Case Reports

Prednisone and Vardenafil Hydrochloride for Refractory Levamisole-Induced Vasculitis

Cutis. 2016 August;98(2):E15-E19

Levamisole is an immunomodulatory drug that was previously used to treat various medical conditions, including parasitic infections, nephrotic syndrome, and colorectal cancer. Over the last few years, increasing amounts of levamisole have been used as an adulterant in cocaine. Levamisole-cut cocaine has become a concern because it is known to cause a necrotizing purpuric rash, autoantibody production, and life-threatening leukopenia. Mixed histologic findings of vasculitis and thrombosis are characteristic of levamisole-induced purpura. The recommended management of levamisole-induced vasculitis currently involves withdrawal of the culprit along with supportive treatment. We describe a patient with levamisole-induced vasculitis who continued to develop skin lesions despite self-reported cocaine cessation. Complete resolution of cutaneous disease occurred with the addition of oral prednisone and vardenafil hydrochloride, suggesting the possibility of a new treatment option in patients with refractory disease. In addition, we review the clinical presentation, disease course, diagnostic approach, laboratory findings, histology, and management of levamisole-induced vasculitis. The harmful effects of levamisole-cut cocaine are serious enough that public alerts have been issued to increase awareness. Clinicians should consider the possibility of levamisole exposure in cocaine users presenting with any combination of fever, neutropenia, and necrotic skin lesions, especially in acral areas including the ears.

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Practice Points

Levamisole is an immunomodulatory drug that, before being withdrawn from the US market in 2000, was previously used to treat various medical conditions.
A majority of the cocaine in the United States is contaminated with levamisole, which is added as an adulterant or bulking agent.
Levamisole-cut cocaine is a concern because it is associated with a life-threatening syndrome involving a necrotizing purpuric rash, autoantibody production, and leukopenia.
Although treatment of levamisole toxicity is primarily supportive and includes cessation of levamisole-cut cocaine, a trial of prednisone and vardenafil hydrochloride can be considered for refractory levamisole-induced vasculopathy or for patients who continue to use the drug.

References

Scheinfeld N, Rosenberg JD, Weinberg JM. Levamisole in dermatology: a review. Am J Clin Dermatol. 2004;5:97-104.
Rongioletti F, Ghio L, Ginevri F, et al. Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol. 1999;140:948-951.
National Drug Threat Assessment 2011. US Department of Justice National Drug Intelligence Center website. https://www.justice.gov/archive/ndic/pubs44/44849/44849p.pdf. Published August 2011. Accessed August 7, 2016.
Buchanan JA, Heard K, Burbach C, et al. Prevalence of levamisole in urine toxicology screens positive for cocaine in an inner-city hospital. JAMA. 2011;305:1657-1658.
Gross RL, Brucker J, Bahce-Altuntas A, et al. A novel cutaneous vasculitis syndrome induced by levamisole-contaminated cocaine. Clin Rheumatol. 2011;30:1385-1392.
Waller JM, Feramisco JD, Alberta-Wszolek L, et al. Cocaine-associated retiform purpura and neutropenia: is levamisole the culprit? J Am Acad Dermatol. 2010;63:530-535.
Poon SH, Baliog CR, Sams RN, et al. Syndrome of cocaine-levamisole-induced cutaneous vasculitis and immune-mediated leukopenia. Semin Arthritis Rheum. 2011;41:434-444.
Brewer JD, Meves A, Bostwick JM, et al. Cocaine abuse: dermatologic manifestations and therapeutic approaches. J Am Acad Dermatol. 2008;59:483-487.
Walsh NMG, Green PJ, Burlingame RW, et al. Cocaine-related retiform purpura: evidence to incriminate the adulterant, levamisole. J Cutan Pathol. 2010;37:1212-1219.
Chung C, Tumeh PC, Birnbaum R, et al. Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole adultered cocaine. J Am Acad Dermatol. 2011;65:722-725.
Kahn TA, Cuchacovich R, Espinoza LR, et al. Vasculopathy, hematological, and immune abnormalities associated with levamisole-contaminated cocaine use. Semin Arthritis Rheum. 2011;41:445-454.
Graf J, Lynch K, Yeh CL, et al. Purpura, cutaneous necrosis, and antineutrophil cytoplasmic antibodies associated with levamisole-adulterated cocaine. Arthritis Rheum. 2011;63:3998-4001.
Farmer RW, Malhotra PS, Mays MP, et al. Necrotizing peripheral vasculitis/vasculopathy following the use of cocaine laced with levamisole. J Burn Care Res. 2012;33:e6-e11.
Ching JA, Smith DJ Jr. Levamisole-induced skin necrosis of skin, soft tissue, and bone: case report and review of literature. J Burn Care Res. 2012;33:e1-e5.
Buchanan JA, Vogel JA, Eberhardt AM. Levamisole-induced occlusive necrotizing vasculitis of the ears after use of cocaine contaminated with levamisole. J Med Toxicol. 2011;7:83-84.
Graff N, Whitworth K, Trigger C. Purpuric skin eruption in an illicit drug user: levamisole-induced vasculitis. Am J Emer Med. 2016;34:1321.
Schwartz BG, Kloner RA. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010;122:88-95.

