Use of tocilizumab in systemic sclerosis: A brief literature review

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Fernández-Codina, J. Fernández-Fernández, A. Fernández-Pantiga" "autores" => array:4 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Fernández-Codina" "email" => array:1 [ 0 => "doccodina@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J." "apellidos" => "Fernández-Fernández" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "A." "apellidos" => "Fernández-Pantiga" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] 3 => array:2 [ "colaborador" => "on behalf VII Master's final workgroup on the Clinical Management of Systemic Autoimmune Diseases of the Spanish Society of Internal Medicine" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "1" "identificador" => "fn0005" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Rheumatology Division, Department of Medicine, University of Western Ontario, London, ON, Canada" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital de Mataró, Mataró, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Universitario Central de Asturias, Oviedo, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilización de tocilizumab en la esclerosis sistémica: breve revisión de la literatura" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1172 "Ancho" => 2167 "Tamanyo" => 196576 ] ] "descripcion" => array:1 [ "en" => "Flow diagram of the literature review." ] ] ] "textoCompleto" => "BackgroundSystemic sclerosis (SS) is a systemic autoimmune disease characterized by the onset of vascular and immunologic disorders and excessive collagen synthesis in the extracellular matrix, which causes obliterative vasculopathy and cutaneous and visceral fibrosis.<a class="elsevierStyleCrossRef" href="#bib0110">1</a>The pathogenesis of SS is complex and not fully understood, although there is evidence of a role for T and B-cells in the production of profibrotic cytokines and fibroblast activation.<a class="elsevierStyleCrossRef" href="#bib0115">2</a> One of the cytokines involved in the pathogenesis of SS is interleukin 6 (IL-6),<a class="elsevierStyleCrossRef" href="#bib0120">3</a> which is found in high concentrations in the skin and serum of patients with SS, which is correlated in turn with disease severity.<a class="elsevierStyleCrossRefs" href="#bib0125">4,5</a>Tocilizumab (TCZ) is a humanized monoclonal IgG1 antibody that acts by blocking the signals mediated by the soluble receptors and by the IL-6 membrane.<a class="elsevierStyleCrossRef" href="#bib0135">6</a> TCZ has shown efficacy in various diseases, such as rheumatoid arthritis and Castleman's disease, and has been used in refractory cases of giant cell arteritis, Takayasu's arteritis and Still's disease.<a class="elsevierStyleCrossRef" href="#bib0140">7</a> TCZ is well tolerated, although adverse effects have been reported, such as the increased risk of infections, cytopenias, hepatic enzyme disorders and increased cholesterol levels. Furthermore, TCZ is an enzyme inducer of cytochrome P450 and therefore decreases the bioavailability of drugs that are metabolized by this pathway. Blocking the IL-6 pathway has been proposed as a possible treatment for some of the manifestations of SS.<a class="elsevierStyleCrossRef" href="#bib0145">8</a>The aim of this study was to conduct a systematic review of the existing literature on the safety and efficacy of TCZ for patients with SS.Material and methodsLiterature reviewWe conducted a systematic literature review through the databases of Medline Central, Cochrane Central Register of Controlled Trials and Clinicaltrials.gov. For the search, we used the keywords “tocilizumab” and “systemic sclerosis”.Study selectionThe search was restricted to articles published (online or hardcopy) in English up to December 2017 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Given the lack of publications, we included all available articles, regardless of type and design.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Data extractionThree researchers performed the data extraction from the selected studies. We obtained data on the design, epidemiology of the included population, results according to the clinical manifestations and safety data.Statistical analysisWe used descriptive statistical parameters (number and percentage) and compared the variables provided in the clinical trials.ResultsWe found 10 studies that reported the results of treatment with TCZ in patients with SS (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The evaluated studies included a randomized, double-blind clinical trial,<a class="elsevierStyleCrossRef" href="#bib0150">9</a> with its open continuation,<a class="elsevierStyleCrossRef" href="#bib0155">10</a> an observational, prospective study<a class="elsevierStyleCrossRef" href="#bib0160">11</a> and 6 case series or isolated case studies.<a class="elsevierStyleCrossRefs" href="#bib0165">12–18</a> There were no control groups in any of the case series.