Review Article
New Therapeutic Targets in Systemic Lupus
Nuevas dianas terapéuticas en el lupus sistémico (parte 1/2)
Walter A. Sifuentes Giraldo, María J. García Villanueva, Alina L. Boteanu, Ana Lois Iglesias, Antonio C. Zea Mendoza
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Servicio de Reumatología, Hospital Universitario Ramón y Cajal, Madrid, Spain
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La célula apoptótica expone en su superficie las vesículas apoptóticas conteniendo antígenos nucleares (1); debido a un deficiente aclaramiento de las partículas apoptóticas por el sistema mononuclearfagocítico, aquellas se acumulan (2) y ganan acceso a los linfocitos B autorreactivos, los cuales sintetizan autoanticuerpos (3); los IC formados por esos anticuerpos y sus respectivos antígenos nucleicos (4) tienen capacidad para activar el complemento y conducir a lesiones en los tejidos (5) y también para activar a las CDP (6); las CDP responden con la producción de IFN-( por vías dependientes de TLR7 y TLR9 (7); IFN-α tiene múltiples efectos sobre el sistema inmunitario que favorecen el desarrollo de autoinmunidad, como la diferenciación de linfocitos B a células plasmáticas productoras de anticuerpos, la activación de células T y la maduración de las células dendríticas. Todo ello conduce a un círculo reverberante que intensifica y perpetúa el proceso autoinmunitario. Otras dianas terapéuticas están representadas por los LB (8) los LT (9), las citocinas (10), las moléculas de coestimulación (11) y las vías de señalización intracelular (12). CDP: células dendríticas plasmocitoides; IC: inmunocomplejos; IFN: interferón; LB: linfocito B; MØ: macrófago; TCR: receptor de células T; TLR: <span class="elsevierStyleItalic">toll-like receptor</span>.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Walter A. Sifuentes Giraldo, María J. García Villanueva, Alina L. Boteanu, Ana Lois Iglesias, Antonio C. Zea Mendoza" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Walter A." "apellidos" => "Sifuentes Giraldo" ] 1 => array:2 [ "nombre" => "María J." "apellidos" => "García Villanueva" ] 2 => array:2 [ "nombre" => "Alina L." "apellidos" => "Boteanu" ] 3 => array:2 [ "nombre" => "Ana" "apellidos" => "Lois Iglesias" ] 4 => array:2 [ "nombre" => "Antonio C." 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Sifuentes Giraldo, María J. García Villanueva, Alina L. Boteanu, Ana Lois Iglesias, Antonio C. Zea Mendoza" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Walter A." "apellidos" => "Sifuentes Giraldo" ] 1 => array:2 [ "nombre" => "María J." "apellidos" => "García Villanueva" ] 2 => array:2 [ "nombre" => "Alina L." "apellidos" => "Boteanu" ] 3 => array:2 [ "nombre" => "Ana" "apellidos" => "Lois Iglesias" ] 4 => array:4 [ "nombre" => "Antonio C." "apellidos" => "Zea Mendoza" "email" => array:1 [ 0 => "azea.hrc@salud.madrid.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Servicio de Reumatología, Hospital Universitario Ramón y Cajal, Madrid, Spain" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuevas dianas terapéuticas en el lupus sistémico (parte 1/2)" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1521 "Ancho" => 2403 "Tamanyo" => 299025 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Spectrum of B cell depleting therapies: anti-CD20, anti-CD22 and anti-CD79 antibodies have an overlapping spectrum of action, including pre B or immature B cells up to activated and memory B cells, without affecting plasma cells. The anti-CD19 spectrum extends from pro B to plasmablasts and some plasma cells.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Mortality in Systemic Lupus Erythematosus (SLE) has been significantly reduced in the past 15<span class="elsevierStyleHsp" style=""></span>years but remains high. Bernatsky et al.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> followed 9<span class="elsevierStyleHsp" style=""></span>547 patients for a mean 8.1<span class="elsevierStyleHsp" style=""></span>years and found a global standardized mortality rate (relationship between observed deaths and expected deaths; SMR) of 2.4, higher in the group of patients under 40 (SMR: 10.7) and in those with a time since onset of disease of less than 1<span class="elsevierStyleHsp" style=""></span>year (SMR: 5.4); among the causes of death, the most important is still lupus nephritis (LN) (SMR: 7.9) and infections (SMR: 5.0). In opposition to the severity of these indicators the therapeutic arsenal against this disease up until some months ago was limited to aspirin, hydroxychloroquine and steroids; the rest of the drugs used, including cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine A and methotrexate, have not been approved for their use in SLE and have an indiscriminate immunosuppressant effect which often leads to severe adverse events and opportunistic infections. In spite of this, the use of these off label drugs, along with improved management of common comorbidities in this disease, including hypertension, dyslipidemia, nephrotic syndrome, etc., has considerably improved its long-term prognosis, although due to their narrow therapeutic margin leads some patients to present adverse events that worsen their life quality and expectancy, some do not reach an adequate control of the disease and others present frequent flares.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> For these reasons, research into new treatments becomes a universally recognized need. Fortunately, a better understanding of the pathogenic mechanisms involved in it has allowed for the identification of new targets that could improve the efficacy and safety of current treatments,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> although doubts on their cost-effectiveness and long-term safety remain.