Levamisole is an immunomodulatory drug that had been used to treat various medical conditions, including parasitic infections, nephrotic syndrome, and colorectal cancer,¹ before being withdrawn from the US market in 2000.The most common reasons for levamisole discontinuation were leukopenia and rashes (1%–2%),¹ many of which included leg ulcers and necrotizing purpura of the ears.^1,2 The drug is currently available only as a deworming agent in veterinary medicine.

Since 2007, increasing amounts of levamisole have been used as an adulterant in cocaine. In 2007, less than 10% of cocaine was contaminated with levamisole, with an increase to 77% by 2010.³ In addition, 78% of 249 urine toxicology screens that were positive for cocaine in an inner city hospital also tested positive for levamisole.⁴ Levamisole-cut cocaine has become a concern because it is associated with a life-threatening syndrome involving a necrotizing purpuric rash, autoantibody production, and leukopenia.⁵

Levamisole-induced vasculitis is an independent entity from cocaine-induced vasculitis, which is associated with skin findings ranging from palpable purpura and chronic ulcers to digital infarction secondary to its vasospastic activity.^6-8 Cocaine-induced vasculopathy has been related to cytoplasmic antineutrophil cytoplasmic antibody positivity and often resembles Wegener granulomatosis.⁶ Although both cocaine and levamisole have reportedly caused acrally distributed purpura and vasculopathy, levamisole is specifically associated with retiform purpura, ear involvement, and leukopenia.^6,9 In addition, levamisole-induced skin reactions have been linked to specific antibodies, including antinuclear, antiphospholipid, and perinuclear antineutrophil cytoplasmic antibody (p-ANCA).^2,5-7,9-14

We present a case of refractory levamisole-induced vasculitis and review its clinical presentation, diagnostic approach, laboratory findings, histology, and management. Furthermore, we discuss the possibility of a new treatment option for levamisole-induced vasculitis for patients with refractory disease or for patients who continue to use levamisole.

References

Scheinfeld N, Rosenberg JD, Weinberg JM. Levamisole in dermatology: a review. Am J Clin Dermatol. 2004;5:97-104.
Rongioletti F, Ghio L, Ginevri F, et al. Purpura of the ears: a distinctive vasculopathy with circulating autoantibodies complicating long-term treatment with levamisole in children. Br J Dermatol. 1999;140:948-951.
National Drug Threat Assessment 2011. US Department of Justice National Drug Intelligence Center website. https://www.justice.gov/archive/ndic/pubs44/44849/44849p.pdf. Published August 2011. Accessed August 7, 2016.
Buchanan JA, Heard K, Burbach C, et al. Prevalence of levamisole in urine toxicology screens positive for cocaine in an inner-city hospital. JAMA. 2011;305:1657-1658.
Gross RL, Brucker J, Bahce-Altuntas A, et al. A novel cutaneous vasculitis syndrome induced by levamisole-contaminated cocaine. Clin Rheumatol. 2011;30:1385-1392.
Waller JM, Feramisco JD, Alberta-Wszolek L, et al. Cocaine-associated retiform purpura and neutropenia: is levamisole the culprit? J Am Acad Dermatol. 2010;63:530-535.
Poon SH, Baliog CR, Sams RN, et al. Syndrome of cocaine-levamisole-induced cutaneous vasculitis and immune-mediated leukopenia. Semin Arthritis Rheum. 2011;41:434-444.
Brewer JD, Meves A, Bostwick JM, et al. Cocaine abuse: dermatologic manifestations and therapeutic approaches. J Am Acad Dermatol. 2008;59:483-487.
Walsh NMG, Green PJ, Burlingame RW, et al. Cocaine-related retiform purpura: evidence to incriminate the adulterant, levamisole. J Cutan Pathol. 2010;37:1212-1219.
Chung C, Tumeh PC, Birnbaum R, et al. Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole adultered cocaine. J Am Acad Dermatol. 2011;65:722-725.
Kahn TA, Cuchacovich R, Espinoza LR, et al. Vasculopathy, hematological, and immune abnormalities associated with levamisole-contaminated cocaine use. Semin Arthritis Rheum. 2011;41:445-454.
Graf J, Lynch K, Yeh CL, et al. Purpura, cutaneous necrosis, and antineutrophil cytoplasmic antibodies associated with levamisole-adulterated cocaine. Arthritis Rheum. 2011;63:3998-4001.
Farmer RW, Malhotra PS, Mays MP, et al. Necrotizing peripheral vasculitis/vasculopathy following the use of cocaine laced with levamisole. J Burn Care Res. 2012;33:e6-e11.
Ching JA, Smith DJ Jr. Levamisole-induced skin necrosis of skin, soft tissue, and bone: case report and review of literature. J Burn Care Res. 2012;33:e1-e5.
Buchanan JA, Vogel JA, Eberhardt AM. Levamisole-induced occlusive necrotizing vasculitis of the ears after use of cocaine contaminated with levamisole. J Med Toxicol. 2011;7:83-84.
Graff N, Whitworth K, Trigger C. Purpuric skin eruption in an illicit drug user: levamisole-induced vasculitis. Am J Emer Med. 2016;34:1321.
Schwartz BG, Kloner RA. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010;122:88-95.

Prednisone and Vardenafil Hydrochloride for Refractory Levamisole-Induced Vasculitis

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