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Vol. 15. Núm. 5.
Páginas e66-e67 (Septiembre - Octubre 2019)
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Vol. 15. Núm. 5.
Páginas e66-e67 (Septiembre - Octubre 2019)
Letter to the Editor
DOI: 10.1016/j.reuma.2017.11.002
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Anti C1q antibodies. A promising biomarker for cocaine-levamisole induced vasculitis
Anticuerpos anti C1q. Un biomarcador prometedor para la vasculitis inducida por cocaína-levamisol
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...
José A. Gómez-Puertaa,b,
Autor para correspondencia
jagomez@clinic.cat

Corresponding author at: Servicio de Reumatología, Hospital Clínic, Villarroel 170, Escala 11-2 Planta, 08036 Barcelona, Spain.
, Carlos H. Muñoza,c, Adriana L. Vanegas-Garcíaa,c, Tomás Urregod, Gloria Vásqueza,d, Luis A. Gonzáleza
a Grupo de Reumatología, Universidad de Antioquia, Medellín, Colombia
b Servicio de Reumatología, Hospital Clínic, Barcelona, Spain
c Hospital Universitario San Vicente Fundación, Medellín, Colombia
d Grupo de Inmunología Celular e Inmunogenética, GICIG, Universidad de Antioquia, Medellín, Colombia
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Tablas (1)
Table 1. Clinical and serological characteristics of LIVEN patients.
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Dear Editor:

During the 1960s, Levamisole was used as an anthelmintic agent. It was subsequently found to have immunomodulatory effects and was used to treat several inflammatory disorders. During the last decade, attention has been focused on the use of levamisole as a cutting agent for cocaine and on several cases of severe agranulocytosis associated with cocaine use.1

Cocaine/levamisole-induced vasculitis – LIVEN – is a heterogeneous vasculopathy characterized by skin necrosis concentrated in acral areas [ears, cheeks, genitals and digital necrosis], retiform purpura, general symptoms and cytopenias.2 Histopathological samples reveal pauci-inflammatory thrombotic diathesis accompanied with intravascular monocytes and evidence of complement activation.3

In 23 consecutive patients with systemic vasculitis from Hospital Universitario San Vicente Fundación, Medellín, Colombia, we analyzed the presence of Anti C1q antibodies, including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, (N=13), polyarteritis nodosa (N=4), LIVEN (N=4) and Takayasu arteritis (N=2). Serum Anti-C1q were measured by ELISA techniques (QUANTA Lite, Inova, USA). This study was approved by the institutional review board at our institution.

From this small pilot study, we found that anti C1q antibodies were more prevalent in LIVEN patients in comparison with other vasculitis (75% vs. 5.3%, p<0.001). Mean anti C1q titers were significantly higher in patients with LIVEN than in other vasculitis (51.0±25.3 vs. 10.4±7.1IU, p=0.04). Main clinical and serological characteristics including serum complement levels are summarized in Table 1.

Table 1.

Clinical and serological characteristics of LIVEN patients.

Case  Age/gender  Type of lesions  Autoantibodies  Serum complementa  Anti C1q antibodies  Treatment 
17/male  Ear necrosis, retiform purpura on legs  Anti MPO  C3: NormalC4: Normal  Positive (20.3IU)  PDN 30mg/day 
21/male  Rapidly progressive glomerulonephritis  Anti MPO, aCL IgG, aCL IgM, lupus anticoagulant  C3: LowC4: Low  Positive (116.4IU)  PDN 60mg/dayCyclo 1g (pulses) 
25/female  Ear necrosis, retiform purpura on legs  Anti MPO, aCL IgG  C3: NormalC4: Low  Positive (64.4IU)  PDN 20mg/day 
36/male  Ear necrosis  ANAs, Anti dsDNAAnti MPO, Anti Ro  C3: NormalC4: Normal  Negative (3.1IU)  MPDN 500mg pulses plus PDN 40m/day 

Cyclo: cyclophosphamide, PDN: prednisolone, MPDN: methylprednisolone.

a

Serum complement close to measurement of Anti-C1q antibodies.

