Systemic lupus erythematosus in children

array:21 ["pii" => "13079815" "issn" => "16954033" "doi" => "10.1157/13079833" "estado" => "S300" "fechaPublicacion" => "2005-10-01" "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "An Pediatr (Barc). 2005;63:321-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 19402 "formatos" => array:3 [ "EPUB" => 113 "HTML" => 17634 "PDF" => 1655 ] ] "Traduccion" => array:1 [ "es" => array:17 [ "pii" => "13079833" "issn" => "16954033" "doi" => "10.1157/13079833" "estado" => "S300" "fechaPublicacion" => "2005-10-01" "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "An Pediatr (Barc). 2005;63:321-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 49523 "formatos" => array:3 [ "EPUB" => 155 "HTML" => 44433 "PDF" => 4935 ] ] "es" => array:11 [ "idiomaDefecto" => true "titulo" => "Lupus eritematoso sistémico pediátrico" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "321" "paginaFinal" => "329" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Systemic lupus erythematosus in children" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "D Stichweh, V Pascual" "autores" => array:2 [ 0 => array:2 [ "Iniciales" => "D" "apellidos" => "Stichweh" ] 1 => array:2 [ "Iniciales" => "V" "apellidos" => "Pascual" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "13079815" "doi" => "10.1157/13079833" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079815?idApp=UINPBA00005H" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079833?idApp=UINPBA00005H" "url" => "/16954033/0000006300000004/v0_201404151142/13079833/v0_201404151142/es/main.assets" ] ] "itemSiguiente" => array:16 [ "pii" => "13079816" "issn" => "16954033" "doi" => "10.1157/13079816" "estado" => "S300" "fechaPublicacion" => "2005-10-01" "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "An Pediatr (Barc). 2005;63:330-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 54509 "formatos" => array:3 [ "EPUB" => 138 "HTML" => 52539 "PDF" => 1832 ] ] "es" => array:11 [ "idiomaDefecto" => true "titulo" => "Síncope en el adolescente. Orientación diagnóstica y terapéutica" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "330" "paginaFinal" => "339" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Syncope in adolescents. Diagnostic and therapeutic approach" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J Eirís Puñal, A Rodríguez Núñez, C Gómez Lado, F Martinón-Torres, M Castro-Gago, JMª Martinón Sánchez" "autores" => array:6 [ 0 => array:2 [ "Iniciales" => "J" "apellidos" => "Eirís Puñal" ] 1 => array:2 [ "Iniciales" => "A" "apellidos" => "Rodríguez Núñez" ] 2 => array:2 [ "Iniciales" => "C" "apellidos" => "Gómez Lado" ] 3 => array:2 [ "Iniciales" => "F" "apellidos" => "Martinón-Torres" ] 4 => array:2 [ "Iniciales" => "M" "apellidos" => "Castro-Gago" ] 5 => array:2 [ "nombre" => "JMª" "apellidos" => "Martinón Sánchez" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079816?idApp=UINPBA00005H" "url" => "/16954033/0000006300000004/v0_201404151142/13079816/v0_201404151143/es/main.assets" ] "itemAnterior" => array:17 [ "pii" => "13079833" "issn" => "16954033" "doi" => "10.1157/13079833" "estado" => "S300" "fechaPublicacion" => "2005-10-01" "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "An Pediatr (Barc). 2005;63:321-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 49523 "formatos" => array:3 [ "EPUB" => 155 "HTML" => 44433 "PDF" => 4935 ] ] "es" => array:11 [ "idiomaDefecto" => true "titulo" => "Lupus eritematoso sistémico pediátrico" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "321" "paginaFinal" => "329" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Systemic lupus erythematosus in children" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "D Stichweh, V Pascual" "autores" => array:2 [ 0 => array:2 [ "Iniciales" => "D" "apellidos" => "Stichweh" ] 1 => array:2 [ "Iniciales" => "V" "apellidos" => "Pascual" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "13079815" "doi" => "10.1157/13079833" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079815?idApp=UINPBA00005H" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079833?idApp=UINPBA00005H" "url" => "/16954033/0000006300000004/v0_201404151142/13079833/v0_201404151142/es/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "titulo" => "Systemic lupus erythematosus in children" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "321" "paginaFinal" => "329" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "D Stichweh, V Pascual" "autores" => array:2 [ 0 => array:3 [ "Iniciales" => "D" "apellidos" => "Stichweh" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "Iniciales" => "V" "apellidos" => "Pascual" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Baylor Institute for Immunology Research. Dallas. Texas. USA." "etiqueta" => "a" "identificador" => "affa" ] ] ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Lupus eritematoso sistémico pediátrico" ] ] "textoCompleto" => "IntroductionSystemic lupus erythematosus (SLE) is a complex, multisystem autoimmune disease which results from the interplay of environmental, hormonal and genetic factors. In children, the presentation, clinical course and immunological findings differ slightly from adults with SLE 1.In the last decade the outcome of SLE patients have improved remarkably, but even though many diagnostic and treatment options are similar for adults and children there are special issues that need to be considered in children and adolescents with SLE. For example, pSLE tends to be more severe and have higher impact on school adjustment and psychosocial aspects related, among others, to physical appearance and growth retardation 2.EpidemiologyPediatric SLE (pSLE) represents approximately 15-20 % of all SLE patients 1,3-5. It is more common in females than in males, with a female to male ratio varying from 2.3:1 to 9:1, depending on the study 6-11.The incidence of the disease varies according to different ethnic groups. In Caucasian females the incidence of SLE with onset before age of 19 years is between 6 and 18.9 cases per 100,000, while it is 20-30 per 100,000 in African American females and 16-36.7 per 100,000 in Puerto Rican females 12. The diagnosis of pSLE is rare before the age of 10, and the average age at presentation is 12.1 years 6-11.Disease damage and mortality in pSLE have been linked to different risk factors which include young age at diagnosis, male sex and non-white ethnicity (African American, Asian, and Hispanic) 5,13,14. African Americans tend to have a greater prevalence and a more severe renal and neuropsychiatric disease (NPSLE) 15. However, the association between any of these risk factors and a poor prognosis remains controversial 14,16.The survival rate for pSLE has improved dramatically over the past 50 years, with a 5-year survival rate increasing from 50 % in 1955 to more than 90 % in 2004 8.General clinical manifestationsClinical characteristics and organ involvement vary depending on age of onset, gender and race. In general children with SLE tend to have a more severe disease at onset with higher rates of organ involvement and a more aggressive clinical course than adult-onset SLE patients 2,17.At onset, 40-90 % of children will present with constitutional symptoms (fever, fatigue or weight loss), 20-82 % will have renal involvement, 20-74 % musculoskeletal symptoms, 22-74 % malar rash, 15-45 % lymphadenopathies and 15-74 % visceromegaly 4,7,9,18.Cutaneous manifestationsThe skin is commonly involved in pSLE. Different cutaneous manifestations have been reported in children during the course of their disease including: malar rash (22-74 %) which is a hallmark of SLE, oral ulcers (26-48 %), vasculitic rash (10-52 %), photosensitivity (16-50 %), alopecia (7-48 %), discoid lesions (5-19 %) and Raynaud's phenomenon (10-20 %) 4,7,9,18,19.Musculoskeletal manifestationsArthritis occurs in more than 3/4 of pediatric patients with SLE 2. It can be variable, but usually presents as a symmetric non-erosive, very painful polyarthritis involving both, large and small joints and is rarely associated with radiographic changes.In general, SLE arthritis responds well to conventional therapy. Indeed, arthritis can be the only presenting manifestation of SLE and some patients who initially meet the American College of Rheumatology (ACR) criteria for juvenile arthritis, subsequently fulfilled clinical and serological criteria for the classification of SLE 2.Myalgia is seen in 20-30 % of patients, however true myositis is less frequent. Musculoskeletal manifestations could be also seen as a side effect of the different drugs used. Treatment-induced musculoskeletal complications include avascular necrosis, osteoporosis and growth failure.Hematological disordersThirty nine percent of children with SLE will develop hematological abnormalities, one of the ACR diagnostic criteria for SLE, during the course of the disease 20,21.Autoimmune thrombocytopenia is the initial manifestation in up to 15 % of the pediatric cases although it can precede the onset of SLE by several years 1,3-5,21,22. It has been suggested that 20 % to 30 % of children with autoimmune idiopathic thrombocytopenic purpura who are ANA positive will evolve into SLE 21. Leukopenia is observed in 27-52 % of pediatric cases primarily due to a decrease in lymphocyte number. Granulocytopenia is also common 3.Coagulation abnormalities are frequently present in pSLE. The Coomb's test is positive in approximately 30-40 % of patients, however less than 10 % will develop overt hemolysis 6. Antiphospholipid antibodies (aPL) are present in 75 % of pSLE patients 23. Pediatric patients with SLE and aPL, specifically lupus anticoagulant (LAC), are at high risk of developing thromboembolic events(TE) and the incidence of TE in LAC positive patients is 54 % 24. Therefore, lifelong anticoagulation must be considered after an initial thromboembolic event.Cardiac manifestationsThe spectrum of cardiac disease in pSLE mirrors that in adults with SLE. It encompasses 4 major types of manifestations: pericarditis (the most common form of cardiac involvement), myocarditis, valvular disease, and coronary artery disease due to either coronary arteritis or atherosclerosis 25. A few studies have reported silent cardiac abnormalities in children with SLE as a common finding 25,26. In fact, myocardial ischemia has been described in 16 % of asymptomatic children 26.Cardiac involvement in pSLE patients is now being recognized as a major cause of morbidity and mortality in this population. Children with SLE have markedly higher rates of coronary heart disease than controls, and these increased rates are partly explained by an increase in the conventional cardiovascular risk factors 27. Identified risk factors for premature atherosclerosis in pSLE include: dyslipidemia, high levels of homocystein, presence of aPL, LAC, hypertension, hyperinsulinemia, nephritic range proteinuria, upregulated CD40-CD40 ligand interactions and steroid-induced obesity 27. Currently, the multicenter Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) study group is assessing the role of statins for the prevention of atherosclerosis in the pediatric population with SLE. Neuropsychiatric manifestationsNeuropsychiatric systemic lupus erythematosus (NPSLE), occuring in 20-45 % of children and adolescents, is the third most common cause for mortality in pSLE 2,28,29. Unlike other manifestations of the disease, central nervous system (CNS) involvement occurs within the first year of disease in approximately 75 % to 80 % of patients 2. NPSLE involvement can range from global cerebral dysfunction with paralysis and seizures, to mild or focal symptoms such as headache or memory loss 2. The presence of aPL is often linked to thrombosis and CNS infarction 30.The diagnosis of NPSLE continues to be difficult since there is a lack of specific serologic studies for its diagnosis and monitoring 2. Although neuroimaging is a clinically useful tool, CSF analysis, EEG, CT scan, and even MRI may be normal in these patients 2. On the other hand, functional imaging may be abnormal in otherwise asymptomatic lupus individuals 28 which makes its interpretation difficult. Multiple imaging modalities have been studied to determine if there is a link between the clinical status and CNS imaging abnormalities, but to date there is no consensus 30.Pulmonary involvementThe lung involved in 5-77 % of pSLE patients 29,31,32 and pulmonary manifestations vary from sub-clinical abnormalities to life-threatening disorders. The clinical spectrum includes pleuritis (the most common), pneumonitis, pneumonia, pneumothorax, diffuse interstitial disease, pulmonary hypertension and pulmonary hemorrhage, a relatively uncommon and potentially lethal complication. In the majority of children, pulmonary symptoms are present at some point during their disease course. Asymptomatic or subclinical lung involvement in pSLE may be more prevalent than realized. Pulmonary function abnormalities were found in up to 40 % of pSLE patients with no evidence of clinical symptoms or radiographic changes 31. The most frequent pattern observed was lung restrictive disease 28. Although pulmonary function tests do not correlate well with pulmonary symptoms, they provide objective quantification of the type and severity of the functional lesion observed 32.Renal involvementNot only does renal involvement represent the first clinical manifestation of the disease in 60-80 % of children with SLE 7,33, but it also determines the course of the disease and the outcome of patients. About 80 % of children and adolescents who develop renal abnormalities generally do so in the first year after diagnosis 7,33,34. Pathological findings can not be predicted from the clinical manifestations and therefore a renal biopsy is required for precise to establish diagnosis and subsequently planning effective therapy 33. In 1982, the World Health Organization (WHO) classified lupus nephritis (LN) based on histologic features into 6 categories 20. WHO class IV is the most common form of pSLE nephritis and is most commonly associated with the development of end stage renal disease or death.Renal flares are common throughout the disease course of LN and can frequently be detected by increasing proteinuria. The presence of hypertension and peripheral edema are usually associated with WHO class III or IV LN 7. The prognosis of children with LN depends primarily on the severity of the histopathological lesions according to the WHO classification. Although in most centers the treatment is determined by the WHO class on biopsy, long-term renal outcome is still unpredictable. Other biopsy indices have been developed to evaluate LN at diagnosis and to predict outcome, including the National Institutes of Health (NIH) classification 35 and more recently an index focused on tubulointerstitial compartment changes in addition to features already included in the activity index and the chronicity indexes 36.The prognosis of pediatric LN has improved dramatically in the past decade. The current 5-year survival rate for children with LN ranges between 78 % and 92 % 7,37 and the 5-year kidney survival from time of diagnosis varying from 44 to 93 % 7,35.DiagnosisThe heterogeneous nature of lupus can result in a diagnostic challenge for physicians. Since there is not a single symptom or finding that in itself is sufficient for making the diagnosis of SLE, the ACR has developed different criteria that can be useful as general clinical guidelines for the initial assessment of patients with suspected SLE. The guidelines, created in 1982 and updated in 1997 (table 1), combine 11 criteria (clinical and laboratory) and a diagnosis can be made when four or more of these criteria are present 38.<img src="37v63n04-13079815tab01.gif"></img>It may be challenging to distinguish active inflammation from symptoms due to cumulative organ damage or medication side effects. A thorough history and physical examination, including all major systems, must be undertaken at each clinic visit (table 2). An assessment of disease activity is crucial for undertaking most treatment decisions. Several activity indices have been validated and are depicted in table 3.<img src="37v63n04-13079815tab02.gif"></img><img src="37v63n04-13079815tab03.gif"></img>PathogenesisAlthough the pathogenesis of SLE remains poorly understood, susceptibility involves a combination of environmental, hormonal and genetic factors. One of the environmental factors that has been involved in lupus is ultraviolet light, which triggers a photosensitive skin rash that may be followed by a generalized disease flare 39. There is also growing evidence for infections, such as Epstein-Barr virus (EBV) as an initial trigger for lupus-specific autoimmune responses. A higher incidence of EBV infection, higher titers of anti-EBV proteins and an abnormally elevated EBV load have been reported in children and adults with SLE when compared to matched healthy individuals 40,41.Genetic factorsThe genetic component of the disease is strongly established through epidemiology data, strong familial aggregation of SLE, and the known disease concordance rate in twins. Siblings of SLE patients have an increased relative risk of developing the disease when compared to the general population 42 and monozygotic twins have increased concordance (> 20 %) compared with dizygotic twins and other full siblings (2-5 %) 43,44. Through association and genetic linkage studies, over 60 loci 45-47, including alleles from the HLA region, region Fcg receptors and complement components have been implicated in the immunopathogenesis of SLE 45,48. Homozygous deficiency of any of the early components of the classical pathway (C1q, C1r, C1s, C4 and C2) have been linked with an increased predisposition to the development of SLE 49. Patients deficient in one of the C1-complex or C4 molecule exhibit the strongest prevalence (> 80 %) and the most severe disease, while strength of association and disease severity decrease in C2-deficient patients 49.Immune alterationsIt is recognized that SLE can arise through many molecular routes and requires contributions by T cells, B cells, dendritic cells, and nonlymphoid cells at sites of tissue injury. The most commonly recognized immune abnormalities are: the ability to produce pathogenic autoantibodies; lack of T-and B-lymphocyte regulation; and defective clearance of autoantigens and immune complexes by the immune system 39.T cellsAlthough numerous abnormalities in T cell functions have been described in SLE, none are common to all patients. There is evidence of T-cell lymphopenia. Many studies report reduction of CD8+ T cells while others report decrease in CD4+ T cells; functional defects, such as decreased cytotoxic activity of CD8+ cells 50, signaling defects and diminished ability to reduce autoantibody production by B cells; sustained activation and abnormal cytokine production 39. T cells of SLE patients exhibit aberrant responses to stimuli with increased calcium influx and decreased production of interferon-a and IL-2 51. SLE T cells display markers of activation such as increased numbers of DR+ antigens 52 and are able to facilitate the production of immunoglobulins by B cells 53. SLE T cells seem to use different mechanisms of survival upon co-stimulation than normal T cells. Indeed, microarray profiling studies have recently shown that activated T cells from SLE patients resist anergy and apoptosis by upregulating cyclooxygenase-2 (COX-2) expression, which in turn increases c-FLIP (cellular homolog of viral