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">A Panoramic View of the Physiopathology of Systemic Lupus Erythematosus</span><p id="par0010" class="elsevierStylePara elsevierViewall">In the pathogenesis of SLE there are at least two well-differentiated compartments. On the one hand, the physiopathology of autoimmunity and its consequence, autoantibodies, which seem a product of interactions genetic and exogenous environmental factors, which act on the immune system leading to events that trigger a flare in a physiologic process, namely autoimmunity. It is known that in this immune response, nuclear antigens and their corresponding autoantibodies lead to an amplifying effect through mechanisms of both innate and acquired immunity. The second compartment of SLE pathogenesis is the development of inflammation and damage in target organs.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Apoptotic cells seem to be the origin of autoantibodies (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>); specifically apoptotic vesicles are exposed on the surface of the apoptotic cell, which contains cellular debris, among it present the nucleic acid and nucleotides. Under normal circumstances, it is the monocytic-macrophagic system, mainly macrophages, which is in charge of removing apoptotic debris from the circulation. The complement system participates in this process, through the opsonization of apoptotic particles by C<span class="elsevierStyleInf">3b</span>.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Other molecules, secreted by the apoptotic cell, also participate in the process, such as lysophosphatidylcholine, allowing the attraction of phagocytes (find me signals) and molecules exposed on their surface, such as oxidized phosphatidylserine, recognized by scavenger receptors on the surface of the phagocyte, such as CD36 and oxLDL, facilitating their internalization (eat me signals).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In SLE there are both an increase in apoptosis as well as a deficient clearance of apoptotic cells and both alterations lead to the accumulation of secondary necrotic material which may trigger inflammation, and modified nuclear fragments that are interpreted as danger signals by the immune system, leading to the production of antibodies for their neutralization on the part of self-reactive B lymphocytes.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">This secretion of autoantibodies and their binding to nuclear antigens lead to the formation of immune complexes (IC), fundamentally DNA/anti-DNA, with a capacity to deposit in tissues where, along with the participation of the complement system, will produce lesions, something best exemplified in the glomerurlus.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> These IC with nucleic products are also taken up by plasmocytoid dendritic cells (PDC) through Fcγ-IIAr receptors and engulfed into endosomes. Toll-like receptors (TLR) 7 and 9, anchored in the endosomal membrane, are activated by these IC which sets in motion a transduction cascade leading to the activation of <span class="elsevierStyleItalic">IRF 7/5</span> and <span class="elsevierStyleItalic">NFκB</span> transcription factors, which derives into the production of great quantities of IFN-α—PDC are the “professional” producers of IFNα—and, to a lesser extent, of other proinflammatory cytokines, such as IL-6.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The capacity of the IC with nucleic content to unleash an IFN response on the part of PDC is the reason they are known as “interpherogenic complexes”. It is interesting to note that hydroxychloroquine, one of the oldest drugs employed in SLE, which inhibits the binding of nucleic acid strands to these TLRs through the elevation of endosomal pH<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and therefore is considered a TLR inhibiting drug.</p><p id="par0025" class="elsevierStylePara elsevierViewall">IFN-α secreted by PDC has autoimmunity enhancing effects: it promotes the maturation of dendritic cells, activates T lymphocytes (TL) (including autoreactive cells that may have escaped central tolerance) and intervenes in BL differentiation to auto-antibody producing dendritic cells, which in time leads to a larger formation of interpherogenic immune complexes. In this manner, IFN-α is a great activator of the immune system and its appearance completes a circuit (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) in which when the presence of plasmatic cells is increased so is autoantibody formation and immune complexes with nucleic acids, which in turn activates more PDC, which then produces more IFN-α and closes a vicious circle that maintains and multiplies the mechanism of autoimmunity.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Microarray studies of oligonucleotides have shown that patients with SLE have an overexpression of INF and granulocyte production-related genes (see below), supporting the hypothesis that IFN-α plays a principal role in the physiopathology of this disease.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Therapeutic Targets</span><p id="par0035" class="elsevierStylePara elsevierViewall">Research into new targets aims at specific intervention at concrete points of the pathogenic pathways; therefore avoiding conventional immunosuppressant mechanisms that, along with the desirable effect, leads to other undesirable ones. Drugs under current research in SLE and other autoimmune diseases are directed both against cell targets, including BL surface molecules (CD20, CD22, and CD19) and costimulation (CTLA-4, CD40/CD40L, ICOS/B7-H2), as well as extracellular (cytokines, chemokines) and intracellular ones, in other words, molecules that intervene in signal transduction and transcription, such as the proteosome.