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The main objective of the phase II Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial<a class="elsevierStyleCrossRef" href="#bib0155">10</a> was to assess the efficacy of TCZ, administered subcutaneously, on skin induration in patients with diffuse SS within the first 5 years of the disease and who presented moderate-severe skin disorder, recent worsening and high inflammatory markers. It is worth noting that 43% and 51% of the patients assigned to the placebo and TCZ branches, respectively, had previously or concomitantly (the article does not specify) been treated with immunosuppressants. Thirty-nine percent and 49% of the included patients, respectively, were simultaneously treated with corticosteroids. Follow-up was conducted at 24 and 48 weeks. The main objective (variation in the modified Rodnan skin score [mRSS]) was set at 24 weeks, similar to previous studies on rheumatoid arthritis. The open continuation to 96 weeks of the faSScinate study has recently been published.<a class="elsevierStyleCrossRef" href="#bib0155">10</a> The patients who were administered placebo at the start went on to receive TCZ, and the group with the active TCZ treatment maintained it.The observational study of the Scleroderma Trials and Research Group (EUSTAR) focused on cases with refractory polyarthritis and myopathy associated with SS.<a class="elsevierStyleCrossRef" href="#bib0165">12</a> The patients were prospectively treated with TCZ (arthritis) and Abatacept (arthritis or myopathy). In the TCZ group, 11 patients maintained their previous glucocorticoid treatment at the start (prednisone <10mg/day), and 8 maintained their previous methotrexate treatment. The other studies were heterogeneous case studies.The main results of these studies are listed below, broken down by type of SS manifestation.Skin disorderThe primary result of the faSScinate study<a class="elsevierStyleCrossRef" href="#bib0150">9</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) was a mean mRSS variation of −2.7 at 24 weeks between the placebo and TCZ groups (95% CI −5.85 to 0.45, p=.09) and −3.55 at 48 weeks (95% CI −7.23 to 0.12, p=.05). The main objective was therefore not achieved. In the extension to 96 weeks,<a class="elsevierStyleCrossRef" href="#bib0155">10</a> the authors observed that the mean mRSS variation in the placebo group who were administered TCZ between weeks 48 and 96 and that of the patients treated from the start with TCZ were similar. Elhai et al.<a class="elsevierStyleCrossRef" href="#bib0165">12</a> also observed no significant changes in the mRSS in either of the 2 treatment groups. Lastly, the isolated case studies and case series suggested an improvement in the skin disorder,<a class="elsevierStyleCrossRefs" href="#bib0165">12,14,16–18</a> except for 1 patient who did not improve.<a class="elsevierStyleCrossRef" href="#bib0170">13</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Pulmonary involvementThe faSScinate clinical trial<a class="elsevierStyleCrossRef" href="#bib0150">9</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) showed a significantly lower reduction, at 24 weeks of treatment, of the percent forced vital capacity (FVC) in the TCZ group than in the placebo group, with a mean difference of 136mL (95% CI 9–264, p=.03). These differences were not maintained significantly at 48 weeks (120mL; 95% CI −23 to 262, p=.09). Worsening of the FVC (>10% of the absolute value) was observed at 24 weeks (3% vs. 19%) and 48 weeks (10% vs. 23%) in fewer patients in the TCZ group than in the placebo group (p=.009 and p=.03). In the study extension,<a class="elsevierStyleCrossRef" href="#bib0160">11</a> none of the patients showed a >10% reduction in their absolute FVC.In the European collaborative study, patients with myopathy treated with abatacept shown FVC stability; however, no functional studies were performed on the patients treated with TCZ.<a class="elsevierStyleCrossRef" href="#bib0160">11</a>In terms of the case studies (<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>), Shima et al.<a class="elsevierStyleCrossRef" href="#bib0165">12</a> and Fernandes das Neves<a class="elsevierStyleCrossRef" href="#bib0175">14</a> both reported similar stability of the interstitial lung disease (ILD).Joint involvementThe faSScinate study<a class="elsevierStyleCrossRef" href="#bib0150">9</a> was not designed to assess joint involvement. The EUSTAR observational study<a class="elsevierStyleCrossRef" href="#bib0160">11</a> showed a significant reduction in DAS28 (disease activity index with a total of 28 joints) from 5.2 to 2.8 (p<.001) after 5 months of treatment with TCZ. Glucocorticoid treatment was discontinued for 2 patients and the dosage lowered for 3 patients. Several clinical case series have reported an improvement in the joint inflammatory activity parameters of patients with overlapping syndromes.<a class="elsevierStyleCrossRefs" href="#bib0170">13–15,18</a>Digital ulcersThe faSScinate study<a class="elsevierStyleCrossRef" href="#bib0155">10</a> observed no statistically significant differences between the placebo arm and the TCZ treatment arm in the number of digital ulcers present at 24 and 48 weeks. The 2 patients with digital ulcers in the study by Fernandes das Neves et al.