It is well known that levamisole induces circulating autoantibodies. Patients commonly have high levels of perinuclear ANCA (p-ANCA) but not always against myeloperoxidase (MPO). p-ANCA titers are often directed against atypical p-ANCA-associated antigens within the neutrophil granules such as: human neutrophil elastase, lactoferrin, and cathepsin G.4

Recently, our group described a series of 11 patients with LIVEN.5 ANCA (91%), lupus anticoagulant (73%), ANAS (45%), anti dsDNA (29%), anti Ro (29%) were most common autoantibodies.5 Given the social difficulties for clinical follow-up in cocaine users, anti C1q antibodies are not measured yet in all patients with LIVEN attending our center.

Anti C1q antibodies have been described in many conditions including hypocomplementic urticarial vasculitis, systemic lupus erythematosus and membranoproliferative glomerulonephritis, among others. To our knowledge, this study is the first on anti C1q antibodies in patients suffering LIVEN.

C1q is a molecule important for the clearance of apoptotic cells. Apoptotic cells express autoantigens in their surface and may induce autoimmunity. Cocaine/levamisole generates repeated release of neutrophil antigens that might act as autoantigens and leads to decreasing tolerance. Neutrophils secrete complement proteins upon activation with PMA, fMLP and C5a. Neutrophil extracellular traps (NETs) have been implied as a potential source of autoantigens.6 Leffler et al.7 demonstrated that in vitro complement interaction with NETs and that C1q bound well and C3b deposited on NETs. The authors argue that decreased degradation of NETs led to deposition of complement and autoantibodies, recruitment of more complement, perpetuating the inflammatory cycle.

Finally, metabolic products of cocaine promote complement synthesis and lead to the deposition of C5b-9. LIVEN is proposed as a membrane attack complex (C5b-9) disease with enhanced apoptosis and prominent vascular expression of ICAM-1.3

Increasing reports signal that LIVEN is a contemporary public health problem. Recent reports from different authorities in the U.S. and the U.K. suggest that cocaine samples are contaminated with levamisole in 50–80% of cases.8 According to local authorities in Colombia, levamisole contaminates 40% of the market.9 Indeed, preventing cocaine use is crucial for mitigating additional cases of LIVEN. Despite awareness of its toxicity by clinicians, identifying new biomarkers is necessary for practitioners that interface with these patients. Given our small sample size, further research is needed to confirm our findings that suggest anti C1q antibodies are useful markers in patients with LIVEN.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

J.A. Gómez-Puerta was supported by Colciencias (convocatoria 656 de 2014). We would like to thank Catalina Perez Koller and Liliana Marcela Peñaranda (Inova/Wefen) for assisting with sample management and analysis of antibodies.

References
[1]
K.C. Lee, B. Ladizinski, D.G. Federman.
Complications associated with use of levamisole-contaminated cocaine: an emerging public health challenge.
Mayo Clin Proc, 87 (2012), pp. 581-586
[2]
A.Q. Carlson, D.S. Tuot, K.Y. Jen, B. Butcher, J. Graf, R. Sam, et al.
Pauci-immune glomerulonephritis in individuals with disease associated with levamisole-adulterated cocaine: a series of 4 cases.
Medicine (Baltimore), 93 (2014), pp. 290-297
[3]
C.M. Magro, X. Wang.
Cocaine-associated retiform purpura: a C5b-9-mediated microangiopathy syndrome associated with enhanced apoptosis and high levels of intercellular adhesion molecule-1 expression.
Am J Dermatopathol, 35 (2013), pp. 722-730
[4]
R. Laux-End, D. Inaebnit, H.A. Gerber, M.G. Bianchetti.
Vasculitis associated with levamisole and circulating autoantibodies.
Arch Dis Child, 75 (1996), pp. 355-356
[5]
C.H. Muñoz, A.L. Vanegas, A. Arbelaez, M. Restrepo, G. Vásquez, L.A. Correa, et al.
Cocaine-levamisole induced vasculitis: a series of 11 cases.
Ann Rheum Dis, 75 (2016), pp. 567
[6]
C. Lood, G.C. Hughes.
Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity.
Rheumatology (Oxford), (2016),
[7]
J. Leffler, M. Martin, B. Gullstrand, H. Tydén, C. Lood, L. Truedsson, et al.
Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease.
J Immunol, 188 (2012), pp. 3522-3531
[8]
J.F. Casale, E.M. Corbeil, A.H. Patrick.
Identification of levamisole impurities found in illicit cocaine exhibits.
Microgram J, 6 (2008), pp. 82-89
Copyright © 2017. Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología
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