A Case of Cutaneous Vasculitis in the Setting of Systemic Lupus Erythematosus and Cocaine Use

Abstract

Cocaine, one of most prevalent illicit substances in the United States, affects a multitude of organ systems and precedes numerous negative health outcomes. Many of the consequences of cocaine are linked to induction of vasoconstriction. For this reason, cocaine users are placed at considerable risk of ischemic stroke, myocardial infarction, and cardiac arrhythmias. Furthermore, a prominent contaminant, levamisole, has been widely implicated in predisposing individuals to developing or exacerbating cutaneous vasculitides. This report details a 31-year-old woman with acute, localized necrotic skin lesions after cocaine use. Her clinical picture was complicated by a 17-year history of systemic lupus erythematosus (SLE) and Raynaud’s phenomenon. This case examines the challenge of forming a differential diagnosis, initiating an appropriate workup, and interpreting serologic-based and immunologic-based studies to differentiate between SLE and drug-based etiologies of skin necrosis. Finally, we discuss appropriate treatment plans to mitigate symptoms and reduce future instances of drug-induced vasculitis.

Introduction

Cocaine is one of the most popular illicit substances in the United States. ¹ Despite usage in the United States declining in recent years, it remains the second most popular illicit substance behind cannabis and has widespread consequences on both individual and public health. ² Neurologically, cocaine disrupts the reward system of the brain by preventing the removal of dopamine from synapses. Chronic cocaine use is also related to the reward pathway of the brain and the stress response system. Cocaine acts upon the mesolimbic reward pathway to produce its effects. This pathway extends from the ventral tegmental area of the midbrain to the nucleus accumbens. The nucleus accumbens is a major center of reward response. Stimulants ranging from food to abused drugs, such as cocaine, can result in synaptic modifications to this pathway and influence an individual’s behavior. ³ These adaptations can induce drug-seeking behavior and can be attributed to the high prevalence of cocaine use disorder among first-time users. Consistent cocaine abuse results in tolerance, leading individuals to continually increase the dose and frequency to result in the same euphoria initially experienced, further increasing the likelihood of overdose or experiencing adverse effects. ² According to the 2020 National Survey on Drug Use and Health, 1.9% of Americans aged 12 years and older reported cocaine use in the last 12 months. Also, 0.5% of Americans had a cocaine use disorder in the previous 12 months. Data collected on school-aged children showed cocaine usage was reported at rates of 0.2% among 8th graders, 0.6% among 10th graders, and 1.2% among 12th graders. Cocaine use is reported to often co-occur in combination with other drugs, including alcohol and opioids. Moreover, cocaine is also often laced with other substances, including levamisole, to potentiate its effects.^4-7 Levamisole contamination of cocaine has been increasing since 2005, with the Centers for Disease Control and Prevention reports indicating 70% of cocaine seized at US borders contained levamisole in 2009. Almost 20 000 Americans died of an overdose involving cocaine in 2020. ⁸

In addition to the public health consequences, there are many potentially irreversible physiological consequences of cocaine abuse. In pregnant women, cocaine can cause preterm labor, placental abruption, and decreased child response to the environment. ⁹ Consequences to the cardiovascular system include myocardial infarction, heart failure, and arrhythmias, as well as an increase in coronary artery disease and atherosclerosis.^10-12 Cocaine is also attributed to an increase in unpredictable and violent behavior. Neurologically, cocaine use may result in ischemic stroke and seizures potentially related to its vasoconstrictive effect on blood vessels in the brain. ¹³ Both hepatic and renal failure can result from cocaine abuse. ¹²

Cutaneous manifestations constitute another significant consequence of cocaine abuse. It is well known that injecting cocaine can result in needle track marks and scarring on the arms or other injection site. ¹⁰ In addition, chronic inhalation of cocaine can also result in ulceration and perforation of the nasal septum and can cause tactile hallucinations or the sensation that bugs are crawling beneath one’s skin. ¹³ Cutaneous manifestations associated with cocaine use range from Raynaud’s phenomenon, ¹⁴ necrotizing granulomatous vasculitis, ¹³ cocaine-induced midline destructive lesions, and antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis. These effects are most often associated with levamisole-contaminated cocaine. ¹⁵ Prior to the discontinuation of levamisole as an antiparasitic and immunomodulatory drug, reports directly linked levamisole to thrombotic vasculitis, leukocytoclastic vasculitis, and/or vascular occlusion in patients treated for pediatric nephrotic syndrome. ¹⁶ Levamisole, originally marketed as an anti-helminth and immunomodulator, has become a popular contaminant of cocaine in recent years because of its synergistic effects with cocaine and its ability to pass common purity tests of cocaine.^15,16 Currently, levamisole is easily accessed because it is commonly used for its anti-helminth properties in veterinary settings and is inexpensive. Levamisole is estimated to be present in 80% of cocaine used in the United States, resulting in an increase in the prevalence of levamisole-associated side effects. ¹⁵

The various cutaneous manifestations of cocaine are still being discovered, resulting in a need for further research and case documentation of cocaine-induced vasculitis and skin disease.