<a class="elsevierStyleCrossRef" href="#bib0175">14</a> completely resolved the ulcers at 6 months of starting TCZ.Side effectsIn the faSScinate study,<a class="elsevierStyleCrossRefs" href="#bib0150">9,10</a> there were no differences between the 2 groups in the number of adverse effects. The most common effects were infections and gastrointestinal, musculoskeletal and skin symptoms. The onset of severe infectious adverse events was 4/100 patient-years in the placebo group versus 12/100 patient-years in the TCZ group. In the study extension, only those patients who started TCZ for the first time developed infections (6/100 patient-years). There was a notable onset of digital osteomyelitis in 6 patients. The number of patients who could not finish the study due to adverse effects at 24 and 48 weeks, respectively, was similar in the placebo group (5 patients, 11%) and the TCZ group (6 patients, 14%). After 48 weeks, 4 patients had died, 3 of them in the TCZ group. Only one death (due to respiratory infection) was directly attributed to the treatment. There were no deaths in the open phase.The observational EUSTAR study<a class="elsevierStyleCrossRef" href="#bib0165">12</a> was not designed to assess the drug's safety. During the follow-up, 1 patient experienced an episode of nausea related to the TCZ infusion, and another patient experienced a transient increase in transaminases. None of the patients discontinued the treatment due to adverse effects. Frech et al.<a class="elsevierStyleCrossRef" href="#bib0185">16</a> reported 2 cases of patients with SS who were treated with TCZ and who developed (one after an unspecified time and another at 24 months) a worsening of the gastroesophageal reflux and intestinal pseudo-obstruction, respectively, which motivated the discontinuation of the TCZ. The patients improved with antibiotic treatment for the intestinal bacterial overgrowth.DiscussionThere are few series that have evaluated TCZ in SS. Nevertheless, the available studies show a modest therapeutic response in both the skin and joints. There is no evidence to support the use of TCZ for the other manifestations.Only one randomized, double-blind, prospective, phase II clinical trial, one prospective trial and various case studies have been published on the use of TCZ in SS.The main objective of the faSScinate clinical trial<a class="elsevierStyleCrossRef" href="#bib0155">10</a> (mRSS variation ≥4.7 at 24 weeks) was not achieved. In diffuse SS, an mRSS variation between 3.2 and 5.3 during the first years of disease progression is considered clinically relevant.<a class="elsevierStyleCrossRef" href="#bib0200">19</a> An excessively demanding primary objective and a short time margin could explain the lack of response in this study. As for its open extension,<a class="elsevierStyleCrossRef" href="#bib0160">11</a> the natural progression of diffuse SS with its tendency to decrease skin thickening over time could also explain part of the improvement in mRSS observed in most patients at 18 and 24 months of the start of the study.Finally, the results of the observational EUSTAR study<a class="elsevierStyleCrossRef" href="#bib0165">12</a> and those of various case studies support the potential benefit of TCZ in treating skin induration. To confirm these hypotheses, the results of a phase III study would be of paramount importance (<a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02453256">NCT02453256</a>).<a class="elsevierStyleCrossRef" href="#bib0205">20</a> This study involves a double-blind, randomized, trial with a TCZ treatment branch and a placebo branch, whose main objective is the mRSS variation at 48 weeks.With regard to ILD, the worsening of the FVC (%) in the patients treated with TCZ appears to be rare in the faSScinate study,<a class="elsevierStyleCrossRef" href="#bib0155">10</a> while the cases described by Fernandes das Neves<a class="elsevierStyleCrossRef" href="#bib0175">14</a> showed stabilization. Documentation of the reduction in biological markers of pulmonary fibrosis such as chemokine CC ligand 18 (typically elevated in patients with ILD) in patients treated with TCZ<a class="elsevierStyleCrossRef" href="#bib0150">9</a> supports its potential therapeutic effect.Treatment for arthritis in SS could be another possible indication for TCZ. Arthritis can affect up to 30% of patients with SS.<a class="elsevierStyleCrossRef" href="#bib0210">21</a> Data from the EUSTAR study corresponded to patients with SS who met the criteria for rheumatoid arthritis. In a strategy similar to that for rheumatoid arthritis, the combination of TCZ and methotrexate or corticosteroids could be effective<a class="elsevierStyleCrossRef" href="#bib0160">11</a> for the arthritis of SS.The safety profile of TCZ appears to be acceptable, with adverse effects very similar to those found in patients with rheumatoid arthritis treated with the drug.For patients with digital ulcers due to SS who are treated with TCZ, special attention should be paid to the possibility that osteomyelitis of the phalanges can occur during the early phases of treatment.The primary limitation of this review is that there are very few studies that have evaluated the use of TCZ in SS. The only randomized clinical trial had few patients, who also had a high risk of progression of the skin disorder, which could have biased the results. The other studies included a small number of patients, the measure of the results was heterogeneous, and the studied manifestations were varied. These results should therefore be interpreted with caution.In conclusion, the few available studies indicate that, although TCZ has shown no significant improvement in treating the skin induration of SS, the drug could be effective in treating the inflammatory arthritis associated with this condition. Severe