prednisone, with a median starting dose of 60 mg/day. Small numbers of patients also received immunosuppressants such as cyclophosphamide and methotrexate, and 14% of patients underwent skin surgical procedures such as skin grafts and debridement. One patient required amputation of the nose and leg.
Three patients died: one from necrotizing pneumonia, a second from an overdose, and a third of cerebral hemorrhage.
Because autoantibodies are often present in levamisole-induced vasculitis, other ANCA-associated vasculitides such as granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) should be ruled out, the researchers said, adding that skin involvement is much more unusual in GPA and MPA, whereas kidney, peripheral nerve, and pulmonary involvement are more common in those conditions. In addition, the leukopenia and neutropenia seen in levamisole-induced vasculitis are unusual in GPA and MPA.
Vasculopathy in a middle-aged woman with skin lesions, double-specific ANCA positivity and/or APL antibodies, and neutropenia/leukopenia should prompt questioning about cocaine use, "because stopping levamisole exposure is essential for remission," the authors concluded.
They said that study limitations were the retrospective nature of the analysis and the possibility of missing data and misdiagnoses.
Disclosures
The authors reported having no conflicts of interest.
Primary Source
Seminars in Arthritis & Rheumatism
Dartevel A, et al "Levamisole-induced vasculopathy: a systematic review" Semin Arthritis Rheum 2018; doi:10.1016/j.semarthrit.2018.07.010.