FLICE inhibitory protein) and attenuates FAS signaling. Only certain COX-2 inhibitors, however, seem able to induce autoreactive T cell apoptosis and suppress the production of pathogenic autoantibodies to DNA in lupus-prone mice 54.B cells and autoantibodiesB cells play a major role in the pathogenesis of SLE as they are responsible for the hypergammaglobulinemia and the production of antibodies against nuclear and cell surface antigens, one of the most prevalent immunological abnormalities in SLE. The development of some autoantibodies, such as anti-dsDNA antibodies, is closely linked to disease onset 51 while others, for instance antiphospholipid and anti-Ro antibodies, can be detected months to years preceding the development of SLE 55.Patients with pSLE have profound B cell lymphopenia, involving both naïve and memory B cells, whereas oligoclonal plasma cell precursors are 3-fold expanded 56.Antibody gene expression studies from single B cells from healthy individuals showed that large numbers of developing B cells in the bone marrow and recent emigrants in the blood express self-reactive antibodies. The majority of self-reactive B cells, however, are removed from the healthy mature blood naïve B cell pool at two discrete early checkpoints of their development 57. These checkpoints are defective in patients with SLE. A 25-50 % of the mature naïve B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5-20 % in controls 58. Dendritic cellsIndividuals with SLE display major alterations in DC homeostasis. There is evidence that unabated IFN-α production differentiates CD14+ blood monocytes from SLE patients into mature dendritic cells able to capture dying cells and present their antigens to autoreactive T and B cells, leading to a break in tolerance 59,60.Although only a fraction of patients with active disease show circulating IFN-α, microarray analyses demonstrate an IFN signature in blood mononuclear cells 60. These studies also demonstrated that high doses of glucocorticoids, broad inhibitors of immune cell function 61 extinguish the IFN signature. Preliminary studies by Palucka et al show that they induce the apoptosis of interferon-producing cells or dendritic cells (Palucka et al unpublished). Glucocorticoids may therefore, act by blocking IFN-α production. ApoptosisA common feature of SLE autoantigens is that they are components of the surface blebs 62 and they come under immune surveillance when they arise to the surface of apoptotic cells. Furthermore, there is increasing evidence that apoptotic material is normally taken up by immature dendritic cells and cross-presented to induce T cell tolerance 63. Deficiency in apoptotic cell removal may provide dendritic cells with an excessive load of nuclear antigens and consequently develop overt SLE.Several other factors that are linked to the pathogenesis of SLE can influence apoptosis such as estrogens, UV light 64, infections 65 and autoantibodies themselves 66.TreatmentTreatment of SLE depends on the clinical manifestations and the presence/absence of major organ involvement (table 4). Corticosteroids are a major cause of morbidity and mortality in pSLE but they continue to be a mainstay of treatment due to their dramatic and rapid impact on lupus flares. Their effectiveness in treating SLE has been recognized since the 1950s. Intravenous (IV) pulse methylprednisolone (MEP) can be successfully used to treat major organ involvement and/or life-threatening manifestations of SLE. Antimalarials are effective for milder manifestations and improve bone-mineral density and dyslipoproteinemia 67. Cyclophosphamide (CYC) remains the first-line treatment for major organ involvement. It has been shown to reduce morbidity and improve mortality in lupus patients. Over 20 years ago a National Institute of Health (NIH) study 68 showed that monthly IV pulses of CYC were as effective, but less toxic, than daily oral CYC. Since then the gold standard immunosuppressive treatment of LN has been monthly IV pulse CYC for 6-7 months, in combination with high-dose glucocorticoids, followed by a 2-year maintenance phase (CYC for 2-3 months). All patients receiving CYC and high-dose glucocorticoids should also receive prophylaxis with low-dose trimethoprim-sulfametoxazole inorder to prevent the most common opportunistic infection, Pneumocystis jiroveci pneumonia.<img src="37v63n04-13079815tab04.gif"></img>Treatment of SLE includes not only pharmacological therapies, but also patient education, such as protection from ultraviolet light, management and prevention of infections, cardiovascular risk factors, and treatment of complications including osteoporosis.Although the prognosis for pSLE has improved over the last few years, pSLE remains a very challenging disease, especially in children with partial response to treatment or treatment resistant who are at a high risk for serious complications. With better understanding of SLE pathogenesis, novel therapies are emerging which will hopefully translate into safer and more efficient treatments for children with SLE (table 5).<img src="37v63n04-13079815tab05.gif"></img>" "pdfFichero" => "37v63n04a13079815pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec313438" "palabras" => array:2 [ 0 => "Lupus eritematoso sistémico" 1 => "Niños" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec313437" "palabras" => array:2 [ 0 => "Systemic lupus erythematosus" 1 => "Children" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "Pediatric systemic lupus erythematosus (pSLE) is a chronic mutisystemic autoimmune disease with complex clinical manifestations. Although the presentation, clinical manifestations, immunological findings and treatment issues of pSLE are similar to those of adult SLE patients, there are special issues which need to be considered when dealing with SLE in children. During the last decade survival has improved remarkably as a result of earlier diagnosis, recognition of milder disease and better approaches to therapy. However, pSLE remains a potentially serious condition. Although the pathogenesis of SLE remains poorly understood, susceptibility involves a combination of environmental, hormonal and genetic factors.Better understanding of SLE pathogenesis will hopefully lead to more specific and less toxic therapies for this disease." ] "es" => array:1 [ "resumen" => "El lupus eritematoso sistémico (LES) pediátrico es una enfermedad autoinmunitaria crónica con manifestaciones clínicas complejas. A pesar de que la presentación, las manifestaciones clínicas, los hallazgos inmunológicos y el tratamiento del LES pediátrico son similares a los de pacientes adultos, hay aspectos especiales que se deben considerar en la población pediátrica. La supervivencia de pacientes con LES ha mejorado notablemente en la última década gracias al diagnóstico precoz de la enfermedad, el reconocimiento de pacientes con formas más leves de la enfermedad y la instauración de tratamientos tempranos y más agresivos. Sin embargo, el pronóstico de pacientes con LES continúa siendo grave. Aunque la patogénesis del LES continúa sin conocerse por completo, diferentes factores interactúan en su desarrollo: factores ambientales, hormonales y genéticos. Con el mejor entendimiento de la patogenia del LES, el desarrollo de tratamientos más específicos y menos tóxicos ayudarán a mejorar el pronóstico a largo plazo de esta enfermedad." ] ] "multimedia" => array:5 [ 0 => array:8 [ "identificador" => "tbl1" "etiqueta" => "TABLE 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "37v63n04-13079815tab01.gif" "imagenAlto" => 1822 "imagenAncho" => 917 "imagenTamanyo" => 111618 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Revised ACR Criteria for the classification of SLE" ] ] 1 => array:8 [ "identificador" => "tbl2" "etiqueta" => "TABLE 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "37v63n04-13079815tab02.gif" "imagenAlto" => 589 "imagenAncho" => 1577 "imagenTamanyo" => 44582 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Suggested routine laboratories and exams for monitoring pediatric systemic lupus erythematosus patients in the outpatient clinic" ] ] 2 => array:8 [ "identificador" => "tbl3" "etiqueta" => "TABLE 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "37v63n04-13079815tab03.gif" "imagenAlto" => 553 "imagenAncho" => 912 "imagenTamanyo" => 26643 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Instruments used for assessing children with systemic lupus erythematosus" ] ] 3 => array:8 [ "identificador" => "tbl4" "etiqueta" => "TABLE 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "37v63n04-13079815tab04.gif" "imagenAlto" => 609 "imagenAncho" => 1578 "imagenTamanyo" => 41493 ] ] ] ] ] "descripcion" => array:1 [ "en" => "Current treatment for pediatric systemic lupus erythematosus" ] ] 4 => array:8 [ "identificador" => "tbl5" "etiqueta" => "TABLE 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "37v63n04-13079815tab05.gif" "imagenAlto" => 802 "imagenAncho" => 1575 "imagenTamanyo" => 73015 ] ] ] ] ] "descripcion" => array:1 [ "en" => "New treatments in development for systemic lupus erythematosus" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:88 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Systemic lupus erythematosus (SLE) in childhood: Analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Font J" 1 => "Cervera R" 2 => "Espinosa G" 3 => "Pallarés L" 4 => "Ramos-Casals M" 5 => "Jiménez S" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "1998" "volumen" => "57" "paginaInicial" => "456" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9797549" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Systemic lupus erythematosus in childhood." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Klein-Gitelman M" 1 => "Reiff A" 2 => "Silverman ED." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rheum Dis Clin North Am" "fecha" => "2002" "volumen" => "28" "paginaInicial" => "561" "paginaFinal" => "77" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12380370" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Adult- and childhood-onset systemic lupus erythematosus: A comparison of onset, clinical features, serology, and outcome." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Tucker LB" 1 => "Menon S" 2 => "Schaller JG" 3 => "Isenberg DA." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br J Rheumatol" "fecha" => "1995" "volumen" => "34" "paginaInicial" => "866" "paginaFinal" => "72" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7582729" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Diversity in presenting manifestations of systemic lupus erythematosus in children." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Iqbal S" 1 => "Sher MR" 2 => "Good RA" 3 => "Cawkwell GD." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "1999" "volumen" => "135" "paginaInicial" => "500" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10518085" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Immunological and clinical differences between juvenile and adult onset of systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Carreno L" 1 => "López-Longo FJ" 2 => "Monteagudo I" 3 => "Rodríguez-Mahou M" 4 => "Bascones M" 5 => "González CM" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "1999" "volumen" => "8" "paginaInicial" => "287" "paginaFinal" => "92" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10413207" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Benseler SM" 1 => "Silverman ED." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.pcl.2005.01.010" "Revista" => array:6 [ "tituloSerie" => "Pediatr Clin North Am" "fecha" => "2005" "volumen" => "52" "paginaInicial" => "443" "paginaFinal" => "67" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15820375" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Lupus nephritis in childhood: A review of 53 patients followed at a single center." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Bogdanovic R" 1 => "Nikolic V" 2 => "Pasic S" 3 => "Dimitrijevic J" 4 => "Lipkovska-Markovic J" 5 => "Eric-Marinkovic J" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00467-003-1278-y" "Revista" => array:6 [ "tituloSerie" => "Pediatr Nephrol" "fecha" => "2004" "volumen" => "19" "paginaInicial" => "36" "paginaFinal" => "44" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14634858" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Gender and ethnic origin have no effect on longterm outcome of childhood-onset systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Miettunen PM" 1 => "Ortiz-Álvarez O" 2 => "Petty RE" 3 => "Cimaz R" 4 => "Malleson PN" 5 => "Cabral DA" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2004" "volumen" => "31" "paginaInicial" => "1650" "paginaFinal" => "4" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15290748" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The incidence and prevalence of neuropsychiatric syndromes in pediatric onset systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Sibbitt WL Jr" 1 => "Brandt JR" 2 => "Johnson CR" 3 => "Maldonado ME" 4 => "Patel SR" 5 => "Ford CC" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2002" "volumen" => "29" "paginaInicial" => "1536" "paginaFinal" => "42" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12136916" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Risk factors for damage in childhood-onset systemic lupus erythematosus: Cumulative disease activity and medication use predict disease damage." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Brunner HI" 1 => "Silverman ED" 2 => "To T" 3 => "Bombardier C" 4 => "Feldman BM." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2002" "volumen" => "46" "paginaInicial" => "436" "paginaFinal" => "44" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11840446" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Sex differences in pediatric systemic lupus erythematosus: A retrospective analysis of 135 cases." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Lo JT" 1 => "Tsai MJ" 2 => "Wang LH" 3 => "Huang MT" 4 => "Yang YH" 5 => "Lin YT" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Microbiol Immunol Infect" "fecha" => "1999" "volumen" => "32" "paginaInicial" => "173" "paginaFinal" => "8" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10637715" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The epidemiology of systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Jiménez S" 1 => "Cervera R" 2 => "Font J" 3 => "Ingelmo M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1385/CRIAI:25:1:3" "Revista" => array:6 [ "tituloSerie" => "Clin Rev Allergy Immunol" "fecha" => "2003" "volumen" => "25" "paginaInicial" => "3" "paginaFinal" => "12" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12794256" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Systemic lupus erythematosus. II. Observations on the occurrence of exacerbations in the disease course: Dutch experience with 110 patients studied prospectively." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Swaak AJ" 1 => "Nossent JC" 2 => "Bronsveld W" 3 => "Van Rooyen A" 4 => "Nieuwenhuys EJ" 5 => "Theuns L" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "1989" "volumen" => "48" "paginaInicial" => "455" "paginaFinal" => "60" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2742400" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Systemic lupus erythematosus in the first decade of life." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Lehman TJ" 1 => "McCurdy DK" 2 => "Bernstein BH" 3 => "King KK" 4 => "Hanson V." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pediatrics" "fecha" => "1989" "volumen" => "83" "paginaInicial" => "235" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2913553" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Outcome in African-American children of neuropsychiatric lupus and lupus nephritis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Vyas S" 1 => "Hidalgo G" 2 => "Baqi N" 3 => "Von Gizyki H" 4 => "Singh A." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s004670200008" "Revista" => array:6 [ "tituloSerie" => "Pediatr Nephrol" "fecha" => "2002" "volumen" => "17" "paginaInicial" => "45" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11793134" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Bombardier C" 1 => "Gladman DD" 2 => "Urowitz MB" 3 => "Caron D" 4 => "Chang CH." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1992" "volumen" => "35" "paginaInicial" => "630" "paginaFinal" => "40" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1599520" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Sensitivity of the systemic lupus erythematosus disease activity index, British Isles Lupus Assessment Group Index, and Systemic Lupus Activity Measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Brunner HI" 1 => "Feldman BM" 2 => "Bombardier C" 3 => "Silverman ED." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1529-0131(199907)42:7<1354::AID-ANR8>3.0.CO;2-4" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1999" "volumen" => "42" "paginaInicial" => "1354" "paginaFinal" => "60" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10403262" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "[Childhood-onset systemic lupus erythematosus]." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Bader-Meunier B" 1 => "Quartier P" 2 => "Deschenes G" 3 => "Cochat P" 4 => "Haddad E" 5 => "Kone-Paut I" 6 => "et al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Pediatr" "fecha" => "2003" "volumen" => "10" "paginaInicial" => "147" "paginaFinal" => "57" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12829358" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Cutaneous manifestations of childhood systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Wananukul S" 1 => "Watana D" 2 => "Pongprasit P." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pediatr Dermatol" "fecha" => "1998" "volumen" => "15" "paginaInicial" => "342" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The 1982 revised criteria for the classification of systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1982" "volumen" => "25" "paginaInicial" => "1271" "paginaFinal" => "7" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Thrombocytopenia and thromboembolism in pediatric systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1067/S0022-3476(03)00389-5" "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "2003" "volumen" => "143" "paginaInicial" => "666" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Medicine (Baltimore)" "fecha" => "1999" "volumen" => "78" "paginaInicial" => "167" "paginaFinal" => "75" ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Antiphospholipid antibodies and antiphospholipid syndrome in 57 children and adolescents with systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2003" "volumen" => "12" "paginaInicial" => "820" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Thromboembolism in paediatric lupus patients." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2003" "volumen" => "12" "paginaInicial" => "741" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Point prevalence of cardiac abnormalities in children with systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2001" "volumen" => "28" "paginaInicial" => "854" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Assessment of myocardial perfusion and function in childhood systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "1998" "volumen" => "132" "paginaInicial" => "109" "paginaFinal" => "16" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "High insulin levels and increased low-density lipoprotein oxidizability in pediatric patients with systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.11472" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2004" "volumen" => "50" "paginaInicial" => "160" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Systemic lupus erythematosus and related disorders of childhood." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Opin Rheumatol" "fecha" => "1999" "volumen" => "11" "paginaInicial" => "384" "paginaFinal" => "92" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Systemic lupus erythematosus in childhood and adolescence. 5th ed. Baltimore: Williams and Wilkins; 1997." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Systemic lupus erythematosus in childhood and adolescence. 5th ed. Baltimore: Williams and Wilkins; 1997." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Systemic lupus erythematosus and antiphospholipid syndrome in children and adolescents." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Opin Rheumatol" "fecha" => "2001" "volumen" => "13" "paginaInicial" => "415" "paginaFinal" => "21" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Pulmonary involvement in juvenile systemic lupus erythematosus: A study on lung function in patients asymptomatic for respiratory disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "1998" "volumen" => "7" "paginaInicial" => "545" "paginaFinal" => "50" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Pulmonary involvement in childhood-onset systemic lupus erythematosus: A report of five cases." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2004" "volumen" => "43" "paginaInicial" => "587" "paginaFinal" => "91" ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Lupus nephropathy in children. Nephrol Dial Transplant. 2001;16 Suppl 6:126-8." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Lupus nephropathy in children. Nephrol Dial Transplant. 2001;16 Suppl 6:126-8." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Childhood systemic lupus erythematosus and neonatal lupus syndrome." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Opin Rheumatol" "fecha" => "1998" "volumen" => "10" "paginaInicial" => "481" "paginaFinal" => "7" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Clinicopathological study of the WHO classification in childhood lupus nephritis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00467-004-1419-y" "Revista" => array:6 [ "tituloSerie" => "Pediatr Nephrol" "fecha" => "2004" "volumen" => "19" "paginaInicial" => "503" "paginaFinal" => "10" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A new morphologic index for the evaluation of renal biopsies in lupus nephritis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1046/j.1523-1755.2000.00272.x" "Revista" => array:6 [ "tituloSerie" => "Kidney Int" "fecha" => "2000" "volumen" => "58" "paginaInicial" => "1160" "paginaFinal" => "73" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Lupus nephritis in childrena review of 167 patients." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pediatrics" "fecha" => "1994" "volumen" => "94" "paginaInicial" => "335" "paginaFinal" => "40" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1529-0131(199709)40:9<1725::AID-ART29>3.0.CO;2-Y" "Revista" => array:5 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1997" "volumen" => "40" "paginaInicial" => "1725" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Immunopathology and the gene therapy of lupus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.gt.3302016" "Revista" => array:6 [ "tituloSerie" => "Gene Ther" "fecha" => "2003" "volumen" => "10" "paginaInicial" => "861" "paginaFinal" => "74" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI119856" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "1997" "volumen" => "100" "paginaInicial" => "3019" "paginaFinal" => "26" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Patients with systemic lupus erythematosus have abnormally elevated Epstein-Barr virus load in blood." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/ar1181" "Revista" => array:6 [ "tituloSerie" => "Arthritis Res Ther" "fecha" => "2004" "volumen" => "6" "paginaInicial" => "R295" "paginaFinal" => "302" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Prevalence of systemic lupus erythematosus in England and Wales, 1981-2." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "1987" "volumen" => "46" "paginaInicial" => "664" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Med" "fecha" => "1975" "volumen" => "59" "paginaInicial" => "533" "paginaFinal" => "52" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A revised estimate of twin concordance in systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1992" "volumen" => "35" "paginaInicial" => "311" "paginaFinal" => "8" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "The genetics of systemic lupus erythematosus: Putting the pieces together. Genes Immun. 2002;3 Suppl 1:71-85." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The genetics of systemic lupus erythematosus: Putting the pieces together. Genes Immun. 2002;3 Suppl 1:71-85." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Delineating the genetic basis of systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Immunity" "fecha" => "2001" "volumen" => "15" "paginaInicial" => "397" "paginaFinal" => "408" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Genetics of systemic lupus erythematosus:How far have we come? Rheum Dis Clin North Am" "fecha" => "2005" "volumen" => "31" "paginaInicial" => "223" "paginaFinal" => "44" ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI119616" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "1997" "volumen" => "100" "paginaInicial" => "1059" "paginaFinal" => "70" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "The role of complement in the development of systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev.immunol.22.012703.104549" "Revista" => array:6 [ "tituloSerie" => "Annu Rev Immunol" "fecha" => "2004" "volumen" => "22" "paginaInicial" => "431" "paginaFinal" => "56" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Natural cell mediated cytotoxicity in systemic lupus erythematosus: Suppression by antilymphocyte antibody." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1980" "volumen" => "23" "paginaInicial" => "1274" "paginaFinal" => "81" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib51" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "T lymphocytes in systemic lupus erythematosus: An update." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Opin Rheumatol" "fecha" => "2004" "volumen" => "16" "paginaInicial" => "548" "paginaFinal" => "52" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib52" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Systemic lupus erythematosus. A disease with a complex pathogenesis. Lancet. 2001;358 Suppl :65." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Systemic lupus erythematosus. A disease with a complex pathogenesis. Lancet. 2001;358 Suppl :65." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib53" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Activated T lymphocytes in the peripheral blood of patients with systemic lupus erythematosus induce B cells to produce immunoglobulin." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Exp Rheumatol" "fecha" => "1988" "volumen" => "6" "paginaInicial" => "269" "paginaFinal" => "76" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib54" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Human lupus T cells resist inactivation and escape death by upregulating COX-2." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nm1005" "Revista" => array:6 [ "tituloSerie" => "Nat Med" "fecha" => "2004" "volumen" => "10" "paginaInicial" => "411" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib55" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Development of autoantibodies before the clinical onset of systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa021933" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2003" "volumen" => "349" "paginaInicial" => "1526" "paginaFinal" => "33" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib56" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "2001" "volumen" => "167" "paginaInicial" => "2361" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib57" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Predominant autoantibody production by early human B cell precursors." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.1086907" "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "2003" "volumen" => "301" "paginaInicial" => "1374" "paginaFinal" => "7" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib58" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Defective B cell tolerance checkpoints in systemic lupus erythematosus. En prensa. J Exp Med. 2005." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Defective B cell tolerance checkpoints in systemic lupus erythematosus. En prensa. J Exp Med. 2005." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib59" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1126/science.1064890" "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "2001" "volumen" => "294" "paginaInicial" => "1540" "paginaFinal" => "3" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib60" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Interferon and granulopoiesis signatures in systemic lupus erythematosus blood." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1084/jem.20021553" "Revista" => array:6 [ "tituloSerie" => "J Exp Med" "fecha" => "2003" "volumen" => "197" "paginaInicial" => "711" "paginaFinal" => "23" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib61" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Nuclear hormone receptors in T lymphocytes. Cell. 2002;109 Suppl :57-66." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Nuclear hormone receptors in T lymphocytes. Cell. 2002;109 Suppl :57-66." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib62" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Exp Med" "fecha" => "1994" "volumen" => "179" "paginaInicial" => "1317" "paginaFinal" => "30" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib63" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Tolerogenic dendritic cells." "idioma" => "it" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev.immunol.21.120601.141040" "Revista" => array:6 [ "tituloSerie" => "Annu Rev Immunol" "fecha" => "2003" "volumen" => "21" "paginaInicial" => "685" "paginaFinal" => "711" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib64" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Differential effects of sex steroids on T and B cells: Modulation of cell cycle phase distribution, apoptosis and bcl-2 protein levels." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "48757" "Revista" => array:6 [ "tituloSerie" => "Pathobiology" "fecha" => "2001" "volumen" => "69" "paginaInicial" => "44" "paginaFinal" => "58" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib65" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Novel packages of viral and self-antigens are generated during apoptosis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Exp Med" "fecha" => "1995" "volumen" => "181" "paginaInicial" => "1557" "paginaFinal" => "61" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib66" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Localization of the apoptosis-inducing activity of lupus anticoagulant in an annexin V-binding antibody subset." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI119889" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "1998" "volumen" => "101" "paginaInicial" => "1951" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib67" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2001" "volumen" => "28" "paginaInicial" => "780" "paginaFinal" => "5" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib68" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM198603063141004" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "1986" "volumen" => "314" "paginaInicial" => "614" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib69" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Assessment of damage in juvenile-onset systemic lupus erythematosus: A multicenter cohort study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.11205" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2003" "volumen" => "49" "paginaInicial" => "501" "paginaFinal" => "7" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib70" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Consistency and validity of patient administered assessment of quality of life by the MOS SF-36; its association with disease activity and damage in patients with systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "1997" "volumen" => "24" "paginaInicial" => "1608" "paginaFinal" => "14" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib71" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Physical disability and psychosocial dysfunction in systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "1988" "volumen" => "15" "paginaInicial" => "959" "paginaFinal" => "64" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib72" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: Results from a randomized, double-blind, placebo-controlled study." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.10763" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2003" "volumen" => "48" "paginaInicial" => "442" "paginaFinal" => "54" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib73" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "LJP 394 (abetimus sodium, Riquent) in the management of systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2004" "volumen" => "13" "paginaInicial" => "323" "paginaFinal" => "7" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib74" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "An open study of B lymphocyte depletion in systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.10541" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2002" "volumen" => "46" "paginaInicial" => "2673" "paginaFinal" => "7" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib75" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.20592" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2004" "volumen" => "50" "paginaInicial" => "3580" "paginaFinal" => "90" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib76" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.10856" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2003" "volumen" => "48" "paginaInicial" => "719" "paginaFinal" => "27" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib77" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2001" "volumen" => "28" "paginaInicial" => "95" "paginaFinal" => "101" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib78" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => ", Merrill JT, Totoritis MC, Wofsy D. Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: A randomized, double-blind, placebo-controlled trial." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.10681" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2002" "volumen" => "46" "paginaInicial" => "3251" "paginaFinal" => "8" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib79" "etiqueta" => "79" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.11299" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2003" "volumen" => "48" "paginaInicial" => "3253" "paginaFinal" => "65" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib80" "etiqueta" => "80" "referencia" => array:1 [ 0 => array:2 [ "referenciaCompleta" => "Safety and pharmacodynamic results of a phase I single and double dose-escalation study of Lymphostat-B in SLE patients. Arthritis Rheum. 2003;48 Suppl :377." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Safety and pharmacodynamic results of a phase I single and double dose-escalation study of Lymphostat-B in SLE patients. Arthritis Rheum. 2003;48 Suppl :377." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib81" "etiqueta" => "81" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "IL-1RA in refractory systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2004" "volumen" => "13" "paginaInicial" => "605" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib82" "etiqueta" => "82" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard.2004.025858" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2005" "volumen" => "64" "paginaInicial" => "630" "paginaFinal" => "3" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib83" "etiqueta" => "83" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Exp Med" "fecha" => "1995" "volumen" => "181" "paginaInicial" => "839" "paginaFinal" => "44" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib84" "etiqueta" => "84" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Prolonged remission without treatment after autologous stem cell transplantation for refractory childhood systemic lupus erythematosus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1529-0131(200103)44:3<728::AID-ANR123>3.0.CO;2-D" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2001" "volumen" => "44" "paginaInicial" => "728" "paginaFinal" => "31" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib85" "etiqueta" => "85" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: Results from phase I/II studies, prospective randomized trials and future directions." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2249.2005.02806.x" "Revista" => array:6 [ "tituloSerie" => "Clin Exp Immunol" "fecha" => "2005" "volumen" => "141" "paginaInicial" => "1" "paginaFinal" => "9" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib86" "etiqueta" => "86" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Autologous hematopoietic stem cell transplantation for autoimmune diseases." "idioma" => "fr" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ …7] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.bmt.1704892" "Revista" => array:6 [ "tituloSerie" => "Bone Marrow Transplant" "fecha" => "2005" "volumen" => "35" "paginaInicial" => "869" "paginaFinal" => "79" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 86 => array:3 [ "identificador" => "bib87" "etiqueta" => "87" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Expression and activity analyses of CTLA4 in peripheral blood lymphocytes in systemic lupus erythematosus patients." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2004" "volumen" => "13" "paginaInicial" => "24" "paginaFinal" => "31" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 87 => array:3 [ "identificador" => "bib88" "etiqueta" => "88" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Block and tackle: CTLA4Ig takes on lupus." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2005" "volumen" => "14" "paginaInicial" => "197" "paginaFinal" => "203" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/16954033/0000006300000004/v0_201404151142/13079815/v0_201404151143/en/main.assets" "Apartado" => array:4 [ "identificador" => "14284" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Artículo especial" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/16954033/0000006300000004/v0_201404151142/13079815/v0_201404151143/en/37v63n04a13079815pdf001.pdf?idApp=UINPBA00005H&text.app=https://analesdepediatria.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079815?idApp=UINPBA00005H"]