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Access to many of these targets has been possible thanks to the advent of biotechnological drugs: monoclonal antibodies, and recombinant fusion proteins. Monoclonal antibodies, usually IgG, are identified by the “mab” suffix (as in <span class="elsevierStyleItalic">monoclonal antibody</span>); the suffix “omab” indicates a murine origin; “ximab” refers to chimeric antibodies (approximately 30% of which is murine); “zumab”, to humanized (under 10% murine), and “umab” referring to completely human antibodies. The “cept” suffix is used for recombinant-derived fusion proteins. To these one has to add SMIPs (small modular immunopharmaceuticals), polypeptides that in a single strand integrate the binding, effector and hinge domains, exactly as an immunoglobulin does, but are small and therefore with a better penetration into tissues and cells.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Intracellular targets, such as <span class="elsevierStyleItalic">tyrosine kinases</span> and <span class="elsevierStyleItalic">Janus kinases</span>, among others, are inhibited through chemical, not biotechnological compounds, with a low molecular weight (<1<span class="elsevierStyleHsp" style=""></span>kDa), called “small molecules”, identified by the “inib” (inhibitor) or “imod” (immunomodulator) suffix. In addition to their size, small molecules have some advantages over biotechnological drugs such as their lower cost, oral administration and the absence of immunogenicity and its consequences, such as the formation of human anti-chimeric antibodies (HACA) or anti-human (HAHA), which inhibit drug action.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Toleragens</span><p id="par0045" class="elsevierStylePara elsevierViewall">As mentioned above, defective clearance of apoptotic debris with nucleic content and a loss of tolerance are considered as the factors that determine the formation of antibodies against nuclear components.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> A target that has called the attention of researchers is to precisely achieve that these nucleic danger signals loose their immunogenic capacity, in other words, to tolerate them with the intention that they not unleash an autoantibody response. With this in mind the so-called “toleragens” have been employed. Among them, abetimus and edretide have come some way but their development was interrupted because, in spite of reducing the production of autoantibodies, do not lead to improvement of disease.<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">–</span><p id="par0050" class="elsevierStylePara elsevierViewall">Abetimus (Riquent<span class="elsevierStyleSup">®</span>, Rentol<span class="elsevierStyleSup">®</span>). It is a synthetic molecule formed by four deoxynucleotide sequences joined by a polyethyleneglycol base, with the ability of cross linking DNA-specific BL receptors in the absence of T cells and inducing anergy or apoptosis. Tested in several SLE trials, it has been seen to reduce the concentration of anti-DNA antibodies and normalize complement<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>; however, they do not shorten the onset of a new episode of nephritis, leading to the interruption of the ambitious ASPEN trial, with 890 patients with LN, in 2009.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">–</span><p id="par0055" class="elsevierStylePara elsevierViewall">Edratide (TV-4710). Something similar occurred with edratide, a 19 amino acid synthetic peptide with a sequence based on the complementarity determining region 1 (hCDR1) of an anti-DNA monoclonal antibody,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> whose development was interrupted due to lack of efficacy after the PRELUDE tiral in 2007.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">–</span><p id="par0060" class="elsevierStylePara elsevierViewall">Lupuzor (P140, IPP-201101, Rigerimod). The 140 phosphopeptide formed by phosphorylated residues 131–151 of the 70<span class="elsevierStyleHsp" style=""></span>K protein of the spliceosome inside the U1-RNP antigen has an incompletely understood mechanism of action but seemingly promotes anergy or deletion of self-reactive T lymphocytes, partially or totally antagonizing the T cell receptor (TCR) or through an effect on regulator TL (Treg). A phase IIb trial results show that in addition to being safe and well tolerated, it is capable of reducing the clinical and biological activity of SLE.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> A phase III trial is currently underway looking to confirm these results.</p></li></ul></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Complement Inhibition</span><p id="par0065" class="elsevierStylePara elsevierViewall">The complement system plays a double role in the physiopathogenesis of SLE: its initial components intervenes in opsonization and clearance of apoptotic bodies so the deficit of the first components lead to the accumulation of dangerous material and predispose the appearance of disease. On the other hand, terminal components intervene in the inflammatory process that leads to tissue damage and is associated with clinical manifestations and disease progression, evidenced by the elevation of serum levels of C<span class="elsevierStyleInf">5a</span> and C<span class="elsevierStyleInf">5b</span>–C<span class="elsevierStyleInf">9</span> during flares.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In mouse models, the administration of anti anti-C<span class="elsevierStyleInf">5</span> improves the progression of renal disease, delays the appearance of proteinuria and increases survival. For these reasons, inhibition of activation of the terminal sequence of complement, conserving the initial cascade, constitutes an attractive target.