Review
Statins and autoimmunity
Estatinas y autoinmunidad
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class="elsevierStyleSup">1</span>" "identificador" => "fn0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Vall d’Hebron, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Inmunología, Hospital Vall d’Hebron, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estatinas y autoinmunidad" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1693 "Ancho" => 2255 "Tamanyo" => 420755 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Immune-mediated necrotizing myopathy. (a) Haematoxylin–eosin. (b) Gomori's trichrome. (c) Immunohistochemical staining with major histocompatibility complex type <span class="elsevierStyleSmallCaps">i</span>. (d) Negative control (courtesy of Professor JM Grau Junyent, Muscle Research Unit, IDIBAPS, Hospital Clinic, Barcelona, Spain).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), more commonly known as statins, are the most commonly used drugs in the treatment of hypercholesterolemia and the prevention of both, primary and secondary cardiovascular diseases and associated atherosclerosis. It is estimated that 50 million people receive statin therapy in the world, and could be many more if the new therapeutic guidelines proposed by some international organizations are approved.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In general, these drugs tend to have a good tolerance. Moreover, in experimental trials, both <span class="elsevierStyleItalic">in vitro</span> as well as <span class="elsevierStyleItalic">in vivo</span>, other biological effects associated with statins have been found, not necessarily related to the reduction of plasma cholesterol, known as pleiotropic effects,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">3</span></a> which are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. The extent of these effects is of such interest and diversity that it helps to explain, at least in part, some of the beneficial actions of statins, particularly in connection with a possible anti-inflammatory, immunomodulatory, or antithrombotic effect, and potentially useful against some chronic diseases, such as osteoporosis, and dementia, including Alzheimer's disease.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The immunomodulatory effects are included among the unexpected effects of statins, which are the object of this review.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">4</span></a> These drugs appear to play an adjuvant therapeutic role in some autoimmune diseases due not only to their possible anti-inflammatory and immunomodulatory nature, but also their ability to minimize the atherogenic potential of both the disease itself and the drugs used for treatment, including glucocorticoids.<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">5–7</span></a> The ability of statins to inhibit the expression of molecules of the major histocompatibility complex (HLA) class <span class="elsevierStyleSmallCaps">ii</span> in antigen presenting cells can cause a decrease in the activation of Th1 lymphocytes and the inhibition of proinflammatory cytokine secretion.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">8</span></a> In addition, the immunomodulatory effect of these drugs may partly depend on a decreased Th17<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">9</span></a> inflammatory response or its ability to activate PPAR (<span class="elsevierStyleItalic">peroxisome proliferator activated receptor</span>) which interfere with NF-kappaB signalling pathway, inhibiting the expression of different cytokines.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">10</span></a> Moreover, despite generally being well tolerated drugs and with a favourable safety profile, some patients have certain immune disorders that may then become an undesirable clinical expression. Recent studies have shown that they can <span class="elsevierStyleItalic">trigger</span> autoimmune phenomena.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">11</span></a> They have been described as potential inducers of diabetes mellitus, systemic lupus erythematosus,<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">12</span></a> dermatomyositis (DM),<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">13–15</span></a> autoimmune hepatitis (AIH),<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">16</span></a> vasculitis with <span class="elsevierStyleItalic">anti-neutrophil cytoplasmic antibodies</span> (ANCA)<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">17</span></a> and immune profile impairment in serum, with or without accompanying clinical expression. The mechanism is unclear, and it is probably not unique; a hypothesis contemplates the behaviour of these drugs as pro-apoptotic agents that would free nuclear antigens into the circulation, or certain molecular changes inducing the production of autoantibodies. The fact that systemic immunosuppressive therapy has proven effective in some of the reported cases supports the immune mechanism. The association of statins to a partly immune-mediated myopathy, the so called immune-mediated necrotizing myopathy (IMNM), seems to define a new model of toxicity, may be extended to other organs different muscle.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Autoimmune phenomena</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Muscle involvement</span><p id="par0020" class="elsevierStylePara elsevierViewall">Muscle toxicity is a well-known side effect associated with the administration of statins, which in some studies reaches 0.4/100,000 person-years.