Estadísticas

Lupus eritematoso sistémico pediátrico

D. Stichweha, V. Pascuala

a Baylor Institute for Immunology Research. Dallas. Texas. USA.

Leído

34030

Veces
se ha leído el artículo

6982

Total PDF

27048

Total HTML

Compartir estadísticas

 array:21 [
  "pii" => "13079815"
  "issn" => "16954033"
  "doi" => "10.1157/13079833"
  "estado" => "S300"
  "fechaPublicacion" => "2005-10-01"
  "documento" => "article"
  "crossmark" => 0
  "subdocumento" => "fla"
  "cita" => "An Pediatr &#40;Barc&#41;. 2005;63:321-9"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:2 [
    "total" => 19402
    "formatos" => array:3 [
      "EPUB" => 113
      "HTML" => 17634
      "PDF" => 1655
    ]
  ]
  "Traduccion" => array:1 [
    "es" => array:17 [
      "pii" => "13079833"
      "issn" => "16954033"
      "doi" => "10.1157/13079833"
      "estado" => "S300"
      "fechaPublicacion" => "2005-10-01"
      "documento" => "article"
      "crossmark" => 0
      "subdocumento" => "fla"
      "cita" => "An Pediatr &#40;Barc&#41;. 2005;63:321-9"
      "abierto" => array:3 [
        "ES" => false
        "ES2" => false
        "LATM" => false
      ]
      "gratuito" => false
      "lecturas" => array:2 [
        "total" => 49523
        "formatos" => array:3 [
          "EPUB" => 155
          "HTML" => 44433
          "PDF" => 4935
        ]
      ]
      "es" => array:11 [
        "idiomaDefecto" => true
        "titulo" => "Lupus eritematoso sist&#233;mico pedi&#225;trico"
        "tienePdf" => "es"
        "tieneTextoCompleto" => "es"
        "tieneResumen" => array:2 [
          0 => "es"
          1 => "en"
        ]
        "paginas" => array:1 [
          0 => array:2 [
            "paginaInicial" => "321"
            "paginaFinal" => "329"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "en" => array:1 [
            "titulo" => "Systemic lupus erythematosus in children"
          ]
        ]
        "contieneResumen" => array:2 [
          "es" => true
          "en" => true
        ]
        "contieneTextoCompleto" => array:1 [
          "es" => true
        ]
        "contienePdf" => array:1 [
          "es" => true
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "D Stichweh, V Pascual"
            "autores" => array:2 [
              0 => array:2 [
                "Iniciales" => "D"
                "apellidos" => "Stichweh"
              ]
              1 => array:2 [
                "Iniciales" => "V"
                "apellidos" => "Pascual"
              ]
            ]
          ]
        ]
      ]
      "idiomaDefecto" => "es"
      "Traduccion" => array:1 [
        "en" => array:9 [
          "pii" => "13079815"
          "doi" => "10.1157/13079833"
          "estado" => "S300"
          "subdocumento" => ""
          "abierto" => array:3 [
            "ES" => false
            "ES2" => false
            "LATM" => false
          ]
          "gratuito" => false
          "lecturas" => array:1 [
            "total" => 0
          ]
          "idiomaDefecto" => "en"
          "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079815?idApp=UINPBA00005H"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079833?idApp=UINPBA00005H"
      "url" => "/16954033/0000006300000004/v0_201404151142/13079833/v0_201404151142/es/main.assets"
    ]
  ]
  "itemSiguiente" => array:16 [
    "pii" => "13079816"
    "issn" => "16954033"
    "doi" => "10.1157/13079816"
    "estado" => "S300"
    "fechaPublicacion" => "2005-10-01"
    "documento" => "article"
    "crossmark" => 0
    "subdocumento" => "fla"
    "cita" => "An Pediatr &#40;Barc&#41;. 2005;63:330-9"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 54509
      "formatos" => array:3 [
        "EPUB" => 138
        "HTML" => 52539
        "PDF" => 1832
      ]
    ]
    "es" => array:11 [
      "idiomaDefecto" => true
      "titulo" => "S&#237;ncope en el adolescente&#46; Orientaci&#243;n diagn&#243;stica y terap&#233;utica"
      "tienePdf" => "es"
      "tieneTextoCompleto" => "es"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "330"
          "paginaFinal" => "339"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Syncope in adolescents&#46; Diagnostic and therapeutic approach"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "es" => true
      ]
      "contienePdf" => array:1 [
        "es" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "J Eir&#237;s Pu&#241;al, A Rodr&#237;guez N&#250;&#241;ez, C G&#243;mez Lado, F Martin&#243;n-Torres, M Castro-Gago, JM&#170; Martin&#243;n S&#225;nchez"
          "autores" => array:6 [
            0 => array:2 [
              "Iniciales" => "J"
              "apellidos" => "Eir&#237;s Pu&#241;al"
            ]
            1 => array:2 [
              "Iniciales" => "A"
              "apellidos" => "Rodr&#237;guez N&#250;&#241;ez"
            ]
            2 => array:2 [
              "Iniciales" => "C"
              "apellidos" => "G&#243;mez Lado"
            ]
            3 => array:2 [
              "Iniciales" => "F"
              "apellidos" => "Martin&#243;n-Torres"
            ]
            4 => array:2 [
              "Iniciales" => "M"
              "apellidos" => "Castro-Gago"
            ]
            5 => array:2 [
              "nombre" => "JM&#170;"
              "apellidos" => "Martin&#243;n S&#225;nchez"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "es"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079816?idApp=UINPBA00005H"
    "url" => "/16954033/0000006300000004/v0_201404151142/13079816/v0_201404151143/es/main.assets"
  ]
  "itemAnterior" => array:17 [
    "pii" => "13079833"
    "issn" => "16954033"
    "doi" => "10.1157/13079833"
    "estado" => "S300"
    "fechaPublicacion" => "2005-10-01"
    "documento" => "article"
    "crossmark" => 0
    "subdocumento" => "fla"
    "cita" => "An Pediatr &#40;Barc&#41;. 2005;63:321-9"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 49523
      "formatos" => array:3 [
        "EPUB" => 155
        "HTML" => 44433
        "PDF" => 4935
      ]
    ]
    "es" => array:11 [
      "idiomaDefecto" => true
      "titulo" => "Lupus eritematoso sist&#233;mico pedi&#225;trico"
      "tienePdf" => "es"
      "tieneTextoCompleto" => "es"
      "tieneResumen" => array:2 [
        0 => "es"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "321"
          "paginaFinal" => "329"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Systemic lupus erythematosus in children"
        ]
      ]
      "contieneResumen" => array:2 [
        "es" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "es" => true
      ]
      "contienePdf" => array:1 [
        "es" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "D Stichweh, V Pascual"
          "autores" => array:2 [
            0 => array:2 [
              "Iniciales" => "D"
              "apellidos" => "Stichweh"
            ]
            1 => array:2 [
              "Iniciales" => "V"
              "apellidos" => "Pascual"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "es"
    "Traduccion" => array:1 [
      "en" => array:9 [
        "pii" => "13079815"
        "doi" => "10.1157/13079833"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => false
          "ES2" => false
          "LATM" => false
        ]
        "gratuito" => false
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "en"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079815?idApp=UINPBA00005H"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079833?idApp=UINPBA00005H"
    "url" => "/16954033/0000006300000004/v0_201404151142/13079833/v0_201404151142/es/main.assets"
  ]
  "en" => array:14 [
    "idiomaDefecto" => true
    "titulo" => "Systemic lupus erythematosus in children"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "321"
        "paginaFinal" => "329"
      ]
    ]
    "autores" => array:1 [
      0 => array:3 [
        "autoresLista" => "D Stichweh, V Pascual"
        "autores" => array:2 [
          0 => array:3 [
            "Iniciales" => "D"
            "apellidos" => "Stichweh"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "affa"
              ]
            ]
          ]
          1 => array:3 [
            "Iniciales" => "V"
            "apellidos" => "Pascual"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "affa"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:1 [
          0 => array:3 [
            "entidad" => "Baylor Institute for Immunology Research. Dallas. Texas. USA."
            "etiqueta" => "<span class="elsevierStyleSup">a</span>"
            "identificador" => "affa"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "en" => array:1 [
        "titulo" => "Lupus eritematoso sist&#233;mico pedi&#225;trico"
      ]
    ]
    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction</span></p><p class="elsevierStylePara">Systemic lupus erythematosus &#40;SLE&#41; is a complex&#44; multisystem autoimmune disease which results from the interplay of environmental&#44; hormonal and genetic factors&#46; In children&#44; the presentation&#44; clinical course and immunological findings differ slightly from adults with SLE <span class="elsevierStyleSup"> 1</span>&#46;</p><p class="elsevierStylePara">In the last decade the outcome of SLE patients have improved remarkably&#44; but even though many diagnostic and treatment options are similar for adults and children there are special issues that need to be considered in children and adolescents with SLE&#46; For example&#44; pSLE tends to be more severe and have higher impact on school adjustment and psychosocial aspects related&#44; among others&#44; to physical appearance and growth retardation <span class="elsevierStyleSup">2</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Epidemiology</span></p><p class="elsevierStylePara">Pediatric SLE &#40;pSLE&#41; represents approximately 15-20 &#37; of all SLE patients <span class="elsevierStyleSup"> 1&#44;3-5</span>&#46; It is more common in females than in males&#44; with a female to male ratio varying from 2&#46;3&#58;1 to 9&#58;1&#44; depending on the study <span class="elsevierStyleSup">6-11</span>&#46;</p><p class="elsevierStylePara">The incidence of the disease varies according to different ethnic groups&#46; In Caucasian females the incidence of SLE with onset before age of 19 years is between 6 and 18&#46;9 cases per 100&#44;000&#44; while it is 20-30 per 100&#44;000 in African American females and 16-36&#46;7 per 100&#44;000 in Puerto Rican females <span class="elsevierStyleSup">12</span>&#46; The diagnosis of pSLE is rare before the age of 10&#44; and the average age at presentation is 12&#46;1 years <span class="elsevierStyleSup"> 6-11</span>&#46;</p><p class="elsevierStylePara">Disease damage and mortality in pSLE have been linked to different risk factors which include young age at diagnosis&#44; male sex and non-white ethnicity &#40;African American&#44; Asian&#44; and Hispanic&#41; <span class="elsevierStyleSup">5&#44;13&#44;14</span>&#46; African Americans tend to have a greater prevalence and a more severe renal and neuropsychiatric disease &#40;NPSLE&#41; <span class="elsevierStyleSup">15</span>&#46; However&#44; the association between any of these risk factors and a poor prognosis remains controversial <span class="elsevierStyleSup">14&#44;16</span>&#46;</p><p class="elsevierStylePara">The survival rate for pSLE has improved dramatically over the past 50 years&#44; with a 5-year survival rate increasing from 50 &#37; in 1955 to more than 90 &#37; in 2004 <span class="elsevierStyleSup">8</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">General clinical manifestations</span></p><p class="elsevierStylePara">Clinical characteristics and organ involvement vary depending on age of onset&#44; gender and race&#46; In general children with SLE tend to have a more severe disease at onset with higher rates of organ involvement and a more aggressive clinical course than adult-onset SLE patients <span class="elsevierStyleSup">2&#44;17</span>&#46;</p><p class="elsevierStylePara">At onset&#44; 40-90 &#37; of children will present with constitutional symptoms &#40;fever&#44; fatigue or weight loss&#41;&#44; 20-82 &#37; will have renal involvement&#44; 20-74 &#37; musculoskeletal symptoms&#44; 22-74 &#37; malar rash&#44; 15-45 &#37; lymphadenopathies and 15-74 &#37; visceromegaly <span class="elsevierStyleSup"> 4&#44;7&#44;9&#44;18</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Cutaneous manifestations</span></p><p class="elsevierStylePara">The skin is commonly involved in pSLE&#46; Different cutaneous manifestations have been reported in children during the course of their disease including&#58; malar rash &#40;22-74 &#37;&#41; which is a hallmark of SLE&#44; oral ulcers &#40;26-48 &#37;&#41;&#44; vasculitic rash &#40;10-52 &#37;&#41;&#44; photosensitivity &#40;16-50 &#37;&#41;&#44; alopecia &#40;7-48 &#37;&#41;&#44; discoid lesions &#40;5-19 &#37;&#41; and Raynaud&#39;s phenomenon &#40;10-20 &#37;&#41; <span class="elsevierStyleSup">4&#44;7&#44;9&#44;18&#44;19</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Musculoskeletal manifestations</span></p><p class="elsevierStylePara">Arthritis occurs in more than 3&#47;4 of pediatric patients with SLE <span class="elsevierStyleSup">2</span>&#46; It can be variable&#44; but usually presents as a symmetric non-erosive&#44; very painful polyarthritis involving both&#44; large and small joints and is rarely associated with radiographic changes&#46;</p><p class="elsevierStylePara">In general&#44; SLE arthritis responds well to conventional therapy&#46; Indeed&#44; arthritis can be the only presenting manifestation of SLE and some patients who initially meet the American College of Rheumatology &#40;ACR&#41; criteria for juvenile arthritis&#44; subsequently fulfilled clinical and serological criteria for the classification of SLE <span class="elsevierStyleSup"> 2</span>&#46;</p><p class="elsevierStylePara">Myalgia is seen in 20-30 &#37; of patients&#44; however true myositis is less frequent&#46; Musculoskeletal manifestations could be also seen as a side effect of the different drugs used&#46; Treatment-induced musculoskeletal complications include avascular necrosis&#44; osteoporosis and growth failure&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Hematological disorders</span></p><p class="elsevierStylePara">Thirty nine percent of children with SLE will develop hematological abnormalities&#44; one of the ACR diagnostic criteria for SLE&#44; during the course of the disease <span class="elsevierStyleSup">20&#44;21</span>&#46;</p><p class="elsevierStylePara">Autoimmune thrombocytopenia is the initial manifestation in up to 15 &#37; of the pediatric cases although it can precede the onset of SLE by several years <span class="elsevierStyleSup">1&#44;3-5&#44;21&#44;22</span>&#46; It has been suggested that 20 &#37; to 30 &#37; of children with autoimmune idiopathic thrombocytopenic purpura who are ANA positive will evolve into SLE <span class="elsevierStyleSup">21</span>&#46; Leukopenia is observed in 27-52 &#37; of pediatric cases primarily due to a decrease in lymphocyte number&#46; Granulocytopenia is also common <span class="elsevierStyleSup">3</span>&#46;</p><p class="elsevierStylePara">Coagulation abnormalities are frequently present in pSLE&#46; The Coomb&#39;s test is positive in approximately 30-40 &#37; of patients&#44; however less than 10 &#37; will develop overt hemolysis <span class="elsevierStyleSup">6</span>&#46; Antiphospholipid antibodies &#40;aPL&#41; are present in 75 &#37; of pSLE patients <span class="elsevierStyleSup"> 23</span>&#46; Pediatric patients with SLE and aPL&#44; specifically lupus anticoagulant &#40;LAC&#41;&#44; are at high risk of developing thromboembolic events&#40;TE&#41; and the incidence of TE in LAC positive patients is 54 &#37; <span class="elsevierStyleSup">24</span>&#46; Therefore&#44; lifelong anticoagulation must be considered after an initial thromboembolic event&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Cardiac manifestations</span></p><p class="elsevierStylePara">The spectrum of cardiac disease in pSLE mirrors that in adults with SLE&#46; It encompasses 4 major types of manifestations&#58; pericarditis &#40;the most common form of cardiac involvement&#41;&#44; myocarditis&#44; valvular disease&#44; and coronary artery disease due to either coronary arteritis or atherosclerosis <span class="elsevierStyleSup">25</span>&#46; A few studies have reported silent cardiac abnormalities in children with SLE as a common finding <span class="elsevierStyleSup">25&#44;26</span>&#46; In fact&#44; myocardial ischemia has been described in 16 &#37; of asymptomatic children <span class="elsevierStyleSup">26</span>&#46;</p><p class="elsevierStylePara">Cardiac involvement in pSLE patients is now being recognized as a major cause of morbidity and mortality in this population&#46; Children with SLE have markedly higher rates of coronary heart disease than controls&#44; and these increased rates are partly explained by an increase in the conventional cardiovascular risk factors <span class="elsevierStyleSup">27</span>&#46; Identified risk factors for premature atherosclerosis in pSLE include&#58; dyslipidemia&#44; high levels of homocystein&#44; presence of aPL&#44; LAC&#44; hypertension&#44; hyperinsulinemia&#44; nephritic range proteinuria&#44; upregulated CD40-CD40 ligand interactions and steroid-induced obesity <span class="elsevierStyleSup">27</span>&#46; Currently&#44; the multicenter Atherosclerosis Prevention in Pediatric Lupus Erythematosus &#40;APPLE&#41; study group is assessing the role of statins for the prevention of atherosclerosis in the pediatric population with SLE&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> Neuropsychiatric manifestations</span></p><p class="elsevierStylePara">Neuropsychiatric systemic lupus erythematosus &#40;NPSLE&#41;&#44; occuring in 20-45 &#37; of children and adolescents&#44; is the third most common cause for mortality in pSLE <span class="elsevierStyleSup">2&#44;28&#44;29</span>&#46; Unlike other manifestations of the disease&#44; central nervous system &#40;CNS&#41; involvement occurs within the first year of disease in approximately 75 &#37; to 80 &#37; of patients <span class="elsevierStyleSup">2</span>&#46; NPSLE involvement can range from global cerebral dysfunction with paralysis and seizures&#44; to mild or focal symptoms such as headache or memory loss <span class="elsevierStyleSup">2</span>&#46; The presence of aPL is often linked to thrombosis and CNS infarction <span class="elsevierStyleSup"> 30</span>&#46;</p><p class="elsevierStylePara">The diagnosis of NPSLE continues to be difficult since there is a lack of specific serologic studies for its diagnosis and monitoring <span class="elsevierStyleSup">2</span>&#46; Although neuroimaging is a clinically useful tool&#44; CSF analysis&#44; EEG&#44; CT scan&#44; and even MRI may be normal in these patients <span class="elsevierStyleSup"> 2</span>&#46; On the other hand&#44; functional imaging may be abnormal in otherwise asymptomatic lupus individuals <span class="elsevierStyleSup">28</span> which makes its interpretation difficult&#46; Multiple imaging modalities have been studied to determine if there is a link between the clinical status and CNS imaging abnormalities&#44; but to date there is no consensus <span class="elsevierStyleSup">30</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Pulmonary involvement</span></p><p class="elsevierStylePara">The lung involved in 5-77 &#37; of pSLE patients <span class="elsevierStyleSup">29&#44;31&#44;32</span> and pulmonary manifestations vary from sub-clinical abnormalities to life-threatening disorders&#46; The clinical spectrum includes pleuritis &#40;the most common&#41;&#44; pneumonitis&#44; pneumonia&#44; pneumothorax&#44; diffuse interstitial disease&#44; pulmonary hypertension and pulmonary hemorrhage&#44; a relatively uncommon and potentially lethal complication&#46; In the majority of children&#44; pulmonary symptoms are present at some point during their disease course&#46; Asymptomatic or subclinical lung involvement in pSLE may be more prevalent than realized&#46; Pulmonary function abnormalities were found in up to 40 &#37; of pSLE patients with no evidence of clinical symptoms or radiographic changes <span class="elsevierStyleSup">31</span>&#46; The most frequent pattern observed was lung restrictive disease <span class="elsevierStyleSup">28</span>&#46; Although pulmonary function tests do not correlate well with pulmonary symptoms&#44; they provide objective quantification of the type and severity of the functional lesion observed <span class="elsevierStyleSup"> 32</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Renal involvement</span></p><p class="elsevierStylePara">Not only does renal involvement represent the first clinical manifestation of the disease in 60-80 &#37; of children with SLE <span class="elsevierStyleSup">7&#44;33</span>&#44; but