<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">–</span><p id="par0070" class="elsevierStylePara elsevierViewall">Eculizumab (Soliris<span class="elsevierStyleSup">®</span>). Humanized monoclonal antibody that blocks C<span class="elsevierStyleInf">5</span> and prevents cleavage into proinflammatory fragments C<span class="elsevierStyleInf">5a</span> and C<span class="elsevierStyleInf">5b</span>, currently approved for the treatment of paroxystic nocturnal hemoglobinuaria. A phase I trial lasting 56<span class="elsevierStyleHsp" style=""></span>days in SLE patients showed its efficacy and safety and led to improvement in this period of time.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> However, the risk of meningococcal infection represented by the inactivation of the terminal sequence of complement may limit its use in humans. In spite of this, a phase II trial is currently underway to evaluate its safety in membranous lupus nephritis.</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">–</span><p id="par0075" class="elsevierStylePara elsevierViewall">Other complement inhibitors. Another monoclonal antibody vs C<span class="elsevierStyleInf">5</span>, pexelizumab, has been used in acute myocardial infarction and a recombinant antagonist of the human receptor for C<span class="elsevierStyleInf">5a</span> (C<span class="elsevierStyleInf">5a</span>RAM; CGS 27913) has been shown to improve nephritis in the mouse MRL/lpr model,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> but for the time being neither has been used in humans.</p></li></ul></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Toll-like Receptor Inhibition</span><p id="par0080" class="elsevierStylePara elsevierViewall">Dendritic cells are a heterogeneous group of cells derived from the bone marrow, which participate in immunovigilance, antigen presentation and tolerance. There are 2 subtypes, conventional dendritic cells and PDC, the latter playing a principal role in the pathogenesis of SLE.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> PDC participate in innate immunity against virus and intracellular bacteria through TLR7 (for single stranded RNA) And TLR9 (for hypomethylated DNA), localized in the endosome and whose activation results in the secretion of type I interferons and among them, IFN-α.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> The great quantities of IFN-α found in patients with SLE, disproportionate to the low concentration of PDC in peripheral blood, are attributed to the presence of activated PDC in lymphoid nodules, skin and other target organs.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">–</span><p id="par0085" class="elsevierStylePara elsevierViewall">IRS 954. The potential role of PDC as a therapeutic target has been tested indirectly in SLE through inhibition of TLR, intending to stop intracellular signaling leading to synthesis of IFN-α by these cells and avoiding its production. Oligo-deoxynucleotides (ODN) containing non-methylated CpG sequences act as antagonists of TLR9, which has led to the development of modified sequences substituting them for methylated ribonucleotides, obtaining antagonists for TLR9, TLR7 or both.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> One of those dual antagonists, IRS 954 has been tested in a mouse model (NZB×NZW)F1, showing an increase in survival and a reduction in specific autoantibody levels, as well as in proteinuria, severity of glomerulonephritis and organ damage.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">–</span><p id="par0090" class="elsevierStylePara elsevierViewall">ST2825. The initial signal produced by TLR7 and TLR9 is transduced exclusively through the adaptor protein MyD88, whose absence reduces renal damage in mouse models.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> A mimetic peptide called ST2825, which interferes with MyD88, interrupting the signaling pathway of these TLRs. ST2825 has shown in vitro to block the activation induced by TLR9 in self-reactive memory BL obtained from SLE patients.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In spite of this being a promising treatment, it has still not been tested in human SLE.</p></li></ul></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Interferon Alpha Antagonists</span><p id="par0095" class="elsevierStylePara elsevierViewall">Current experimental and genetic evidence indicates that IFN-α is a key mediator in the pathogenesis of SLE. In addition to its elevated levels on the blood of patients with SLE and its known effect on BL and TL, studies with oligonucleotide microarrays showing that up to 70% of adults and 95% of children with SLE have an overexpression of IFN and granulocyte production related genes have to be added, introducing the notion that neutrophils play a pathogenic role in SLE. This pattern of gene expression is called the IFN <span class="elsevierStyleItalic">signature</span>.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> This signature has been found in other autoimmune diseases, such as RA and multiple sclerosis (MS) and not all patients with SLE have this characteristic, making it more a signature of autoimmunity than of SLE. A process called <span class="elsevierStyleItalic">necrosis extracellular trap</span> (NET), occurring after the death of neutrophils (therefore called NETosis), could be the link between IFN and neutrophils in the pathogenesis of SLE.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Both for its biologic and genetic effects, IFN-α is considered one of the most sought after therapeutic targets today. 