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">18</span></a> However, there is no consensus on the exact definition (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). In any case, it seems that the presence of isolated myalgia, moderate elevations of creatine phosphokinase (CPK) or the dreaded and fortunately rare rhabdomyolysis with extreme elevation of CPK and renal failure seem to be the myopathic syndromes associated with the use of statins, to which the aforementioned IMNM must be added, where it appears that the pathogenic mechanism contemplates a toxicity associated with the presence of autoimmune disorders, including the enzyme on which the statin (HMGCR) is used as antigen source.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The precise mechanisms underlying the statin myopathy are not well known, and include lowering cholesterol content in muscle cell membranes, depletion of isoprenoids (farnesyl pyrophosphate and geranyl pyrophosphate) or coenzyme Q10, which favours mitochondrial dysfunction.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">19</span></a> In addition, some factors such as consumption of alcohol, hypothyroidism, or certain genetic polymorphisms may play a key role in muscle toxicity.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">20</span></a> The recently described partly immune-mediated toxicity must be added to all these mechanisms, whose clinical expression appears to be the IMNM.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Immune-mediated necrotizing myopathy</span><p id="par0030" class="elsevierStylePara elsevierViewall">Different groups of researchers in muscular disease described a new form of statin-related muscle toxicity, where the immune system appears to play an important role.<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">21–23</span></a> The significance of this entity lies not only in the fact that the pathogenic mechanism involves the immune system and this can be a model to study, but it is also of interest from a therapeutic point of view, since drug withdrawal is sometimes not enough to solve the clinical picture, requiring intervention with immunomodulatory drugs on this toxicity's immunopathological component.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Needham et al.<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">21</span></a> first, in Australia, and Grable-Esposito et al.,<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">22</span></a> in Boston, afterwards, identified a number of patients with muscle weakness, elevated levels of CPK and necrotizing myopathy without inflammation, all of whom were on statin therapy; this clinical picture persisted in some patients despite drug withdrawal, requiring the administration of immunosuppressive therapy in the latter cases.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Subsequently, researchers from the Myositis Centre at the Johns Hopkins University in Baltimore (USA) identified a new antibody against a 100–200 <span class="elsevierStyleHsp" style=""></span>kDa molecule in the sera of these patients, which in further studies could be identified as HMGCR, the enzyme on which the statins act (anti-HMGCR).<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">23,24</span></a> This same group described the association between these anti-HMGCR and a characteristic HLA (DRB1*11:01)<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">25</span></a> and analyzed the presence of this new autoantibody in a sample of about 2000 subjects treated with statins in the community and in a cohort of 51 suffering from severe familial hypercholesterolemia, with or without myalgia, finding that positivity for this autoantibody was practically non-existent.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">26</span></a> Therefore, although being a perfectly recognizable entity, its prevalence in the overall population of subjects receiving statins is low, estimated at 1.2 new cases per million/year.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">27</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Clinically, it presents with progressive muscular weakness around the waist, which can be intense and intractable myalgia, with little or no systemic involvement. CPK values range between 950 and 45,000<span class="elsevierStyleHsp" style=""></span>IU/L and electrophysiological findings support the diagnosis of this entity, which is confirmed by a muscle biopsy.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">28</span></a> The presence of anti-HMGCR serum antibodies and the HLA-DRB1*11:01 allele association support the immune-mediated nature of the process. It is essential to conduct immunohistochemical studies, since the presence of widespread muscle necrosis in the absence of inflammatory component, along with class <span class="elsevierStyleSmallCaps">i</span> HLA antigen expression in necrotic and non-necrotic muscle fibres confirms the diagnosis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). IMNM recognition is relevant because sometimes drug withdrawal is not enough, instead, the appropriate immunosuppressive therapy must be established, which in most cases is effective and solves the clinical picture, eventually allowing therapy withdrawal. In general, plasma levels of anti-HMGCR correlate with CPK and the progression of the clinical picture, even to the point of becoming negative, hence the importance of its early determination to confirm positivity.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">29</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Given the available data, it has been suggested that exposure to statins increase the expression of HMGCR and that this would be accompanied by an aberrant proteolysis of this molecule, with the consequent release of protein peptides which, in turn, would be expressed by the HLA class <span class="elsevierStyleSmallCaps">ii antigen-presenting cells,</span>promoting an immune response against the continued exposure to statins. Immune-mediated muscle necrosis resulting from this process would promote the appearance of regenerative muscle fibres, known to be expressing HMGCR in excess, against which the anti-HMGCR would act, thus closing the autoimmune injury vicious circle.