infections are the most significant adverse effect resulting from the use of this drug. We need to wait for the results of future studies to better define the role of TCZ in the therapeutic algorithms of SS.Conflict of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1066225" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1014100" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1066226" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1014101" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Literature review" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Study selection" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Data extraction" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0035" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Skin disorder" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Pulmonary involvement" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Joint involvement" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Digital ulcers" ] 4 => array:2 [ "identificador" => "sec0060" "titulo" => "Side effects" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-12-23" "fechaAceptado" => "2018-02-17" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1014100" "palabras" => array:3 [ 0 => "Systemic sclerosis" 1 => "Tocilizumab" 2 => "Treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1014101" "palabras" => array:3 [ 0 => "Esclerosis sistémica" 1 => "Tocilizumab" 2 => "Tratamiento" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The available treatments for systemic sclerosis (SS) have limited effectiveness. Treatment with tocilizumab (TCZ), a biological drug that inhibits interleukin 6 (IL-6), has recently been proposed. In this study, we conducted a literature review to assess the safety and efficacy of TCZ in SS. We found 52 articles, 10 of which we selected after evaluating the articles. In a randomized clinical trial, TCZ showed a nonsignificant improvement in the degree of skin induration, while another observational study showed neutral results. In this same clinical trial, the functional respiratory parameters showed a certain degree of stabilization. The safety profile of TCZ is acceptable; however, the current evidence regarding treatment of SS with TCZ is highly limited, although the drug could have a beneficial effect in skin disorder. New clinical trials are needed to determine the usefulness of TCZ in SS." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los tratamientos disponibles para la esclerosis sistémica (ES) tienen una efectividad limitada. Recientemente se ha propuesto el tratamiento con tocilizumab (TCZ), un fármaco biológico que inhibe la interleucina 6 (IL6). En este trabajo se realiza una revisión de la literatura para evaluar la eficacia y seguridad de TCZ en ES. Se han encontrado 52 artículos, de los que, tras su evaluación, se han seleccionado solo 10. En un ensayo clínico aleatorizado TCZ demostró una mejoría no significativa del grado de induración cutánea, mientras que en un estudio observacional los resultados fueron neutros. En dicho ensayo clínico, los parámetros funcionales respiratorios mostraron cierto grado de estabilización. El perfil de seguridad de TCZ es aceptable. La evidencia actual en cuanto al tratamiento de la ES con TCZ es muy limitada, aunque el fármaco podría tener un efecto beneficioso en la afectación cutánea. Se requieren nuevos ensayos clínicos para comprobar su utilidad en ES." ] ] "NotaPie" => array:2 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "The other coauthors of the VII Master's final workgroup on the Clinical Management of Systemic Autoimmune Diseases of the Spanish Society of Internal Medicine are: María Fontecha Ortega (Department of Internal Medicine, University Hospital of Getafe, Getafe, Spain), María José Forner (Department of Internal Medicine, University Clinic Hospital, Valencia, Spaina), Inmaculada Fernández-Galante (Department of Internal Medicine, Healthcare Complex of Segovia, Segovia, Spain), Carmen Pilar Simeón-Aznar (Systemic Autoimmune Diseases Unit, Department of Internal Medicine, University Hospital Vall d’Hebron, Barcelona, Spain)." "identificador" => "fn0005" ] 1 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Fernández-Codina A, Fernández-Fernández J, Fernández-Pantiga A, en nombre del grupo vii de trabajo de final de máster en Manejo Clínico de Enfermedades Autoinmunes Sistémicas de la Sociedad Española de Medicina Interna. Utilización de tocilizumab en la esclerosis sistémica: breve revisión de la literatura. Rev Clin Esp. 2018;218:298–304." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1172 "Ancho" => 2167 "Tamanyo" => 196576 ] ] "descripcion" => array:1 [ "en" => "Flow diagram of the literature review." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: ACA, anticentromere antibodies; ACPA, anticitrullinated peptide antibodies; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; anti-PM/Scl 100, anti-PM/Scl 100 antibodies; anti-RNAP III, anti-RNA polymerase III antibodies; anti-Scl-70, antitopoisomerase antibodies; dSSc, diffuse systemic sclerosis; DU, digital ulcers; ILD, interstitial lung disease; iv, intravenous; MTX, methotrexate; ND, no data; N-TCZ, number of patients treated with tocilizumab; PAH, pulmonary arterial hypertension; PBO, placebo; RF, rheumatoid factor; sc, subcutaneous; SRC, scleroderma renal crisis; TCZ, tocilizumab." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author/year \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study type \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Duration \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N (treated with TCZ) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Women, n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">dSSc, N (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Autoantibodies, n (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Noncutaneous manifestations, N \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Elhai et al.<a class="elsevierStyleCrossRef" href="#bib0160">11</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational prospective multicenter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TCZ 8mg/kg a month sc vs. abatacept 10mg/kg a month sc \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27 (15) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23 (85) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 (51.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anti-Scl-70 14 (52) ACA 5 (19) RF 7 (26) ACPA 7 (26) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arthritis (18) Myopathy (7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Frech et al.<a class="elsevierStyleCrossRef" href="#bib0185">16</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anti-RNAP III 1 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arthritis (1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fernandes das Neves et al.<a class="elsevierStyleCrossRef" href="#bib0175">14</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TCZ 8mg/kg at 1month \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (66.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anti-Scl-70 2 (67) Anti-PM/Scl-100 1 (33) RF 1 (33) ACPA 1 (33) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DU (2) Arthritis (1) ILD (3) Intestinal (2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Khanna et al.<a class="elsevierStyleCrossRef" href="#bib0150">9</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Randomized, double-blind phase II clinical trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TCZ 162mg weekly sc vs. placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">87 (43) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">67 (77) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">87 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anti-RNAP III 30 (34) Anti-Scl-70 28 (32) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Khanna et al.<a class="elsevierStyleCrossRef" href="#bib0160">11</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Randomized, open, phase II clinical trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TCZ 162mg weekly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">96weeks initial TCZ group/48weeks initial PBO group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">61 (61) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49 (80) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">61 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kondo et al.<a class="elsevierStyleCrossRef" href="#bib0180">15</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TCZ 8mg/kg every 14 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ANA RF ACPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Myopathy Arthritis DU \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kono et al.<a class="elsevierStyleCrossRef" href="#bib0195">18</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TCZ 162mg every 2weeks sc; TCZ 8mg/kg a month iv \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">54 and 108weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACPA 2 (100) Anti-Scl-70 1 (50) U1-RNP 1 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arthritis (2) ILD (2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Saito et al.<a class="elsevierStyleCrossRef" href="#bib0170">13</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TCZ 600mg a month sc+MTX 6mg weekly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACA RF ACPA AMA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arthritis Primary biliary cirrhosis Adenopathies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shima et al.<a class="elsevierStyleCrossRef" href="#bib0165">12</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Tocilizumab 8mg/kg a month \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ANA 2 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SRC (1) ILD (1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shima et al.<a class="elsevierStyleCrossRef" href="#bib0190">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TCZ 8mg/kg a month sc+methylprednisolone 8mg a day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">64weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anti-RNAP III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SRC Gastrointestinal PAH \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1818486.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Design and epidemiological and clinical characteristics of the reviewed studies that included patients with systemic scleroderma treated with tocilizumab." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Abbreviations: FVC, forced vital capacity; Δ mRSS, variation on the modified Rodnan skin score; NS, no significant; ND, no data; TCZ, tocilizumab." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author/year/study \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study type \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline mRSS \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Final mRSS \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Δ mRSS \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Result \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline FVC % \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Final FVC % \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Δ FVC % \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Result \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Elhai et al.<a class="elsevierStyleCrossRef" href="#bib0160">11</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Observational \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nonsignificant improvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Frech et al.<a class="elsevierStyleCrossRef" href="#bib0185">16</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22/27 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND/6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sustained improvement in a patient \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fernandes das Neves et al.<a class="elsevierStyleCrossRef" href="#bib0175">14</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17/41/7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11/25/5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−7/−16/−2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Improvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DLCO stability in 2 patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Khanna et al.<a class="elsevierStyleCrossRef" href="#bib0150">9</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Randomized, phase II clinical trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25.6/26.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−2.77/−6.33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nonsignificant improvement in mRSS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82/80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−6.3/−2.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.037 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Less decrease in FVC % \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Khanna et al.<a class="elsevierStyleCrossRef" href="#bib0155">10</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Randomized, continuation, open, phase II clinical trial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24.6/25.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−9.4/−9.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Maintained response in initial TCZ and similar response in initial placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80/78 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No significant worsening (>10%) of the FVC % \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kondo et al.<a class="elsevierStyleCrossRef" href="#bib0180">15</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kono et al.<a class="elsevierStyleCrossRef" href="#bib0195">18</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25/14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8/5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">−17/−9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Improvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Saito et al.<a class="elsevierStyleCrossRef" href="#bib0170">13</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The sclerodactyly did not improve \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shima et al.<a class="elsevierStyleCrossRef" href="#bib0165">12</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case series \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27/26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13/20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14/6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Improvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND/71.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND/69.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SD/−1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No improvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shima et al.<a class="elsevierStyleCrossRef" href="#bib0190">17</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Improved joint range of motion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1818487.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Results on skin and lung involvement in studies on patients with systemic sclerosis treated with tocilizumab." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:21 [ 0 => array:3 [ "identificador" => "bib0110" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Scleroderma (systemic sclerosis): classification, subsets and pathogenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.C. 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Use of tocilizumab in systemic sclerosis: A brief literature review

Utilización de tocilizumab en la esclerosis sistémica: breve revisión de la literatura

A. Fernández-Codinaa,b,

Corresponding author

doccodina@gmail.com

Corresponding author.