it also determines the course of the disease and the outcome of patients&#46; About 80 &#37; of children and adolescents who develop renal abnormalities generally do so in the first year after diagnosis <span class="elsevierStyleSup">7&#44;33&#44;34</span>&#46; Pathological findings can not be predicted from the clinical manifestations and therefore a renal biopsy is required for precise to establish diagnosis and subsequently planning effective therapy <span class="elsevierStyleSup">33</span>&#46; In 1982&#44; the World Health Organization &#40;WHO&#41; classified lupus nephritis &#40;LN&#41; based on histologic features into 6 categories <span class="elsevierStyleSup">20</span>&#46; WHO class IV is the most common form of pSLE nephritis and is most commonly associated with the development of end stage renal disease or death&#46;</p><p class="elsevierStylePara">Renal flares are common throughout the disease course of LN and can frequently be detected by increasing proteinuria&#46; The presence of hypertension and peripheral edema are usually associated with WHO class III or IV LN <span class="elsevierStyleSup">7</span>&#46; The prognosis of children with LN depends primarily on the severity of the histopathological lesions according to the WHO classification&#46; Although in most centers the treatment is determined by the WHO class on biopsy&#44; long-term renal outcome is still unpredictable&#46; Other biopsy indices have been developed to evaluate LN at diagnosis and to predict outcome&#44; including the National Institutes of Health &#40;NIH&#41; classification <span class="elsevierStyleSup">35</span> and more recently an index focused on tubulointerstitial compartment changes in addition to features already included in the activity index and the chronicity indexes <span class="elsevierStyleSup">36</span>&#46;</p><p class="elsevierStylePara">The prognosis of pediatric LN has improved dramatically in the past decade&#46; The current 5-year survival rate for children with LN ranges between 78 &#37; and 92 &#37; <span class="elsevierStyleSup">7&#44;37</span> and the 5-year kidney survival from time of diagnosis varying from 44 to 93 &#37; <span class="elsevierStyleSup">7&#44;35</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Diagnosis</span></p><p class="elsevierStylePara">The heterogeneous nature of lupus can result in a diagnostic challenge for physicians&#46; Since there is not a single symptom or finding that in itself is sufficient for making the diagnosis of SLE&#44; the ACR has developed different criteria that can be useful as general clinical guidelines for the initial assessment of patients with suspected SLE&#46; The guidelines&#44; created in 1982 and updated in 1997 &#40;table 1&#41;&#44; combine 11 criteria &#40;clinical and laboratory&#41; and a diagnosis can be made when four or more of these criteria are present <span class="elsevierStyleSup"> 38</span>&#46;</p><p class="elsevierStylePara"><img src="37v63n04-13079815tab01.gif"></img></p><p class="elsevierStylePara">It may be challenging to distinguish active inflammation from symptoms due to cumulative organ damage or medication side effects&#46; A thorough history and physical examination&#44; including all major systems&#44; must be undertaken at each clinic visit &#40;table 2&#41;&#46; An assessment of disease activity is crucial for undertaking most treatment decisions&#46; Several activity indices have been validated and are depicted in table 3&#46;</p><p class="elsevierStylePara"><img src="37v63n04-13079815tab02.gif"></img></p><p class="elsevierStylePara"><img src="37v63n04-13079815tab03.gif"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Pathogenesis</span></p><p class="elsevierStylePara">Although the pathogenesis of SLE remains poorly understood&#44; susceptibility involves a combination of environmental&#44; hormonal and genetic factors&#46; One of the environmental factors that has been involved in lupus is ultraviolet light&#44; which triggers a photosensitive skin rash that may be followed by a generalized disease flare <span class="elsevierStyleSup"> 39</span>&#46; There is also growing evidence for infections&#44; such as Epstein-Barr virus &#40;EBV&#41; as an initial trigger for lupus-specific autoimmune responses&#46; A higher incidence of EBV infection&#44; higher titers of anti-EBV proteins and an abnormally elevated EBV load have been reported in children and adults with SLE when compared to matched healthy individuals <span class="elsevierStyleSup">40&#44;41</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Genetic factors</span></p><p class="elsevierStylePara">The genetic component of the disease is strongly established through epidemiology data&#44; strong familial aggregation of SLE&#44; and the known disease concordance rate in twins&#46; Siblings of SLE patients have an increased relative risk of developing the disease when compared to the general population <span class="elsevierStyleSup">42</span> and monozygotic twins have increased concordance &#40;&#62; 20 &#37;&#41; compared with dizygotic twins and other full siblings &#40;2-5 &#37;&#41; <span class="elsevierStyleSup">43&#44;44</span>&#46; Through association and genetic linkage studies&#44; over 60 loci <span class="elsevierStyleSup"> 45-47</span>&#44; including alleles from the HLA region&#44; region Fcg receptors and complement components have been implicated in the immunopathogenesis of SLE <span class="elsevierStyleSup">45&#44;48</span>&#46; Homozygous deficiency of any of the early components of the classical pathway &#40;C1q&#44; C1r&#44; C1s&#44; C4 and C2&#41; have been linked with an increased predisposition to the development of SLE <span class="elsevierStyleSup"> 49</span>&#46; Patients deficient in one of the C1-complex or C4 molecule exhibit the strongest prevalence &#40;&#62; 80 &#37;&#41; and the most severe disease&#44; while strength of association and disease severity decrease in C2-deficient patients <span class="elsevierStyleSup"> 49</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Immune alterations</span></p><p class="elsevierStylePara">It is recognized that SLE can arise through many molecular routes and requires contributions by T cells&#44; B cells&#44; dendritic cells&#44; and nonlymphoid cells at sites of tissue injury&#46; The most commonly recognized immune abnormalities are&#58; the ability to produce pathogenic autoantibodies&#59; lack of T-and B-lymphocyte regulation&#59; and defective clearance of autoantigens and immune complexes by the immune system <span class="elsevierStyleSup">39</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">T cells</span></p><p class="elsevierStylePara">Although numerous abnormalities in T cell functions have been described in SLE&#44; none are common to all patients&#46; There is evidence of T-cell lymphopenia&#46; Many studies report reduction of CD8&#43; T cells while others report decrease in CD4&#43; T cells&#59; functional defects&#44; such as decreased cytotoxic activity of CD8&#43;  cells <span class="elsevierStyleSup">50</span>&#44; signaling defects and diminished ability to reduce autoantibody production by B cells&#59; sustained activation and abnormal cytokine production <span class="elsevierStyleSup">39</span>&#46; T cells of SLE patients exhibit aberrant responses to stimuli with increased calcium influx and decreased production of interferon-a and IL-2 <span class="elsevierStyleSup">51</span>&#46; SLE T cells display markers of activation such as increased numbers of DR&#43; antigens <span class="elsevierStyleSup">52</span> and are able to facilitate the production of immunoglobulins by B cells <span class="elsevierStyleSup">53</span>&#46; SLE T cells seem to use different mechanisms of survival upon co-stimulation than normal T cells&#46; Indeed&#44; microarray profiling studies have recently shown that activated T cells from SLE patients resist anergy and apoptosis by upregulating cyclooxygenase-2 &#40;COX-2&#41; expression&#44; which in turn increases c-FLIP &#40;cellular homolog of viral FLICE inhibitory protein&#41; and attenuates FAS signaling&#46; Only certain COX-2 inhibitors&#44; however&#44; seem able to induce autoreactive T cell apoptosis and suppress the production of pathogenic autoantibodies to DNA in lupus-prone mice <span class="elsevierStyleSup">54</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">B cells and autoantibodies</span></p><p class="elsevierStylePara">B cells play a major role in the pathogenesis of SLE as they are responsible for the hypergammaglobulinemia and the production of antibodies against nuclear and cell surface antigens&#44; one of the most prevalent immunological abnormalities in SLE&#46; The development of some autoantibodies&#44; such as anti-dsDNA antibodies&#44; is closely linked to disease onset <span class="elsevierStyleSup">51</span> while others&#44; for instance antiphospholipid and anti-Ro antibodies&#44; can be detected months to years preceding the development of SLE <span class="elsevierStyleSup">55</span>&#46;</p><p class="elsevierStylePara">Patients with pSLE have profound B cell lymphopenia&#44; involving both na&#239;ve and memory B cells&#44; whereas oligoclonal plasma cell precursors are 3-fold expanded <span class="elsevierStyleSup">56</span>&#46;</p><p class="elsevierStylePara">Antibody gene expression studies from single B cells from healthy individuals showed that large numbers of developing B cells in the bone marrow and recent emigrants in the blood express self-reactive antibodies&#46; The majority of self-reactive B cells&#44; however&#44; are removed from the healthy mature blood na&#239;ve B cell pool at two discrete early checkpoints of their development <span class="elsevierStyleSup">57</span>&#46; These checkpoints are defective in patients with SLE&#46; A 25-50 &#37; of the mature na&#239;ve B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5-20 &#37; in controls <span class="elsevierStyleSup">58</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> Dendritic cells</span></p><p class="elsevierStylePara">Individuals with SLE display major alterations in DC homeostasis&#46; There is evidence that unabated IFN-&#945;  production differentiates CD14&#43; blood monocytes from SLE patients into mature dendritic cells able to capture dying cells and present their antigens to autoreactive T and B cells&#44; leading to a break in tolerance <span class="elsevierStyleSup">59&#44;60</span>&#46;</p><p class="elsevierStylePara">Although only a fraction of patients with active disease show circulating IFN-&#945;&#44; microarray analyses demonstrate an IFN signature in blood mononuclear cells <span class="elsevierStyleSup">60</span>&#46; These studies also demonstrated that high doses of glucocorticoids&#44; broad inhibitors of immune cell function <span class="elsevierStyleSup"> 61</span> extinguish the IFN signature&#46; Preliminary studies by Palucka et al show that they induce the apoptosis of interferon-producing cells or dendritic cells &#40;Palucka et al unpublished&#41;&#46; Glucocorticoids may therefore&#44; act by blocking IFN-&#945;  production&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> Apoptosis</span></p><p class="elsevierStylePara">A common feature of SLE autoantigens is that they are components of the surface blebs <span class="elsevierStyleSup">62</span> and they come under immune surveillance when they arise to the surface of apoptotic cells&#46; Furthermore&#44; there is increasing evidence that apoptotic material is normally taken up by immature dendritic cells and cross-presented to induce T cell tolerance <span class="elsevierStyleSup">63</span>&#46; Deficiency in apoptotic cell removal may provide dendritic cells with an excessive load of nuclear antigens and consequently develop overt SLE&#46;</p><p class="elsevierStylePara">Several other factors that are linked to the pathogenesis of SLE can influence apoptosis such as estrogens&#44; UV light <span class="elsevierStyleSup">64</span>&#44; infections <span class="elsevierStyleSup">65</span> and autoantibodies themselves <span class="elsevierStyleSup"> 66</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Treatment</span></p><p class="elsevierStylePara">Treatment of SLE depends on the clinical manifestations and the presence&#47;absence of major organ involvement &#40;table 4&#41;&#46; Corticosteroids are a major cause of morbidity and mortality in pSLE but they continue to be a mainstay of treatment due to their dramatic and rapid impact on lupus flares&#46; Their effectiveness in treating SLE has been recognized since the 1950s&#46; Intravenous &#40;IV&#41; pulse methylprednisolone &#40;MEP&#41; can be successfully used to treat major organ involvement and&#47;or life-threatening manifestations of SLE&#46; Antimalarials are effective for milder manifestations and improve bone-mineral density and dyslipoproteinemia <span class="elsevierStyleSup">67</span>&#46; Cyclophosphamide &#40;CYC&#41; remains the first-line treatment for major organ involvement&#46; It has been shown to reduce morbidity and improve mortality in lupus patients&#46; Over 20 years ago a National Institute of Health &#40;NIH&#41; study <span class="elsevierStyleSup">68</span> showed that monthly IV pulses of CYC were as effective&#44; but less toxic&#44; than daily oral CYC&#46; Since then the gold standard immunosuppressive treatment of LN has been monthly IV pulse CYC for 6-7 months&#44; in combination with high-dose glucocorticoids&#44; followed by a 2-year maintenance phase &#40;CYC for 2-3 months&#41;&#46; All patients receiving CYC and high-dose glucocorticoids should also receive prophylaxis with low-dose trimethoprim-sulfametoxazole inorder to prevent the most common opportunistic infection&#44; <span class="elsevierStyleItalic">Pneumocystis jiroveci</span> pneumonia&#46;</p><p class="elsevierStylePara"><img src="37v63n04-13079815tab04.gif"></img></p><p class="elsevierStylePara">Treatment of SLE includes not only pharmacological therapies&#44; but also patient education&#44; such as protection from ultraviolet light&#44; management and prevention of infections&#44; cardiovascular risk factors&#44; and treatment of complications including osteoporosis&#46;</p><p class="elsevierStylePara">Although the prognosis for pSLE has improved over the last few years&#44; pSLE remains a very challenging disease&#44; especially in children with partial response to treatment or treatment resistant who are at a high risk for serious complications&#46; With better understanding of SLE pathogenesis&#44; novel therapies are emerging which will hopefully translate into safer and more efficient treatments for children with SLE &#40;table 5&#41;&#46;</p><p class="elsevierStylePara"><img src="37v63n04-13079815tab05.gif"></img></p>"
    "pdfFichero" => "37v63n04a13079815pdf001.pdf"
    "tienePdf" => true
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec313438"
          "palabras" => array:2 [
            0 => "Lupus eritematoso sist&#233;mico"
            1 => "Ni&#241;os"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec313437"
          "palabras" => array:2 [
            0 => "Systemic lupus erythematosus"
            1 => "Children"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:1 [
        "resumen" => "Pediatric systemic lupus erythematosus &#40;pSLE&#41; is a chronic mutisystemic autoimmune disease with complex clinical manifestations&#46; Although the presentation&#44; clinical manifestations&#44; immunological findings and treatment issues of pSLE are similar to those of adult SLE patients&#44; there are special issues which need to be considered when dealing with SLE in children&#46; During the last decade survival has improved remarkably as a result of earlier diagnosis&#44; recognition of milder disease and better approaches to therapy&#46; However&#44; pSLE remains a potentially serious condition&#46; Although the pathogenesis of SLE remains poorly understood&#44; susceptibility involves a combination of environmental&#44; hormonal and genetic factors&#46;Better understanding of SLE pathogenesis will hopefully lead to more specific and less toxic therapies for this disease&#46;"
      ]
      "es" => array:1 [
        "resumen" => "El lupus eritematoso sist&#233;mico &#40;LES&#41; pedi&#225;trico es una enfermedad autoinmunitaria cr&#243;nica con manifestaciones cl&#237;nicas complejas&#46; A pesar de que la presentaci&#243;n&#44; las manifestaciones cl&#237;nicas&#44; los hallazgos inmunol&#243;gicos y el tratamiento del LES pedi&#225;trico son similares a los de pacientes adultos&#44; hay aspectos especiales que se deben considerar en la poblaci&#243;n pedi&#225;trica&#46; La supervivencia de pacientes con LES ha mejorado notablemente en la &#250;ltima d&#233;cada gracias al diagn&#243;stico precoz de la enfermedad&#44; el reconocimiento de pacientes con formas m&#225;s leves de la enfermedad y la instauraci&#243;n de tratamientos tempranos y m&#225;s agresivos&#46; Sin embargo&#44; el pron&#243;stico de pacientes con LES contin&#250;a siendo grave&#46; Aunque la patog&#233;nesis del LES contin&#250;a sin conocerse por completo&#44; diferentes factores interact&#250;an en su desarrollo&#58; factores ambientales&#44; hormonales y gen&#233;ticos&#46; Con el mejor entendimiento de la patogenia del LES&#44; el desarrollo de tratamientos m&#225;s espec&#237;ficos y menos t&#243;xicos ayudar&#225;n a mejorar el pron&#243;stico a largo plazo de esta enfermedad&#46;"
      ]
    ]
    "multimedia" => array:5 [
      0 => array:8 [
        "identificador" => "tbl1"
        "etiqueta" => "TABLE 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "37v63n04-13079815tab01.gif"
                  "imagenAlto" => 1822
                  "imagenAncho" => 917
                  "imagenTamanyo" => 111618
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "Revised ACR Criteria for the classification of SLE"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl2"
        "etiqueta" => "TABLE 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "37v63n04-13079815tab02.gif"
                  "imagenAlto" => 589
                  "imagenAncho" => 1577
                  "imagenTamanyo" => 44582
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "Suggested routine laboratories and exams for monitoring pediatric systemic lupus erythematosus patients in the outpatient clinic"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl3"
        "etiqueta" => "TABLE 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "37v63n04-13079815tab03.gif"
                  "imagenAlto" => 553
                  "imagenAncho" => 912
                  "imagenTamanyo" => 26643
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "Instruments used for assessing children with systemic lupus erythematosus"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl4"
        "etiqueta" => "TABLE 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "37v63n04-13079815tab04.gif"
                  "imagenAlto" => 609
                  "imagenAncho" => 1578
                  "imagenTamanyo" => 41493
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "Current treatment for pediatric systemic lupus erythematosus"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl5"
        "etiqueta" => "TABLE 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tablaImagen" => array:1 [
                0 => array:4 [
                  "imagenFichero" => "37v63n04-13079815tab05.gif"
                  "imagenAlto" => 802
                  "imagenAncho" => 1575
                  "imagenTamanyo" => 73015
                ]
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "New treatments in development for systemic lupus erythematosus"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Bibliography"
      "seccion" => array:1 [
        0 => array:1 [
          "bibliografiaReferencia" => array:88 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Systemic lupus erythematosus &#40;SLE&#41; in childhood&#58; Analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Font J"
                            1 => "Cervera R"
                            2 => "Espinosa G"
                            3 => "Pallar&#233;s L"
                            4 => "Ramos-Casals M"
                            5 => "Jim&#233;nez S"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "1998"
                        "volumen" => "57"
                        "paginaInicial" => "456"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9797549"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Systemic lupus erythematosus in childhood&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Klein-Gitelman M"
                            1 => "Reiff A"
                            2 => "Silverman ED&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Rheum Dis Clin North Am"
                        "fecha" => "2002"
                        "volumen" => "28"