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Autoimmune hepatitis</span><p id="par0055" class="elsevierStylePara elsevierViewall">AIH, a chronic necroinflammatory disease of unknown aetiology, characterized by the presence of circulating autoantibodies, elevated serum globulins and lymphoplasmacytic infiltration of the liver tissue, it can be triggered by various environmental factors, including viruses (measles, hepatitis C and HSV) and drugs (minocycline, hydralazine, procainamide), in genetically predisposed patients.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">30</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The asymptomatic elevation of serum aminotransferases is common in patients treated with statins, but severe liver toxicity is rare, and usually stems from a direct toxicity mechanism on hepatocytes. However, AIH cases have been published in connection with statin exposure, generally, just a few months after administration, although the latency time may be greater.<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">31–33</span></a> The production mechanism of this AIH is not well known, but it looks like immune activation pathways may be involved in producing an expansion of CD8<span class="elsevierStyleSup">+</span>T lymphocytes, which shows the participation of class <span class="elsevierStyleSmallCaps">i</span> molecules of the HLA system in the antigen presentation.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">34</span></a> In a similar way to what has been described, the drug appears to act as a <span class="elsevierStyleItalic">trigger</span>, generating liver toxicity with autoantibodies, and would persist despite drug withdrawal,<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">14</span></a> requiring, in most cases, the administration of immunosuppressive treatment to solve the process, very similar to the scenario proposed in the IMNM.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Other autoimmune phenomena associated with statins</span><p id="par0065" class="elsevierStylePara elsevierViewall">Since the 90s some publications have emphasized the association between the use of statins and the development of autoimmune diseases such as lupus erythematosus,<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">11,12,35–37</span></a> DM,<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">13–15</span></a> vasculitis<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">38–41</span></a> or interstitial lung disease.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The association between lupus and statins is probably the best studied one. There has been speculation on the role of specific cellular antigens released into the circulation by apoptosis and the immunomodulatory effects of T cells as mechanisms underlying the onset of lupus or similar manifestations. A systematic review of the medical literature over the period 1966–2005<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">11</span></a> and large pharmacovigilance epidemiological studies<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">12</span></a> seem to find a modest but obvious association between exposure to statins and disease onset.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Also, a total of 11 DM cases have been reported in connection with the administration of statins.<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">13,15</span></a> The pathogenic mechanisms involved are similar to those involved in lupus patients. It should be noted that these DM cases do not correspond to the clinical picture of IMNM, previously mentioned, which is related to the presence of specific anti-HMGCR antibodies.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Drug-induced vasculitis is a well-known entity.<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">38–41</span></a> Hypersensitivity to certain drugs is well documented. Hydralazine and propylthiouracil may induce an ANCA-positive systemic vasculitis. Myeloperoxidase, elastase and lactoferrin are the antigenic specificities that have been associated more often with ANCA-positive drug induced vasculitis. There have been reports that show a clear association between statin use and the presence of ANCA positive vasculitis, with resolution after drug withdrawal or the use of immunosuppressive therapy.</p><p id="par0085" class="elsevierStylePara elsevierViewall">As for the presence of interstitial pneumonitis caused by statins, the isolated cases that have been published supporting this relationship could not be confirmed in some cohort studies, so their relationship remains in the realm of speculation.<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">42–45</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0090" class="elsevierStylePara elsevierViewall">Statins are still the most effective drugs available for the treatment of dyslipidaemia and play an important role in the treatment of atherosclerosis and their cardiovascular complications. Some individuals, probably with a certain genetic predisposition, will present phenomena and/or autoimmune diseases in connection with the administration of these drugs, among which IMNM has its own importance.</p><p id="par0095" class="elsevierStylePara elsevierViewall">In genetically predisposed individuals, statins may act as triggers in some cases, acting as proapoptotic agents, releasing nuclear antigens into the bloodstream or causing molecular changes susceptible to induce the production of autoantibodies. Drug withdrawal is often not sufficient, requiring immunosuppressive therapy in order to control the autoimmune disorder associated with statins. The effectiveness of this treatment is an additional argument in favour of the existence of an immunological conflict at this level.