2 monoclonal antibodies block IFN-α, sifalimumab and rontalizumab, and immunization against this cytokine through a cuinoid has started being tested in humans.<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">–</span><p id="par0100" class="elsevierStylePara elsevierViewall">Sifalimumab (MEDI-545). A completely human anti-IFN-α antibody, it has been tested in phase I trials showing a dose dependent inhibition of the expression of IFN-α induced genes (IFN signature), as well as a tendency to improve activity with respect to the placebo group, a reduced need for immunosuppressants and a significant reduction in flares.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> A phase IIb trial is currently in its recruitment stage.</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">–</span><p id="par0105" class="elsevierStylePara elsevierViewall">Rontalizumab. An anti-IFN-α humanized antibody currently undergoing phase II trial (ROSE) in 210 patients with moderate to severe SLE (active July 2011).<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">–</span><p id="par0110" class="elsevierStylePara elsevierViewall">IFN-α-quinoide. An alternative to the administration of monoclonal antibodies is the generation of a natural secretion of anti-IFN-α neutralizing antibodies, akin to a vaccine, called quinoid. Quinoids are being developed vs TNF-α and al VEGF. Quinoids are formed by heterocomplexes of the target cytokine, in this case IFN-α, with a carrier protein such as barnacle hemocyanin, which induce a natural polyclonal response vs IFNα epitopes. A mouse model, where this IFN-α-quinoid was used induced neutralizing antibodies without a cell response or apparent collateral effects, capable of controlling lupus manifestations, including renal lesion.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The results of a phase I-II in patients with mild to moderate SLE have recently been presented<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> and indicate that IFN-α-quinoid leads to a strong enough anti-IFN-α antibody response to neutralize the IFN signature and elevate C<span class="elsevierStyleInf">3</span> levels.</p></li></ul></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Interferon Gamma Antagonists</span><p id="par0115" class="elsevierStylePara elsevierViewall">Along with IFN-α’s important role, IFN-γ intervenes in the pathogenesis of SLE by being a potent mediator of inflammation and inducing the expression of the BL soluble stimulator (BLyS).<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> A completely human monoclonal antibody has been developed against IFN-γ (AMG 811, fontolizumab), with phase I trials in recruitment stages for LN<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> and discoid lupus.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">B Cell Depletion</span><p id="par0120" class="elsevierStylePara elsevierViewall">Another point where the pathogenic circle that we have referred to can be inhibited (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) is BL, aiming for their depletion.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> Although the initial objective was to reduce the production of auto-antibodies it has been noticed that B cells, in addition to synthesizing antibodies, have other equally important functions: they are efficient antigen presenting cells (APC), regulate the function of self-reactive T cells, influence other APC and produce diverse cytokines. Regulator B cells (Breg) constitute a recently described subpopulation that produce IL-10 and TGFβ, 2 cytokines with immune suppressing activity: they inhibit T cell differentiation to an inflammatory Th2 phenotype as well as activation of macrophages and the proinflammatory functions of dendritic cells, among others.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> These BL regulating functions are induced through activation of the B cell receptor (BCR, CD40) or TLR9 and mediated by IL-10. This explains why B cell depletion not only leads to a diminished production of antibodies but also produces many more effects, some of which are beneficial in suppressing autoimmunity and therefore convenient to maintain. The concept of Breg cells will oblige researchers, sooner or later, to reanalyze B cell depletion therapeutic strategies.</p><p id="par0125" class="elsevierStylePara elsevierViewall">B cell depletion can be achieved by 2 pathways: through monoclonal antibodies vs surface molecules, such as CD19, CD20, and CD22, or inhibiting survival factors such as BLyS (B lymphocyte stimulator) or APRIL (A proliferation-inducing ligand).</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Anti-CD20 Antibodies</span><p id="par0130" class="elsevierStylePara elsevierViewall">CD20 is a membrane protein expressed on pre B and mature B lymphocytes, but not plasma cells (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). In light of the central roles BL play in the pathogenesis of SLE, a lot of research has delved onto the development of at least 6 anti-CD20 monoclonal antibodies, each with its own characteristics. In addition to rituximab (RTX), there is ocrelizumab (OCZ), with a greater affinity for CD20 than its competitors; ofatumumab that induces greater apoptosis and has been tested in MS; veltuzumab, tested only in lymphoma, and finally two drugs produced with SMIP technology: SBI-087 and TRU-015. All of these lead to B cell depletion through a triple mechanism that to a certain degree involves apoptosis, cell mediated cytotoxicity or antibody-mediated cytotoxicity.<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">–</span><p id="par0135" class="elsevierStylePara elsevierViewall">Rituximab. 