Letter to the Editor
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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A promising biomarker for cocaine-levamisole induced vasculitis" "tieneTextoCompleto" => true "saludo" => "Dear Editor:" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "e66" "paginaFinal" => "e67" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "José A. Gómez-Puerta, Carlos H. Muñoz, Adriana L. Vanegas-García, Tomás Urrego, Gloria Vásquez, Luis A. González" "autores" => array:6 [ 0 => array:4 [ "nombre" => "José A." "apellidos" => "Gómez-Puerta" "email" => array:1 [ 0 => "jagomez@clinic.cat" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Carlos H." 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"apellidos" => "González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Grupo de Reumatología, Universidad de Antioquia, Medellín, Colombia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Reumatología, Hospital Clínic, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hospital Universitario San Vicente Fundación, Medellín, Colombia" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Grupo de Inmunología Celular e Inmunogenética, GICIG, Universidad de Antioquia, Medellín, Colombia" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Servicio de Reumatología, Hospital Clínic, Villarroel 170, Escala 11-2 Planta, 08036 Barcelona, Spain." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Anticuerpos anti C1q. Un biomarcador prometedor para la vasculitis inducida por cocaína-levamisol" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a> Histopathological samples reveal pauci-inflammatory thrombotic diathesis accompanied with intravascular monocytes and evidence of complement activation.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">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, (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>13), polyarteritis nodosa (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4), LIVEN (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4) and Takayasu arteritis (<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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.</p><p id="par0020" class="elsevierStylePara elsevierViewall">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%, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). Mean anti C1q titers were significantly higher in patients with LIVEN than in other vasculitis (51.0<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>25.3 vs. 10.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.1<span class="elsevierStyleHsp" style=""></span>IU, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.04). Main clinical and serological characteristics including serum complement levels are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Recently, our group described a series of 11 patients with LIVEN.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a> ANCA (91%), lupus anticoagulant (73%), ANAS (45%), anti dsDNA (29%), anti Ro (29%) were most common autoantibodies.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a> 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.</p><p id="par0035" class="elsevierStylePara elsevierViewall">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.</p><p id="par0040" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a> Leffler et al.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a> demonstrated that <span class="elsevierStyleItalic">in vitro</span> 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.</p><p id="par0045" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> According to local authorities in Colombia, levamisole contaminates 40% of the market.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a> 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.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interest" ] 1 => array:2 [ "identificador" => "xack431397" "titulo" => "Acknowledgments" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cyclo: cyclophosphamide, PDN: prednisolone, MPDN: methylprednisolone.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age/gender \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of lesions \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Autoantibodies \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Serum complement<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Anti C1q antibodies \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17/male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ear necrosis, retiform purpura on legs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti MPO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C3: NormalC4: Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive (20.3<span class="elsevierStyleHsp" style=""></span>IU) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN 30<span class="elsevierStyleHsp" style=""></span>mg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21/male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rapidly progressive glomerulonephritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti MPO, aCL IgG, aCL IgM, lupus anticoagulant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C3: LowC4: Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive (116.4<span class="elsevierStyleHsp" style=""></span>IU) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN 60<span class="elsevierStyleHsp" style=""></span>mg/dayCyclo 1<span class="elsevierStyleHsp" style=""></span>g (pulses) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25/female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ear necrosis, retiform purpura on legs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti MPO, aCL IgG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C3: NormalC4: Low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive (64.4<span class="elsevierStyleHsp" style=""></span>IU) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDN 20<span class="elsevierStyleHsp" style=""></span>mg/day \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36/male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ear necrosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ANAs, Anti dsDNAAnti MPO, Anti Ro \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C3: NormalC4: Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative (3.1<span class="elsevierStyleHsp" style=""></span>IU) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MPDN 500<span class="elsevierStyleHsp" style=""></span>mg pulses plus PDN 40<span class="elsevierStyleHsp" style=""></span>m/day \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2151628.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Serum complement close to measurement of Anti-C1q antibodies.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical and serological characteristics of LIVEN patients.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Complications associated with use of levamisole-contaminated cocaine: an emerging public health challenge" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "K.C. 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We would like to thank Catalina Perez Koller and Liliana Marcela Peñaranda (Inova/Wefen) for assisting with sample management and analysis of antibodies.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/21735743/0000001500000005/v1_201910260908/S2173574319301339/v1_201910260908/en/main.assets" "Apartado" => array:4 [ "identificador" => "8400" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735743/0000001500000005/v1_201910260908/S2173574319301339/v1_201910260908/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574319301339?idApp=UINPBA00004M" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 1 | 8 | 9 |
| 2024 October | 32 | 33 | 65 |
| 2024 September | 25 | 16 | 41 |
| 2024 August | 46 | 39 | 85 |
| 2024 July | 31 | 30 | 61 |
| 2024 June | 34 | 27 | 61 |
| 2024 May | 50 | 24 | 74 |
| 2024 April | 33 | 24 | 57 |
| 2024 March | 28 | 29 | 57 |
| 2024 February | 30 | 26 | 56 |
| 2024 January | 32 | 22 | 54 |
| 2023 December | 27 | 22 | 49 |
| 2023 November | 42 | 25 | 67 |
| 2023 October | 54 | 27 | 81 |
| 2023 September | 97 | 32 | 129 |
| 2023 August | 29 | 17 | 46 |
| 2023 July | 23 | 15 | 38 |
| 2023 June | 16 | 24 | 40 |
| 2023 May | 26 | 19 | 45 |
| 2023 April | 19 | 5 | 24 |
| 2023 March | 50 | 19 | 69 |
| 2023 February | 42 | 21 | 63 |
| 2023 January | 26 | 22 | 48 |
| 2022 December | 45 | 24 | 69 |
| 2022 November | 30 | 19 | 49 |
| 2022 October | 51 | 27 | 78 |
| 2022 September | 25 | 19 | 44 |
| 2022 August | 27 | 38 | 65 |
| 2022 July | 29 | 35 | 64 |
| 2022 June | 24 | 25 | 49 |
| 2022 May | 23 | 41 | 64 |
| 2022 April | 28 | 31 | 59 |
| 2022 March | 28 | 57 | 85 |
| 2022 February | 45 | 27 | 72 |
| 2022 January | 52 | 27 | 79 |
| 2021 December | 39 | 45 | 84 |
| 2021 November | 40 | 36 | 76 |
| 2021 October | 38 | 46 | 84 |
| 2021 September | 27 | 40 | 67 |
| 2021 August | 21 | 28 | 49 |
| 2021 July | 21 | 17 | 38 |
| 2021 June | 13 | 25 | 38 |
| 2021 May | 34 | 39 | 73 |
| 2021 April | 64 | 90 | 154 |
| 2021 March | 36 | 22 | 58 |
| 2021 February | 24 | 16 | 40 |
| 2021 January | 21 | 16 | 37 |
| 2020 December | 26 | 18 | 44 |
| 2020 November | 22 | 17 | 39 |
| 2020 October | 17 | 15 | 32 |
| 2020 September | 25 | 17 | 42 |
| 2020 August | 19 | 22 | 41 |
| 2020 July | 13 | 15 | 28 |
| 2020 June | 10 | 6 | 16 |
| 2020 May | 19 | 15 | 34 |
| 2020 April | 17 | 11 | 28 |
| 2020 March | 4 | 2 | 6 |
| 2019 November | 1 | 0 | 1 |
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