                        "paginaInicial" => "561"
                        "paginaFinal" => "77"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12380370"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Adult- and childhood-onset systemic lupus erythematosus&#58; A comparison of onset&#44; clinical features&#44; serology&#44; and outcome&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Tucker LB"
                            1 => "Menon S"
                            2 => "Schaller JG"
                            3 => "Isenberg DA&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Rheumatol"
                        "fecha" => "1995"
                        "volumen" => "34"
                        "paginaInicial" => "866"
                        "paginaFinal" => "72"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7582729"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Diversity in presenting manifestations of systemic lupus erythematosus in children&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Iqbal S"
                            1 => "Sher MR"
                            2 => "Good RA"
                            3 => "Cawkwell GD&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr"
                        "fecha" => "1999"
                        "volumen" => "135"
                        "paginaInicial" => "500"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10518085"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Immunological and clinical differences between juvenile and adult onset of systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Carreno L"
                            1 => "L&#243;pez-Longo FJ"
                            2 => "Monteagudo I"
                            3 => "Rodr&#237;guez-Mahou M"
                            4 => "Bascones M"
                            5 => "Gonz&#225;lez CM"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lupus"
                        "fecha" => "1999"
                        "volumen" => "8"
                        "paginaInicial" => "287"
                        "paginaFinal" => "92"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10413207"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Benseler SM"
                            1 => "Silverman ED&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.pcl.2005.01.010"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Clin North Am"
                        "fecha" => "2005"
                        "volumen" => "52"
                        "paginaInicial" => "443"
                        "paginaFinal" => "67"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15820375"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Lupus nephritis in childhood&#58; A review of 53 patients followed at a single center&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Bogdanovic R"
                            1 => "Nikolic V"
                            2 => "Pasic S"
                            3 => "Dimitrijevic J"
                            4 => "Lipkovska-Markovic J"
                            5 => "Eric-Marinkovic J"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00467-003-1278-y"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Nephrol"
                        "fecha" => "2004"
                        "volumen" => "19"
                        "paginaInicial" => "36"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14634858"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Gender and ethnic origin have no effect on longterm outcome of childhood-onset systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Miettunen PM"
                            1 => "Ortiz-&#193;lvarez O"
                            2 => "Petty RE"
                            3 => "Cimaz R"
                            4 => "Malleson PN"
                            5 => "Cabral DA"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "2004"
                        "volumen" => "31"
                        "paginaInicial" => "1650"
                        "paginaFinal" => "4"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15290748"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The incidence and prevalence of neuropsychiatric syndromes in pediatric onset systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Sibbitt WL Jr"
                            1 => "Brandt JR"
                            2 => "Johnson CR"
                            3 => "Maldonado ME"
                            4 => "Patel SR"
                            5 => "Ford CC"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "2002"
                        "volumen" => "29"
                        "paginaInicial" => "1536"
                        "paginaFinal" => "42"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12136916"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Risk factors for damage in childhood-onset systemic lupus erythematosus&#58; Cumulative disease activity and medication use predict disease damage&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Brunner HI"
                            1 => "Silverman ED"
                            2 => "To T"
                            3 => "Bombardier C"
                            4 => "Feldman BM&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2002"
                        "volumen" => "46"
                        "paginaInicial" => "436"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11840446"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Sex differences in pediatric systemic lupus erythematosus&#58; A retrospective analysis of 135 cases&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Lo JT"
                            1 => "Tsai MJ"
                            2 => "Wang LH"
                            3 => "Huang MT"
                            4 => "Yang YH"
                            5 => "Lin YT"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Microbiol Immunol Infect"
                        "fecha" => "1999"
                        "volumen" => "32"
                        "paginaInicial" => "173"
                        "paginaFinal" => "8"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10637715"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The epidemiology of systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Jim&#233;nez S"
                            1 => "Cervera R"
                            2 => "Font J"
                            3 => "Ingelmo M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1385/CRIAI:25:1:3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Rev Allergy Immunol"
                        "fecha" => "2003"
                        "volumen" => "25"
                        "paginaInicial" => "3"
                        "paginaFinal" => "12"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12794256"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Systemic lupus erythematosus&#46; II&#46; Observations on the occurrence of exacerbations in the disease course&#58; Dutch experience with 110 patients studied prospectively&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Swaak AJ"
                            1 => "Nossent JC"
                            2 => "Bronsveld W"
                            3 => "Van Rooyen A"
                            4 => "Nieuwenhuys EJ"
                            5 => "Theuns L"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "1989"
                        "volumen" => "48"
                        "paginaInicial" => "455"
                        "paginaFinal" => "60"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2742400"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Systemic lupus erythematosus in the first decade of life&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Lehman TJ"
                            1 => "McCurdy DK"
                            2 => "Bernstein BH"
                            3 => "King KK"
                            4 => "Hanson V&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatrics"
                        "fecha" => "1989"
                        "volumen" => "83"
                        "paginaInicial" => "235"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2913553"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Outcome in African-American children of neuropsychiatric lupus and lupus nephritis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Vyas S"
                            1 => "Hidalgo G"
                            2 => "Baqi N"
                            3 => "Von Gizyki H"
                            4 => "Singh A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s004670200008"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Nephrol"
                        "fecha" => "2002"
                        "volumen" => "17"
                        "paginaInicial" => "45"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11793134"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Derivation of the SLEDAI&#46; A disease activity index for lupus patients&#46; The Committee on Prognosis Studies in SLE&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Bombardier C"
                            1 => "Gladman DD"
                            2 => "Urowitz MB"
                            3 => "Caron D"
                            4 => "Chang CH&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "1992"
                        "volumen" => "35"
                        "paginaInicial" => "630"
                        "paginaFinal" => "40"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1599520"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Sensitivity of the systemic lupus erythematosus disease activity index&#44; British Isles Lupus Assessment Group Index&#44; and Systemic Lupus Activity Measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Brunner HI"
                            1 => "Feldman BM"
                            2 => "Bombardier C"
                            3 => "Silverman ED&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/1529-0131(199907)42:7<1354::AID-ANR8>3.0.CO;2-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "1999"
                        "volumen" => "42"
                        "paginaInicial" => "1354"
                        "paginaFinal" => "60"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10403262"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "&#91;Childhood-onset systemic lupus erythematosus&#93;&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [
                            0 => "Bader-Meunier B"
                            1 => "Quartier P"
                            2 => "Deschenes G"
                            3 => "Cochat P"
                            4 => "Haddad E"
                            5 => "Kone-Paut I"
                            6 => "et al&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Pediatr"
                        "fecha" => "2003"
                        "volumen" => "10"
                        "paginaInicial" => "147"
                        "paginaFinal" => "57"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12829358"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Cutaneous manifestations of childhood systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Wananukul S"
                            1 => "Watana D"
                            2 => "Pongprasit P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Dermatol"
                        "fecha" => "1998"
                        "volumen" => "15"
                        "paginaInicial" => "342"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The 1982 revised criteria for the classification of systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "1982"
                        "volumen" => "25"
                        "paginaInicial" => "1271"
                        "paginaFinal" => "7"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Thrombocytopenia and thromboembolism in pediatric systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1067/S0022-3476(03)00389-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr"
                        "fecha" => "2003"
                        "volumen" => "143"
                        "paginaInicial" => "666"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Morbidity and mortality in systemic lupus erythematosus during a 5-year period&#46; A multicenter prospective study of 1&#44;000 patients&#46; European Working Party on Systemic Lupus Erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Medicine (Baltimore)"
                        "fecha" => "1999"
                        "volumen" => "78"
                        "paginaInicial" => "167"
                        "paginaFinal" => "75"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Antiphospholipid antibodies and antiphospholipid syndrome in 57 children and adolescents with systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lupus"
                        "fecha" => "2003"
                        "volumen" => "12"
                        "paginaInicial" => "820"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Thromboembolism in paediatric lupus patients&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lupus"
                        "fecha" => "2003"
                        "volumen" => "12"
                        "paginaInicial" => "741"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Point prevalence of cardiac abnormalities in children with systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "2001"
                        "volumen" => "28"
                        "paginaInicial" => "854"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Assessment of myocardial perfusion and function in childhood systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr"
                        "fecha" => "1998"
                        "volumen" => "132"
                        "paginaInicial" => "109"
                        "paginaFinal" => "16"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "High insulin levels and increased low-density lipoprotein oxidizability in pediatric patients with systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.11472"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2004"
                        "volumen" => "50"
                        "paginaInicial" => "160"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Systemic lupus erythematosus and related disorders of childhood&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Rheumatol"
                        "fecha" => "1999"
                        "volumen" => "11"
                        "paginaInicial" => "384"
                        "paginaFinal" => "92"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Systemic lupus erythematosus in childhood and adolescence. 5th ed. Baltimore: Williams and Wilkins; 1997."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Systemic lupus erythematosus in childhood and adolescence&#46; 5th ed&#46; Baltimore&#58; Williams and Wilkins&#59; 1997&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib30"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Systemic lupus erythematosus and antiphospholipid syndrome in children and adolescents&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Rheumatol"
                        "fecha" => "2001"
                        "volumen" => "13"
                        "paginaInicial" => "415"
                        "paginaFinal" => "21"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib31"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Pulmonary involvement in juvenile systemic lupus erythematosus&#58; A study on lung function in patients asymptomatic for respiratory disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lupus"
                        "fecha" => "1998"
                        "volumen" => "7"
                        "paginaInicial" => "545"
                        "paginaFinal" => "50"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib32"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Pulmonary involvement in childhood-onset systemic lupus erythematosus&#58; A report of five cases&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Rheumatology (Oxford)"
                        "fecha" => "2004"
                        "volumen" => "43"
                        "paginaInicial" => "587"
                        "paginaFinal" => "91"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib33"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Lupus nephropathy in children. Nephrol Dial Transplant. 2001;16 Suppl 6:126-8."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Lupus nephropathy in children&#46; Nephrol Dial Transplant&#46; 2001&#59;16 Suppl 6&#58;126-8&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib34"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Childhood systemic lupus erythematosus and neonatal lupus syndrome&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Rheumatol"
                        "fecha" => "1998"
                        "volumen" => "10"
                        "paginaInicial" => "481"
                        "paginaFinal" => "7"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib35"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Clinicopathological study of the WHO classification in childhood lupus nephritis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00467-004-1419-y"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Nephrol"
                        "fecha" => "2004"
                        "volumen" => "19"
                        "paginaInicial" => "503"
                        "paginaFinal" => "10"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib36"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "A new morphologic index for the evaluation of renal biopsies in lupus nephritis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1046/j.1523-1755.2000.00272.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Kidney Int"
                        "fecha" => "2000"
                        "volumen" => "58"
                        "paginaInicial" => "1160"
                        "paginaFinal" => "73"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib37"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Lupus nephritis in children&#173;a review of 167 patients&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatrics"
                        "fecha" => "1994"
                        "volumen" => "94"
                        "paginaInicial" => "335"
                        "paginaFinal" => "40"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib38"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/1529-0131(199709)40:9&lt;1725::AID-ART29&gt;3.0.CO;2-Y"
                      "Revista" => array:5 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "1997"
                        "volumen" => "40"
                        "paginaInicial" => "1725"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib39"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Immunopathology and the gene therapy of lupus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.gt.3302016"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gene Ther"
                        "fecha" => "2003"
                        "volumen" => "10"
                        "paginaInicial" => "861"
                        "paginaFinal" => "74"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib40"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI119856"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "1997"
                        "volumen" => "100"
                        "paginaInicial" => "3019"
                        "paginaFinal" => "26"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib41"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Patients with systemic lupus erythematosus have abnormally elevated Epstein-Barr virus load in blood&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/ar1181"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Res Ther"
                        "fecha" => "2004"
                        "volumen" => "6"
                        "paginaInicial" => "R295"
                        "paginaFinal" => "302"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib42"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Prevalence of systemic lupus erythematosus in England and Wales&#44; 1981-2&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "1987"
                        "volumen" => "46"
                        "paginaInicial" => "664"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib43"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Studies of twins with systemic lupus erythematosus&#46; A review of the literature and presentation of 12 additional sets&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Med"
                        "fecha" => "1975"
                        "volumen" => "59"