</p><p id="par0100" class="elsevierStylePara elsevierViewall">The entity recently described as IMNM with anti-HMGCR antibodies in connection with the administration of statins is an example of toxicity in which the immune system is involved, and could serve as a model to explain some autoimmune phenomena associated with statins.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interests</span><p id="par0105" class="elsevierStylePara elsevierViewall">There is no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres633045" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec645692" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres633046" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec645693" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Autoimmune phenomena" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Muscle involvement" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Immune-mediated necrotizing myopathy" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Autoimmune hepatitis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Other autoimmune phenomena associated with statins" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interests" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-11-12" "fechaAceptado" => "2014-11-27" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec645692" "palabras" => array:4 [ 0 => "Statins" 1 => "Pleiotropic" 2 => "Immunosuppressive" 3 => "Autoimmunity" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec645693" "palabras" => array:4 [ 0 => "Estatinas" 1 => "Pleoitrópico" 2 => "Inmunodepresor" 3 => "Autoinmunitario" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Statins are the most widely used drugs for both primary and secondary prevention of cardiovascular diseases and those associated with atherosclerosis. About 25 million people are on statin therapy in the world. Although they are well tolerated by most patients and have a safety profile, some patients have muscle level alterations. The biological effects associated with these drugs are known as pleiotropic; they are of such interest and diversity that explains, in part, some of the actions of statins, especially in relation to inflammation and the immune system. Some patients have certain immune disorders that can turn into an undesirable clinical expression. Recent studies have shown that they can trigger autoimmune phenomena. Pathologies have been described in which these agents act as triggers such as immune-mediated necrotizing myopathy or indirectly in dermatomyositis or autoimmune hepatitis, among others. Given the high number of people being treated with statins, we believe that this is a clinically relevant problem and therefore worthy of study.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Las estatinas son los fármacos más utilizados en la prevención tanto primaria como secundaria de enfermedades cardiovasculares y asociadas a aterosclerosis. Alrededor de 25 millones de personas están en tratamiento con estatinas en el mundo. A pesar de que son bien toleradas por la mayoría de los pacientes y de tener un perfil muy seguro, algunos pacientes presentan alteraciones, especialmente a nivel muscular. Los efectos biológicos asociados a estos fármacos son conocidos como pleiotrópicos; son de tal interés y diversidad que explican, en parte, algunas de las acciones de las estatinas, especialmente en relación con la inflamación y el sistema inmunitario. Algunos pacientes presentan ciertas alteraciones inmunológicas que puede transformarse luego en expresión clínica no deseable. Estudios recientes han mostrado que pueden desencadenar fenómenos autoinmunitarios. Han sido descritas enfermedades en las que actúan como desencadenantes, como la miopatía necrosante inmunomediada, o indirectamente en dermatomiositis o hepatitis autoinmunitaria, entre otras. Es así por lo que dado el elevado número de personas en tratamiento con estatinas, creemos que se trata de un problema clínicamente relevante y, por tanto, merecedor de estudio.</p></span>" ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Alvarado Cárdenas M, Marín Sánchez A, Lima Ruiz J, en representación del Grupo para estudio de Autoinmunidad y Estatinas. Estatinas y autoinmunidad. Med Clin (Barc). 2015;145:399–403.</p>" ] 1 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Members’ names of the Group for Study of Autoimmunity and Statins can be found in the <a class="elsevierStyleCrossRef" href="#sec0045">Appendix 1</a>.</p>" "identificador" => "fn0005" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0110" class="elsevierStylePara elsevierViewall">Xavier Mundet-Tuduri (Research Support Unit, Barcelona, IDIAP Jordi Gol, Autonomous University of Barcelona, Barcelona, Spain); Montserrat Farrús-Palou, Manuel Iglesias-Rodal, Rosa-Gimbert Rafols (Centre d’Atenció Primària Carmel, Institut Català de la Salut, Barcelona, Spain); Josep M. Grau Junyent, José Milisenda, Pedro Rodriguez Moreno (Muscle Research Unit, IDIBAPS, Hospital Clínic, Barcelona, Spain); M. Angeles Martinez, Candido Juárez (Immunology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain); Albert Selva-O’Callaghan, Moses Labrador Horrillo, Eva Balada, Iago Pinal Fernandez (Department of Internal Medicine, Hospital Vall d’Hebron, Barcelona, Spain); Victor Vargas Blasco (Department of Hepatology, Hospital Vall d’Hebron, Barcelona, Spain); Ricardo Pujol Borrell (Immunology Department, Hospital Vall d’Hebron, Barcelona, Spain).