Case Report

A 31-year-old woman with a 17-year history of systemic lupus erythematosus (SLE) presented to the emergency department with a 3-day history of black necrotic lesions on the left cheek and bilateral toes. Medical history was significant for Raynaud’s phenomenon and limited systemic scleroderma. The lesions arose suddenly upon waking and had never occurred previously. The patient was concurrently experiencing bilateral numbness and tingling in the hands and feet as well as a 1-month history of worsening shortness of breath. The patient endorsed arthritis and arthralgia of metacarpophalangeal joints, proximal interphalangeal joints, and wrist. She also endorsed myalgia and recent mouth ulcers. Her medical history was complicated by lupus nephritis confirmed via renal biopsy showing membranous glomerulopathy 10 years ago. Autoimmune workup approximately 1 year earlier was positive for perinuclear antineutrophil cytoplasmic autoantibodies (p-ANCA) and anticentromere antibody with an antinuclear antibody (ANA) titer of >1:1280, anti-Smith antibody IgG 2.2 (<1.0 AI), anti-SM/RNP antibody IgG 5.3 (<1.0 AI), and anti-cardiolipin-negative and RNA polymerase 3 IgG 7 (<19 units). She also had a history of recurrent deep venous thrombosis and pulmonary embolism, most recently occurring 5 years ago. Her home medications included apixaban 5 mg twice a day for lifelong anticoagulation for recurrent thrombotic events (duration of use: 5 years), gabapentin 300 mg three times a day for pain management (unknown duration), hydroxychloroquine 200 mg twice a day for SLE management (duration: 6 years), mycophenolate mofetil 1500 mg once a day for SLE management (duration: 11 years), and sulindac 200 mg twice a day for inflammatory arthritis (duration: 12 years); however, the patient admitted to not taking apixaban at home for the past month. The patient denied use of alcohol, illicit drugs, marijuana, and cigarettes, but admitted to regular vaping. The patient denied chest pain, cough, fever, visual disturbances, headache, abdominal pain, nausea, vomiting, diarrhea, or recent changes in weight.

Physical examination revealed black necrotic lesions on the left upper cheek and bilateral toes (Figure 1). The patient denied tenderness to palpation but complained of mild, constant 7/10 in severity “throbbing” pain localized to the lesions. Cardiopulmonary examination was unremarkable. The patient was afebrile and normotensive. Urinalysis was positive for leukocyte esterase, protein (50 mg/dL), red blood cells (47/hpf), white blood cells (12/hpf), and a protein-creatinine ratio of 1.08 (baseline approximately 3, nl < 0.2). The urine toxicology screen was positive for cocaine and opiates. Creatine kinase, erythrocyte sedimentation rate, and C-reactive protein (CRP) were elevated at 373 (24-170 U/L), 53 (0-20 mm/h), and 3.3 (<0.744 mg/dL), respectively. B-type natriuretic peptide and D-dimer were elevated at 297 (<100 pg/mL) and 2066 (<255 ng/mL D-dimer units), respectively. Complete blood count (CBC) and comprehensive metabolic panel (CMP) were unremarkable except for serum creatinine of 1.09 (baseline approximately 0.8). Magnesium was low at 1.1 (1.8-2.6 mg/dL) and improved to 1.8 with replacement. Thyroid-stimulating hormone, T4, and coagulation studies (prothrombin time, activated partial thromboplastin time, international normalized ratio) were within normal limits. The patient was negative for HIV, hepatitis B infection, and hepatitis C antibodies. Chest radiograph was significant for possible small bilateral pleural effusions with an otherwise stable chest.

Figure 1.

Black, necrotic skin lesions localized to the left cheek (A), right toes (B), and left toes (C).