2 large randomized clinical trials with RTX in SLE have been undertaken. The EXPLORER trial, in 169 patients with non-renal and non-neurological SLE, with moderate to severe activity, had the objective of evaluating complete or partial response based on the BILAG scale and the absence of flares. No difference with placebo was found; however, the response in Hispanics and African Americans was better (33.8% vs 15.7%; <span class="elsevierStyleItalic">P</span>=.04) and an important reduction in anti-DNA levels as well as improvement of hypocomplementemia was seen.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> The LUNAR trial, done in 72 patients with type III and IV LN had the objective of evaluating complete and partial responses at week 52 of treatment. In spite of a larger number of responders in the RTX group, no significant difference was found compared to placebo. As in EXPLORER, better responses and anti-DNA normalization was seen in African Americans and hispanics.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Both studies used 2 doses of 1<span class="elsevierStyleHsp" style=""></span>g separated by 15<span class="elsevierStyleHsp" style=""></span>days.</p></li></ul></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">These results stand in contrast with several open studies that found improvement with RTX in approximately 60% of cases and a renal response in up to 66%.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> This has led to controversy and a detailed analysis of the methodology employed. Among the possibilities explaining these discrepancies are the fact that some trials allowed the use of steroids and immunosuppressants that could have masked the antiCD20 effect that studies were too short (with RTX being more effective in the medium to long terms) that they included patients who were not severely ill and that BILAG is a very demanding score to evaluate response to treatment.<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">–</span><p id="par0145" class="elsevierStylePara elsevierViewall">Ocrelizumab. Humanized anti-CD20 that theoretically reduces the development of HACA that occur with the chimerical RTX. It has been tested in the BELONG trial in patients with type III and IV LN, in which 127 patients received the 400<span class="elsevierStyleHsp" style=""></span>mg dose and 128 received 1000<span class="elsevierStyleHsp" style=""></span>mg. The objective was to evaluate the both complete and partial responses at weeks 48 and 96; however, the study had to be interrupted due to an unexpected incidence of severe adverse events, including severe infections. The analysis of the results obtained up until its untimely interruption. At week 32, showed a numerical superiority in the OCZ group compared to placebo, but this difference was not statistically significant, and no differences were found between doses.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p></li></ul></p><p id="par0150" class="elsevierStylePara elsevierViewall">The BEGIN trial, a phase II study designed to evaluate safety and efficacy of OCZ in patients with moderate to severe SLE without renal affection was interrupted due to negative data attained by RTX in a study with overlapping designs.<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">–</span><p id="par0155" class="elsevierStylePara elsevierViewall">SBI-087. Is a SMIP<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> developed for SLE and currently undergoing phase I studies and with preliminary results that suggest it is well tolerated.</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">–</span><p id="par0160" class="elsevierStylePara elsevierViewall">TRU-015. It is also a single chain against CD20 with a longer half life than conventional anti-CD20, designed to increase the potency of antibodies acting through cellular cytotoxicity; its phase II results in RA are promising and confirmed its capacity to produce B cell deletion. Phase I studies have been done in SLE.</p></li></ul></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Anti-CD22 Antibodies</span><p id="par0165" class="elsevierStylePara elsevierViewall">CD22 is a carbohydrate binding transmembrane glycoprotein, like sialic acid, with an Ig domain on its N-terminal. Once active it is internalized and functions as a receptor-inhibitor regulating migration and BL activity.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a><ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">–</span><p id="par0170" class="elsevierStylePara elsevierViewall">Epratuzumab. EPZ is the only anti-CD22 used in SLE. The first 2 trials, ALLEVIATE A (moderate SLE) and ALLEVIATE B (severe SLE), evaluated the efficacy of 360<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> and 720<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> doses of EPZ vs placebo, but were suspended due to lack of drug availability. In spite of this, result analysis at the moment of its final precipitate demonstrated an important reduction in clinical activity and steroid requirements, as well as improvements in the quality of life.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> The third trial, EMBLEM, was carried out in 227 patients with moderate or severe SLE excluding LN III–IV and severe neuropsychiatric lupus; it showed a significant difference in the percentage of responding patients in the active group compared to placebo (43% vs 21%; <span class="elsevierStyleItalic">P</span>=.02), with no differences in adverse events.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> These promising results have led to a global trial, EMBODY, with patient recruitment currently underway.