</p>" "etiqueta" => "Appendix 1" "titulo" => "Autoimmunity and Statins Study Group" "identificador" => "sec0045" ] ] ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1693 "Ancho" => 2255 "Tamanyo" => 420755 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Immune-mediated necrotizing myopathy. (a) Haematoxylin–eosin. (b) Gomori's trichrome. (c) Immunohistochemical staining with major histocompatibility complex type <span class="elsevierStyleSmallCaps">i</span>. (d) Negative control (courtesy of Professor JM Grau Junyent, Muscle Research Unit, IDIBAPS, Hospital Clinic, Barcelona, Spain).</p>" ] ] 1 => 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:1 [ "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Regulation of the endothelial nitric oxide synthase and improved pathophysiological response, including vasoconstriction and re-endothelialization promotion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antioxidant effect through the inhibition of nicotinamide adenine dinucleotide phosphate oxidase and its oxidation reaction \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anti-inflammatory properties, including the reduction of C-reactive protein, interleukin 6, tumour necrosis factor-alpha and nuclear factor <span class="elsevierStyleItalic">k</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Decrease of cytokines and chemokines \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Stabilization of atherosclerotic plaques and inhibition of plaque inflammation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Decreased coagulation cascade activation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Normalization of the sympathetic outflow tract \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Induction of autophagy in angiogenesis inhibition of cancer cells \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neuroprotection and support of blood-brain barrier functions \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1038327.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Proposed mechanisms underlying pleiotropic effects.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">ACC/AHA/NHLBI: American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute; FDA: Food and Drug Administration; ULN: upper limit of normal; NLA: National Lipid Association.</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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical entity \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ACC/AHA/NHLBI \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">NLA \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">FDA \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Myopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">General term that refers to any disease of the muscles \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The symptoms of myalgia (muscle pain or swelling), weakness or cramps, as well as CPK<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>10 times ULN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CPK<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>ULN \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Myalgia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Muscle pain or weakness without elevated creatine phosphokinase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No data \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No data \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Myositis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Muscle symptoms with elevated creatine phosphokinase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No data \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No data \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rhabdomyolysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Muscle symptoms with significant elevation of creatine phosphokinase (typically >10<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>ULN), and elevated creatinine (usually with brown urine and urinary myoglobin) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Creatine phosphokinase >10,000<span class="elsevierStyleHsp" style=""></span>IU/L or creatine phosphokinase >10<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>ULN, apart from a rise in serum creatinine or medical intervention with intravenous hydration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Creatine phosphokinase>50<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>ULN and evidence of organ damage, such as renal impairment \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1038328.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Proposed definitions for statin-related myopathy.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib0230" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "Cholesterol Treatment Trialists’ (CTT) Collaborators" "etal" => false "autores" => array:6 [ 0 => "C. Baigent" 1 => "A. Keech" 2 => "P.M. Kearney" 3 => "L. Blackwell" 4 => "G. Buck" 5 => "C. Pollicino" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(05)67394-1" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2005" "volumen" => "366" "paginaInicial" => "1267" "paginaFinal" => "1278" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16214597" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0235" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Statins for millions more?" ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(14)60240-3" "Revista" => array:5 [ "tituloSerie" => "Lancet" "fecha" => "2014" "volumen" => "383" "paginaInicial" => "669" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24560042" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0240" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antiinflammatory and immunomodulatory properties of statins" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "O. 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