Rheumatology labs

• Anti-cardiolipin IgA: <2.0 [0-19.9 IgA phospholipid binding units (APL)]

• Anti-cardiolipin IgM: <1.5 [0-19.9 IgM phospholipid binding units (MPL)]

• Anti-cardiolipin IgG: <1.6 [0-19.9 IgG phospholipid binding units (GPL)]

• β-2 glycoprotein IgM: <2.0 [0-19.9 IgA phospholipid binding units (APL)]

• β-2 glycoprotein IgA: <1.5 [0-19.9 IgM phospholipid binding units (MPL)]

• β-2 glycoprotein IgG: <1.4 [0-19.9 IgG phospholipid binding units (GPL)]

• Anti-dsDNA (double-stranded DNA): 1 (<5 IU/mL)

• Anti-Smith IgG: 2.8 [<1.0 antibody index (AI)]

• Anti-RNP IgG: 0.5 [<1.0 antibody index (AI)]

• C3 complement: 113 (86-184 mg/dL)

• C4 complement: 29 (16-47 mg/dL)

• c-ANCA: negative

• p-ANCA: negative

• Proteinase-3 Ab: <0.2 [<1.0 antibody index (AI)]

• Myeloperoxidase Ab: <0.2 [<1.0 antibody index (AI)]

Upon admission, the patient was started on apixaban 5 mg twice a day and home medications were resumed. During the initial interview, the patient denied drug use; however, when presented with results of the positive urine toxicology screen, the patient admitted to recent cocaine use via nostril inhalation.

On day 2 of admission, the patient had reduced pain to 6/10 in severity with improvements in her symptoms of extremity numbness and tingling. There were no significant changes on repeat CBC with differential and CMP. Diagnoses including SLE flare with secondary vasculitis, antiphospholipid antibody syndrome, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis were considered. However, rheumatology consultation supported a high suspicion for levamisole-cocaine-induced ANCA vasculitis given the patient’s clinical presentation after using cocaine with her prior positive ANCA status. For treatment of levamisole-cocaine-induced vasculitis, prednisone 10 mg orally daily was continued, and the patient was counseled to cease cocaine use. Despite an elevated urine protein-creatinine ratio of 1.08 (nl < 0.2), there was no indication of kidney involvement or need for kidney biopsy given the patient’s baseline creatinine ratio of 3. Normal values returned for anti-dsDNA and complement levels (C3 and C4), both of which often fluctuate with SLE disease activity, making a diagnosis of SLE flare less likely. With continued pain improvement, the patient was discharged on day 3 of admission. Given that the cornerstone treatment of levamisole-induced vasculitis is cessation of cocaine usage, we counseled the patient on cocaine usage and vasculitis effects and offered resources for cocaine cessation. ¹⁷

The patient returned to the outpatient rheumatology clinic approximately 1 month after discharge without complaints of the lesions. At that time, she continued to report widespread soreness and edema, predominantly in the bilateral hands. She also had persistent shortness of breath and chest pain. Laboratory studies revealed elevated CRP (5.13 mg/dL, nl <0.744 mg/dL) and erythrocyte sedimentation rate (84 mm/h, nl 0-20 mm/h). Complement C3 (132 mg/mL, nl 86-184 mg/dL) and C4 (132 mg/dL, nl 16-47 mg/dL) levels remained within normal limits. The patient was continued on her current medication regimen with planned follow-up in 3 months.

The patient was discharged on her home medication regimen with the addition of prednisone. Serious adverse outcomes associated with these medications include hemorrhage (apixaban), gastrointestinal bleeding, ulceration, or perforation (sulindac, prednisone), thrombotic events (sulindac), central nervous system depression (gabapentin), cardiomyopathy/conduction abnormalities, hypoglycemia, myopathy, psychosis, retinopathy (hydroxychloroquine), myopathy (hydroxychloroquine, prednisone), increased susceptibility to infections and malignancies (mycophenolate mofetil, prednisone), and adrenal suppression, psychiatric disturbances, Cushing syndrome, hyperglycemia, osteoporosis, and increased intraocular pressure (prednisone). If superimposed on continued use of cocaine, these medication complications may contribute to future patient morbidity.

Discussion

Here, we report a clinical case study of a patient with a history of SLE now complicated by new-onset vasculitis after recent cocaine use. More specifically, this patient presented with acute-onset necrotic lesions of the face and toes after cocaine ingestion. Numerous international case series report cocaine-levamisole-induced vasculitis and it is recognized as a prevalent phenomenon given the abundance of levamisole in cocaine products.^18,19 Informal diagnostic criteria include cutaneous manifestations, serological markers, and a history of cocaine abuse. This phenomenon is a diagnosis of exclusion, although it should remain a consideration in the setting of associated drug/cocaine use.