</p></li></ul></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Other Anti-B Cell Molecules</span><p id="par0175" class="elsevierStylePara elsevierViewall">Although no trials exist for human lupus, other potential surface molecules that may act as therapeutic targets on B cells are:<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">–</span><p id="par0180" class="elsevierStylePara elsevierViewall">Anti-CD79. CD79 is a BCR associated transmembrane protein with an overlapping spectrum of depletion with anti-CD20 (pre-B to mature B) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a> but acts through a combination of depletion and BCR signal interruption.</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">–</span><p id="par0185" class="elsevierStylePara elsevierViewall">Anti-CD19 (MDX-1342). Probably the likeliest candidate for an SLE trial, it has a depletion spectrum ranging from pro-B to a fraction of plasma cells<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). So far it has only been tested for RA and hematologic diseases.</p></li></ul></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ethical disclosures</span><p id="par0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Protection of human and animal subjects</span>. The authors declare that no experiments were performed on humans or animals for this investigation.</p><p id="par0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Confidentiality of data</span>. The authors declare that no patient data appears in this article.</p><p id="par0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Right to privacy and informed consent</span>. The authors declare that no patient data appears in this article.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of Interest</span><p id="par0205" class="elsevierStylePara elsevierViewall">Antonio C. Zea Mendoza is PI for clinical trials by Abbott Lab., MSD, Astra-Zeneca and UCB Pharma.</p><p id="par0210" class="elsevierStylePara elsevierViewall">Alina L. Boteanu collaborates in a study with Astra-Zeneca.</p><p id="par0215" class="elsevierStylePara elsevierViewall">Walter A. Sifuentes Giraldo, María J. García Villanueva and Ana Lois Iglesias have no disclosures to make.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:2 [ "identificador" => "xres125832" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec113127" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres125831" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec113126" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "A Panoramic View of the Physiopathology of Systemic Lupus Erythematosus" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Therapeutic Targets" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Toleragens" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Complement Inhibition" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Toll-like Receptor Inhibition" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Interferon Alpha Antagonists" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Interferon Gamma Antagonists" ] 12 => array:3 [ "identificador" => "sec0045" "titulo" => "B Cell Depletion" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Anti-CD20 Antibodies" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Anti-CD22 Antibodies" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Other Anti-B Cell Molecules" ] ] ] 13 => array:2 [ "identificador" => "sec0065" "titulo" => "Ethical disclosures" ] 14 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of Interest" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-12-26" "fechaAceptado" => "2012-01-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec113127" "palabras" => array:4 [ 0 => "Lupus erythematosus" 1 => "Pathogenesis" 2 => "Treatment" 3 => "Biological therapies" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec113126" "palabras" => array:4 [ 0 => "Lupus eritematoso sistémico" 1 => "Patogenia" 2 => "Tratamiento" 3 => "Terapias biológicas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Glucocorticoids, aspirin, antimalarials and conventional immunosuppressants are the mainstay of treatment of Systemic Lupus Erythematosus (SLE). Until recently, the first three were the only agents approved for treatment. A better understanding of the pathophysiology of the immune system has identified new therapeutic targets. In fact, belimumab, a human monoclonal antibody to BLyS inhibitor has become, in recent months, the first drug approved for the treatment of SLE since 1957, underscoring difficulties of all kinds, including economic and organizational ones inherent to clinical trials on this disease. Many other molecules are in various stages of development and soon will have concrete results. In this review, we examined the mechanism of action and most relevant clinical data for these molecules.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Glucocorticoides, aspirina, antipalúdicos e inmunosupresores convencionales constituyen la base del tratamiento del lupus eritematoso sistémico (LES). Hasta recientemente, los 3 primeros eran los únicos agentes aprobados para su tratamiento. El mejor conocimiento de la fisiopatología del sistema inmunitario ha permitido identificar nuevas dianas terapéuticas. De hecho, belimumab, un anticuerpo monoclonal humano inhibidor de BLyS, se ha convertido hace pocos meses en el primer fármaco aprobado para el tratamiento del LES desde 1957, lo que subraya las dificultades de todo tipo, incluyendo las económicas y organizativas, inherentes a los ensayos clínicos sobre esta enfermedad. Otras muchas moléculas se encuentran en distintas fases de desarrollo y en poco tiempo dispondremos de resultados concretos. En esta revisión repasamos el mecanismo de acción y los datos clínicos más relevantes de estas moléculas.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Sifuentes Giraldo WA, et al. Nuevas dianas terapéuticas en el lupus sistémico (parte 1/2). Reumatol Clin. 2012;8:201–7.