                        "paginaInicial" => "533"
                        "paginaFinal" => "52"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib44"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "A revised estimate of twin concordance in systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "1992"
                        "volumen" => "35"
                        "paginaInicial" => "311"
                        "paginaFinal" => "8"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib45"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "The genetics of systemic lupus erythematosus: Putting the pieces together. Genes Immun. 2002;3 Suppl 1:71-85."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The genetics of systemic lupus erythematosus&#58; Putting the pieces together&#46; Genes Immun&#46; 2002&#59;3 Suppl 1&#58;71-85&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib46"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Delineating the genetic basis of systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Immunity"
                        "fecha" => "2001"
                        "volumen" => "15"
                        "paginaInicial" => "397"
                        "paginaFinal" => "408"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib47"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Genetics of systemic lupus erythematosus:How far have we come? Rheum Dis Clin North Am"
                        "fecha" => "2005"
                        "volumen" => "31"
                        "paginaInicial" => "223"
                        "paginaFinal" => "44"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib48"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "A novel polymorphism of FcgammaRIIIa &#40;CD16&#41; alters receptor function and predisposes to autoimmune disease&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI119616"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "1997"
                        "volumen" => "100"
                        "paginaInicial" => "1059"
                        "paginaFinal" => "70"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib49"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "The role of complement in the development of systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1146/annurev.immunol.22.012703.104549"
                      "Revista" => array:6 [
                        "tituloSerie" => "Annu Rev Immunol"
                        "fecha" => "2004"
                        "volumen" => "22"
                        "paginaInicial" => "431"
                        "paginaFinal" => "56"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib50"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Natural cell mediated cytotoxicity in systemic lupus erythematosus&#58; Suppression by antilymphocyte antibody&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "1980"
                        "volumen" => "23"
                        "paginaInicial" => "1274"
                        "paginaFinal" => "81"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib51"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "T lymphocytes in systemic lupus erythematosus&#58; An update&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Rheumatol"
                        "fecha" => "2004"
                        "volumen" => "16"
                        "paginaInicial" => "548"
                        "paginaFinal" => "52"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib52"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Systemic lupus erythematosus. A disease with a complex pathogenesis. Lancet. 2001;358 Suppl :65."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Systemic lupus erythematosus&#46; A disease with a complex pathogenesis&#46; Lancet&#46; 2001&#59;358 Suppl &#58;65&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib53"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Activated T lymphocytes in the peripheral blood of patients with systemic lupus erythematosus induce B cells to produce immunoglobulin&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Rheumatol"
                        "fecha" => "1988"
                        "volumen" => "6"
                        "paginaInicial" => "269"
                        "paginaFinal" => "76"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib54"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Human lupus T cells resist inactivation and escape death by upregulating COX-2&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nm1005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Med"
                        "fecha" => "2004"
                        "volumen" => "10"
                        "paginaInicial" => "411"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib55"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Development of autoantibodies before the clinical onset of systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa021933"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2003"
                        "volumen" => "349"
                        "paginaInicial" => "1526"
                        "paginaFinal" => "33"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib56"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunol"
                        "fecha" => "2001"
                        "volumen" => "167"
                        "paginaInicial" => "2361"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib57"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Predominant autoantibody production by early human B cell precursors&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/science.1086907"
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "2003"
                        "volumen" => "301"
                        "paginaInicial" => "1374"
                        "paginaFinal" => "7"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib58"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Defective B cell tolerance checkpoints in systemic lupus erythematosus. En prensa. J Exp Med. 2005."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Defective B cell tolerance checkpoints in systemic lupus erythematosus&#46; En prensa&#46; J Exp Med&#46; 2005&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib59"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1126/science.1064890"
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "2001"
                        "volumen" => "294"
                        "paginaInicial" => "1540"
                        "paginaFinal" => "3"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib60"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Interferon and granulopoiesis signatures in systemic lupus erythematosus blood&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1084/jem.20021553"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Exp Med"
                        "fecha" => "2003"
                        "volumen" => "197"
                        "paginaInicial" => "711"
                        "paginaFinal" => "23"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib61"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Nuclear hormone receptors in T lymphocytes. Cell. 2002;109 Suppl :57-66."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Nuclear hormone receptors in T lymphocytes&#46; Cell&#46; 2002&#59;109 Suppl &#58;57-66&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib62"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Exp Med"
                        "fecha" => "1994"
                        "volumen" => "179"
                        "paginaInicial" => "1317"
                        "paginaFinal" => "30"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib63"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Tolerogenic dendritic cells&#46;"
                      "idioma" => "it"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1146/annurev.immunol.21.120601.141040"
                      "Revista" => array:6 [
                        "tituloSerie" => "Annu Rev Immunol"
                        "fecha" => "2003"
                        "volumen" => "21"
                        "paginaInicial" => "685"
                        "paginaFinal" => "711"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib64"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Differential effects of sex steroids on T and B cells&#58; Modulation of cell cycle phase distribution&#44; apoptosis and bcl-2 protein levels&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "48757"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pathobiology"
                        "fecha" => "2001"
                        "volumen" => "69"
                        "paginaInicial" => "44"
                        "paginaFinal" => "58"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib65"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Novel packages of viral and self-antigens are generated during apoptosis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Exp Med"
                        "fecha" => "1995"
                        "volumen" => "181"
                        "paginaInicial" => "1557"
                        "paginaFinal" => "61"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib66"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Localization of the apoptosis-inducing activity of lupus anticoagulant in an annexin V-binding antibody subset&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI119889"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "1998"
                        "volumen" => "101"
                        "paginaInicial" => "1951"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib67"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "2001"
                        "volumen" => "28"
                        "paginaInicial" => "780"
                        "paginaFinal" => "5"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib68"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Therapy of lupus nephritis&#46; Controlled trial of prednisone and cytotoxic drugs&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM198603063141004"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "1986"
                        "volumen" => "314"
                        "paginaInicial" => "614"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib69"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Assessment of damage in juvenile-onset systemic lupus erythematosus&#58; A multicenter cohort study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.11205"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2003"
                        "volumen" => "49"
                        "paginaInicial" => "501"
                        "paginaFinal" => "7"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib70"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Consistency and validity of patient administered assessment of quality of life by the MOS SF-36&#59; its association with disease activity and damage in patients with systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "1997"
                        "volumen" => "24"
                        "paginaInicial" => "1608"
                        "paginaFinal" => "14"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib71"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Physical disability and psychosocial dysfunction in systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "1988"
                        "volumen" => "15"
                        "paginaInicial" => "959"
                        "paginaFinal" => "64"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib72"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus&#58; Results from a randomized&#44; double-blind&#44; placebo-controlled study&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.10763"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2003"
                        "volumen" => "48"
                        "paginaInicial" => "442"
                        "paginaFinal" => "54"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib73"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "LJP 394 &#40;abetimus sodium&#44; Riquent&#41; in the management of systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lupus"
                        "fecha" => "2004"
                        "volumen" => "13"
                        "paginaInicial" => "323"
                        "paginaFinal" => "7"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib74"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "An open study of B lymphocyte depletion in systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.10541"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2002"
                        "volumen" => "46"
                        "paginaInicial" => "2673"
                        "paginaFinal" => "7"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib75"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.20592"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2004"
                        "volumen" => "50"
                        "paginaInicial" => "3580"
                        "paginaFinal" => "90"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib76"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "A short course of BG9588 &#40;anti-CD40 ligand antibody&#41; improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.10856"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2003"
                        "volumen" => "48"
                        "paginaInicial" => "719"
                        "paginaFinal" => "27"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib77"
              "etiqueta" => "77"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Phase I clinical trial of a monoclonal antibody against CD40-ligand &#40;IDEC-131&#41; in patients with systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Rheumatol"
                        "fecha" => "2001"
                        "volumen" => "28"
                        "paginaInicial" => "95"
                        "paginaFinal" => "101"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib78"
              "etiqueta" => "78"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "&#44; Merrill JT&#44; Totoritis MC&#44; Wofsy D&#46; Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154&#58; A randomized&#44; double-blind&#44; placebo-controlled trial&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.10681"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2002"
                        "volumen" => "46"
                        "paginaInicial" => "3251"
                        "paginaFinal" => "8"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            78 => array:3 [
              "identificador" => "bib79"
              "etiqueta" => "79"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Generation and characterization of LymphoStat-B&#44; a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/art.11299"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2003"
                        "volumen" => "48"
                        "paginaInicial" => "3253"
                        "paginaFinal" => "65"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            79 => array:3 [
              "identificador" => "bib80"
              "etiqueta" => "80"
              "referencia" => array:1 [
                0 => array:2 [
                  "referenciaCompleta" => "Safety and pharmacodynamic results of a phase I single and double dose-escalation study of Lymphostat-B in SLE patients. Arthritis Rheum. 2003;48 Suppl :377."
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Safety and pharmacodynamic results of a phase I single and double dose-escalation study of Lymphostat-B in SLE patients&#46; Arthritis Rheum&#46; 2003&#59;48 Suppl &#58;377&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            80 => array:3 [
              "identificador" => "bib81"
              "etiqueta" => "81"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "IL-1RA in refractory systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lupus"
                        "fecha" => "2004"
                        "volumen" => "13"
                        "paginaInicial" => "605"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            81 => array:3 [
              "identificador" => "bib82"
              "etiqueta" => "82"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/ard.2004.025858"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Rheum Dis"
                        "fecha" => "2005"
                        "volumen" => "64"
                        "paginaInicial" => "630"
                        "paginaFinal" => "3"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            82 => array:3 [
              "identificador" => "bib83"
              "etiqueta" => "83"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Exp Med"
                        "fecha" => "1995"
                        "volumen" => "181"
                        "paginaInicial" => "839"
                        "paginaFinal" => "44"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            83 => array:3 [
              "identificador" => "bib84"
              "etiqueta" => "84"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Prolonged remission without treatment after autologous stem cell transplantation for refractory childhood systemic lupus erythematosus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/1529-0131(200103)44:3<728::AID-ANR123>3.0.CO;2-D"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arthritis Rheum"
                        "fecha" => "2001"
                        "volumen" => "44"
                        "paginaInicial" => "728"
                        "paginaFinal" => "31"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            84 => array:3 [
              "identificador" => "bib85"
              "etiqueta" => "85"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease&#58; Results from phase I&#47;II studies&#44; prospective randomized trials and future directions&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2249.2005.02806.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Immunol"
                        "fecha" => "2005"
                        "volumen" => "141"
                        "paginaInicial" => "1"
                        "paginaFinal" => "9"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            85 => array:3 [
              "identificador" => "bib86"
              "etiqueta" => "86"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Autologous hematopoietic stem cell transplantation for autoimmune diseases&#46;"
                      "idioma" => "fr"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:7 [ …7]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.bmt.1704892"
                      "Revista" => array:6 [
                        "tituloSerie" => "Bone Marrow Transplant"
                        "fecha" => "2005"
                        "volumen" => "35"
                        "paginaInicial" => "869"
                        "paginaFinal" => "79"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            86 => array:3 [
              "identificador" => "bib87"
              "etiqueta" => "87"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Expression and activity analyses of CTLA4 in peripheral blood lymphocytes in systemic lupus erythematosus patients&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lupus"
                        "fecha" => "2004"
                        "volumen" => "13"
                        "paginaInicial" => "24"
                        "paginaFinal" => "31"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            87 => array:3 [
              "identificador" => "bib88"
              "etiqueta" => "88"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:3 [
                      "titulo" => "Block and tackle&#58; CTLA4Ig takes on lupus&#46;"
                      "idioma" => "en"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lupus"
                        "fecha" => "2005"
                        "volumen" => "14"
                        "paginaInicial" => "197"
                        "paginaFinal" => "203"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/16954033/0000006300000004/v0_201404151142/13079815/v0_201404151143/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "14284"
    "tipo" => "SECCION"
    "es" => array:2 [
      "titulo" => "Art&#237;culo especial"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "es"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/16954033/0000006300000004/v0_201404151142/13079815/v0_201404151143/en/37v63n04a13079815pdf001.pdf?idApp=UINPBA00005H&text.app=https://analesdepediatria.org/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/13079815?idApp=UINPBA00005H"
]