Clinical presentations include skin lesions manifesting as retiform purpura; necrosis of the ear, genitals, and digits; cutaneous and oral ulcers; hemorrhagic bullae; subcutaneous nodules; and pyoderma gangrenosum. The most common lesion sites include the limbs, buttocks, face, and abdomen. Cutaneous manifestations of the digits have also been reported, as also seen in this present report. Pathology was not pursued in this case study, although others have reported evidence of thrombotic vasculopathy, leukocytoclastic vasculitis, pseudovasculitis, pyoderma gangrenosum, panniculitis, and necrosis in skin biopsies from suspected cocaine-induced vasculitis patients. ¹⁹

Other presenting clinical signs include arthralgias, fever, night sweats, and weight loss.^20,21 Laboratory findings most commonly include positive p-ANCA with specificity for anti-myeloperoxidase and proteinase 3 (PR3) as well as other autoantigens such as antinuclear antibodies, lupus anticoagulant, anti-cardiolipin, anti-dsDNA, and anti-β2 glycoprotein. These antibodies are also associated with ANCA-associated vasculitis, antiphospholipid syndrome, and SLE, demonstrating the potential crossover with rheumatological diseases. Neutropenia and low complement levels are also reported as a common serological feature. Renal involvement including membranous glomerulonephritis and immune complex–mediated proliferative glomerulonephritis, and pulmonary manifestations including pulmonary hypertension, bronchitis, bronchiolitis, interstitial pneumonia, nodules, and alveolar hemorrhage have also been reported in patients with suspected cocaine-levamisole-induced vasculitis.^16-18

This patient endorsed medical nonadherence of apixaban without explanation. Potential underlying factors contributing to medical nonadherence include lack of understanding of the importance of the medication to her health and wellbeing, a belief that the benefits of the medication do not outweigh the costs, the complex nature of the medication regimen, or the patient did not believe the medication is effective. ²² Medical nonadherence may persist for this patient prompting relapses in her chronic diseases. Close follow-up with her primary care provider and rheumatologist was recommended to facilitate medical adherence.

Conclusion

The patient reported herein presented with cutaneous manifestations in agreement with prior reports of cocaine-levamisole-induced vasculitis. We cannot confirm the presence of levamisole as we did not pursue urine testing for levamisole given its short half-life and the necessity of gas chromatography and mass spectrometry for detection. ²³ Of note, in this patient, serological findings did not include neutropenia and positive p-ANCA, which are argued to have a strong association with cocaine-levamisole-induced vasculitis.

The absence of positive p-ANCA may be, in part, explained by the concomitant, chronic use of the immunosuppressant agent, mycophenolate mofetil, in this patient as a treatment for SLE, given that serology from 1 year prior was positive for p-ANCA and ANA. Mycophenolate mofetil has been shown to lead to normalization of ANCA levels.^24,25 Thus, given that it has been suggested that p-ANCA may contribute to neutropenia in the setting of autoimmune disease, ²⁶ the normal neutrophil count in this patient could be a consequence of mycophenolate mofetil. Nonetheless, cutaneous manifestations arising from SLE remain on the differential diagnosis given the range of skin presentations seen in this disease. ²⁷ This patient also presented with arthralgia and signs of peripheral neuropathy, which are nonspecifically associated with cocaine use, as well as SLE. This is a noteworthy case report because it describes a patient with probable cocaine-levamisole-induced vasculitis with a history of SLE and Raynaud’s phenomenon. One previous study describes a case of cocaine-levamisole-induced vasculitis, specifically pyoderma gangrenosum, in a patient with a history of SLE. Authors conclude that cutaneous manifestations were related to cocaine use, rather than SLE, because the skin lesions resolved with a tapering dose of steroids and cocaine cessation. ²⁸

There are no available treatment guidelines for this process due to its relative rarity. The most common pursued approach includes cocaine cessation, glucocorticoids, and other immunosuppressants such as azathioprine, chloroquine, methotrexate, and cyclophosphamide. The most effective treatment is cocaine cessation. ¹⁹ Overall, this report describes a patient with probable cocaine-levamisole-induced vasculitis in the setting of cutaneous manifestations with serological findings that could have been masked by chronic immunosuppressant use.