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2028 "Ancho" => 3139 "Tamanyo" => 764648 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Panoramic vision of pathogenesis of Systemic Lupus Erythematosus. The apoptotic cell exposes on its surface apoptotic vesicles with nuclear antigens (1); due to a deficient clearance mechanism by the macrophage system, they accumulate (2) and gain access to autoreactive B lymphocytes, which synthesize autoantibodies (3); the IC formed (4) have the capacity to activate complement and damage tissue (5) and activate PDC (6); these respond by producing IFN-( by TLR7 and TLR9 dependent pathways (7); IFN-α has multiple effects on the immune system that favors autoimmunity, such as the differentiation of B cells to antibody producing plasma cells, T cell activation and dendritic cell maturation. All of these lead to a vicious circle that intensifies and perpetuates the autoimmune process. Other therapeutic targets are BL (8) TL (9), cytokines (10), costimulation molecules (11) and intracellular signaling pathways (12). PDC, plasmocytoid dendritic cells; IC, immune complexes; IFN, interferon; BL, B lymphocyte; MØ, macrophage; TCR, T cell receptor; TLR, <span class="elsevierStyleItalic">toll-like receptor</span>.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1521 "Ancho" => 2403 "Tamanyo" => 299025 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Spectrum of B cell depleting therapies: anti-CD20, anti-CD22 and anti-CD79 antibodies have an overlapping spectrum of action, including pre B or immature B cells up to activated and memory B cells, without affecting plasma cells. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 14 | 21 | 35 |
| 2024 October | 115 | 61 | 176 |
| 2024 September | 84 | 55 | 139 |
| 2024 August | 119 | 70 | 189 |
| 2024 July | 93 | 56 | 149 |
| 2024 June | 100 | 67 | 167 |
| 2024 May | 101 | 50 | 151 |
| 2024 April | 147 | 52 | 199 |
| 2024 March | 81 | 61 | 142 |
| 2024 February | 90 | 74 | 164 |
| 2024 January | 87 | 50 | 137 |
| 2023 December | 76 | 37 | 113 |
| 2023 November | 104 | 60 | 164 |
| 2023 October | 96 | 52 | 148 |
| 2023 September | 238 | 72 | 310 |
| 2023 August | 245 | 22 | 267 |
| 2023 July | 84 | 40 | 124 |
| 2023 June | 137 | 49 | 186 |
| 2023 May | 192 | 28 | 220 |
| 2023 April | 78 | 20 | 98 |
| 2023 March | 120 | 71 | 191 |
| 2023 February | 113 | 50 | 163 |
| 2023 January | 76 | 45 | 121 |
| 2022 December | 96 | 63 | 159 |
| 2022 November | 138 | 50 | 188 |
| 2022 October | 106 | 77 | 183 |
| 2022 September | 113 | 74 | 187 |
| 2022 August | 146 | 47 | 193 |
| 2022 July | 96 | 54 | 150 |
| 2022 June | 88 | 48 | 136 |
| 2022 May | 84 | 68 | 152 |
| 2022 April | 106 | 68 | 174 |
| 2022 March | 93 | 79 | 172 |
| 2022 February | 82 | 78 | 160 |
| 2022 January | 89 | 66 | 155 |
| 2021 December | 41 | 49 | 90 |
| 2021 November | 60 | 56 | 116 |
| 2021 October | 117 | 82 | 199 |
| 2021 September | 64 | 56 | 120 |
| 2021 August | 67 | 67 | 134 |
| 2021 July | 45 | 61 | 106 |
| 2021 June | 66 | 62 | 128 |
| 2021 May | 81 | 64 | 145 |
| 2021 April | 187 | 150 | 337 |
| 2021 March | 100 | 46 | 146 |
| 2021 February | 45 | 33 | 78 |
| 2021 January | 52 | 37 | 89 |
| 2020 December | 38 | 41 | 79 |
| 2020 November | 64 | 32 | 96 |
| 2020 October | 36 | 17 | 53 |
| 2020 September | 55 | 43 | 98 |
| 2020 August | 50 | 36 | 86 |
| 2020 July | 28 | 28 | 56 |
| 2020 June | 46 | 38 | 84 |
| 2020 May | 47 | 28 | 75 |
| 2020 April | 28 | 23 | 51 |
| 2020 March | 25 | 9 | 34 |
| 2020 February | 1 | 0 | 1 |
| 2020 January | 4 | 0 | 4 |
| 2019 September | 6 | 0 | 6 |
| 2019 June | 2 | 0 | 2 |
| 2019 March | 2 | 0 | 2 |
| 2019 January | 1 | 0 | 1 |
| 2018 May | 17 | 1 | 18 |
| 2018 April | 183 | 12 | 195 |
| 2018 March | 186 | 19 | 205 |
| 2018 February | 219 | 4 | 223 |
| 2018 January | 121 | 3 | 124 |
| 2017 December | 204 | 7 | 211 |
| 2017 November | 148 | 9 | 157 |
| 2017 October | 128 | 8 | 136 |
| 2017 September | 128 | 11 | 139 |
| 2017 August | 137 | 10 | 147 |
| 2017 July | 159 | 10 | 169 |
| 2017 June | 201 | 9 | 210 |
| 2017 May | 209 | 13 | 222 |
| 2017 April | 149 | 12 | 161 |
| 2017 March | 229 | 7 | 236 |
| 2017 February | 240 | 5 | 245 |
| 2017 January | 141 | 10 | 151 |
| 2016 December | 229 | 29 | 258 |
| 2016 November | 223 | 22 | 245 |
| 2016 October | 247 | 16 | 263 |
| 2016 September | 312 | 20 | 332 |
| 2016 August | 351 | 14 | 365 |
| 2016 July | 109 | 31 | 140 |
| 2015 December | 3 | 0 | 3 |
| 2015 November | 1 | 30 | 31 |
| 2015 October | 7 | 27 | 34 |
| 2015 September | 5 | 0 | 5 |
| 2015 August | 2 | 0 | 2 |
| 2015 July | 83 | 14 | 97 |
| 2015 June | 123 | 15 | 138 |
| 2015 May | 186 | 28 | 214 |
| 2015 April | 171 | 31 | 202 |
| 2015 March | 232 | 21 | 253 |
| 2015 February | 222 | 26 | 248 |
| 2015 January | 134 | 24 | 158 |
| 2014 December | 154 | 15 | 169 |
| 2014 November | 160 | 24 | 184 |
| 2014 October | 164 | 16 | 180 |
| 2014 September | 130 | 22 | 152 |
| 2014 August | 172 | 29 | 201 |
| 2014 July | 134 | 25 | 159 |
| 2014 June | 158 | 26 | 184 |
| 2014 May | 154 | 29 | 183 |
| 2014 April | 166 | 20 | 186 |
| 2014 March | 189 | 39 | 228 |
| 2014 February | 153 | 24 | 177 |
| 2014 January | 141 | 27 | 168 |
| 2013 December | 148 | 30 | 178 |
| 2013 November | 168 | 27 | 195 |
| 2013 October | 150 | 42 | 192 |
| 2013 September | 136 | 39 | 175 |
| 2013 August | 149 | 53 | 202 |
| 2013 July | 155 | 39 | 194 |
| 2013 June | 118 | 51 | 169 |
| 2013 May | 131 | 66 | 197 |
| 2013 April | 160 | 59 | 219 |
| 2013 March | 113 | 86 | 199 |
| 2013 February | 112 | 63 | 175 |
| 2013 January | 165 | 80 | 245 |
| 2012 December | 144 | 51 | 195 |
| 2012 November | 198 | 49 | 247 |
| 2012 October | 164 | 40 | 204 |
| 2012 September | 59 | 17 | 76 |
Show all