Información del artículo

ISSN: 16954033
Idioma original: Inglés

DOI:10.1157/13079833

Datos actualizados diariamente

año/Mes	Html	Pdf	Total

2024 Noviembre	30	23	53
2024 Octubre	205	144	349
2024 Septiembre	232	129	361
2024 Agosto	244	151	395
2024 Julio	235	111	346
2024 Junio	216	120	336
2024 Mayo	303	213	516
2024 Abril	303	177	480
2024 Marzo	228	146	374
2024 Febrero	204	141	345
2024 Enero	185	116	301
2023 Diciembre	199	67	266
2023 Noviembre	227	160	387
2023 Octubre	213	192	405
2023 Septiembre	154	132	286
2023 Agosto	121	70	191
2023 Julio	140	122	262
2023 Junio	145	98	243
2023 Mayo	234	114	348
2023 Abril	157	127	284
2023 Marzo	165	101	266
2023 Febrero	159	80	239
2023 Enero	154	103	257
2022 Diciembre	168	106	274
2022 Noviembre	175	126	301
2022 Octubre	196	113	309
2022 Septiembre	178	92	270
2022 Agosto	164	93	257
2022 Julio	120	110	230
2022 Junio	157	99	256
2022 Mayo	178	147	325
2022 Abril	192	169	361
2022 Marzo	251	116	367
2022 Febrero	237	79	316
2022 Enero	178	76	254
2021 Diciembre	182	69	251
2021 Noviembre	148	77	225
2021 Octubre	475	89	564
2021 Septiembre	249	78	327
2021 Agosto	108	63	171
2021 Julio	136	82	218
2021 Junio	120	104	224
2021 Mayo	129	77	206
2021 Abril	202	113	315
2021 Marzo	139	47	186
2021 Febrero	71	37	108
2021 Enero	77	33	110
2020 Diciembre	71	39	110
2020 Noviembre	93	26	119
2020 Octubre	57	39	96
2020 Septiembre	62	16	78
2020 Agosto	61	23	84
2020 Julio	72	22	94
2020 Junio	74	31	105
2020 Mayo	82	35	117
2020 Abril	63	19	82
2020 Marzo	71	28	99
2020 Febrero	77	38	115
2020 Enero	54	24	78
2019 Diciembre	81	25	106
2019 Noviembre	101	33	134
2019 Octubre	120	17	137
2019 Septiembre	109	49	158
2019 Agosto	73	31	104
2019 Julio	89	36	125
2019 Junio	87	47	134
2019 Mayo	143	102	245
2019 Abril	490	65	555
2019 Marzo	87	38	125
2019 Febrero	72	39	111
2019 Enero	73	40	113
2018 Diciembre	82	44	126
2018 Noviembre	110	56	166
2018 Octubre	115	39	154
2018 Septiembre	65	33	98
2018 Agosto	3	0	3
2018 Julio	4	0	4
2018 Junio	8	0	8
2018 Mayo	14	0	14
2018 Abril	52	0	52
2018 Marzo	45	0	45
2018 Febrero	29	0	29
2018 Enero	36	0	36
2017 Diciembre	48	0	48
2017 Noviembre	30	0	30
2017 Octubre	35	0	35
2017 Septiembre	40	0	40
2017 Agosto	38	0	38
2017 Julio	43	13	56
2017 Junio	56	47	103
2017 Mayo	90	60	150
2017 Abril	38	28	66
2017 Marzo	30	71	101
2017 Febrero	104	50	154
2017 Enero	18	15	33
2016 Diciembre	50	24	74
2016 Noviembre	77	35	112
2016 Octubre	98	19	117
2016 Septiembre	147	21	168
2016 Agosto	30	11	41
2016 Julio	19	22	41
2016 Junio	7	0	7
2016 Mayo	5	0	5
2016 Abril	10	0	10
2016 Marzo	3	0	3
2016 Febrero	4	0	4
2016 Enero	4	0	4
2015 Diciembre	11	0	11
2015 Noviembre	3	0	3
2015 Octubre	6	14	20
2015 Septiembre	5	12	17
2015 Agosto	2	14	16
2015 Julio	36	15	51
2015 Junio	22	7	29
2015 Mayo	30	12	42
2015 Abril	33	13	46
2015 Marzo	29	0	29
2015 Febrero	31	8	39
2015 Enero	29	6	35
2014 Diciembre	62	3	65
2014 Noviembre	44	9	53
2014 Octubre	40	3	43
2014 Septiembre	56	6	62
2014 Agosto	70	3	73
2014 Julio	79	6	85
2014 Junio	176	10	186
2014 Mayo	477	24	501
2014 Abril	497	24	521
2014 Marzo	516	29	545
2014 Febrero	435	25	460
2014 Enero	335	23	358
2013 Diciembre	286	26	312
2013 Noviembre	397	28	425
2013 Octubre	226	24	250
2013 Septiembre	173	37	210
2013 Agosto	156	46	202
2013 Julio	129	29	158
2013 Junio	17	6	23
2013 Mayo	18	3	21
2013 Abril	7	1	8
2013 Marzo	24	5	29
2013 Febrero	48	13	61
2013 Enero	68	3	71
2012 Diciembre	50	2	52
2012 Noviembre	31	5	36
2012 Octubre	30	6	36
2012 Septiembre	3	0	3
2005 Septiembre	9729	0	9729

Mostrar todo

Indexada en:

Síguenos:

Suscribirse:

Estadísticas

Indexada en:

Síguenos:

Suscribirse:

Estadísticas

Suscríbase a la newsletter