, J. Fernández-Fernándezc, A. Fernández-Pantigad, on behalf VII Master's final workgroup on the Clinical Management of Systemic Autoimmune Diseases of the Spanish Society of Internal Medicine 1

a Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitari Vall d’Hebron, Barcelona, Spain

b Rheumatology Division, Department of Medicine, University of Western Ontario, London, ON, Canada

c Servicio de Medicina Interna, Hospital de Mataró, Mataró, Spain

d Servicio de Medicina Interna, Hospital Universitario Central de Asturias, Oviedo, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Systemic sclerosis &#40;SS&#41; is a systemic autoimmune disease characterized by the onset of vascular and immunologic disorders and excessive collagen synthesis in the extracellular matrix&#44; which causes obliterative vasculopathy and cutaneous and visceral fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The pathogenesis of SS is complex and not fully understood&#44; although there is evidence of a role for T and B-cells in the production of profibrotic cytokines and fibroblast activation&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">2</span></a> One of the cytokines involved in the pathogenesis of SS is interleukin 6 &#40;IL-6&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">3</span></a> which is found in high concentrations in the skin and serum of patients with SS&#44; which is correlated in turn with disease severity&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">4&#44;5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Tocilizumab &#40;TCZ&#41; is a humanized monoclonal IgG1 antibody that acts by blocking the signals mediated by the soluble receptors and by the IL-6 membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">6</span></a> TCZ has shown efficacy in various diseases&#44; such as rheumatoid arthritis and Castleman&#39;s disease&#44; and has been used in refractory cases of giant cell arteritis&#44; Takayasu&#39;s arteritis and Still&#39;s disease&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">7</span></a> TCZ is well tolerated&#44; although adverse effects have been reported&#44; such as the increased risk of infections&#44; cytopenias&#44; hepatic enzyme disorders and increased cholesterol levels&#46; Furthermore&#44; TCZ is an enzyme inducer of cytochrome P450 and therefore decreases the bioavailability of drugs that are metabolized by this pathway&#46; Blocking the IL-6 pathway has been proposed as a possible treatment for some of the manifestations of SS&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this study was to conduct a systematic review of the existing literature on the safety and efficacy of TCZ for patients with SS&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Literature review</span><p id="par0025" class="elsevierStylePara elsevierViewall">We conducted a systematic literature review through the databases of Medline Central&#44; Cochrane Central Register of Controlled Trials and Clinicaltrials&#46;gov&#46; For the search&#44; we used the keywords &#8220;tocilizumab&#8221; and &#8220;systemic sclerosis&#8221;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Study selection</span><p id="par0030" class="elsevierStylePara elsevierViewall">The search was restricted to articles published &#40;online or hardcopy&#41; in English up to December 2017 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Given the lack of publications&#44; we included all available articles&#44; regardless of type and design&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Data extraction</span><p id="par0035" class="elsevierStylePara elsevierViewall">Three researchers performed the data extraction from the selected studies&#46; We obtained data on the design&#44; epidemiology of the included population&#44; results according to the clinical manifestations and safety data&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Statistical analysis</span><p id="par0040" class="elsevierStylePara elsevierViewall">We used descriptive statistical parameters &#40;number and percentage&#41; and compared the variables provided in the clinical trials&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Results</span><p id="par0045" class="elsevierStylePara elsevierViewall">We found 10 studies that reported the results of treatment with TCZ in patients with SS &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The evaluated studies included a randomized&#44; double-blind clinical trial&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> with its open continuation&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> an observational&#44; prospective study<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a> and 6 case series or isolated case studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">12&#8211;18</span></a> There were no control groups in any of the case series&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The main objective of the phase II Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis &#40;faSScinate&#41; trial<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> was to assess the efficacy of TCZ&#44; administered subcutaneously&#44; on skin induration in patients with diffuse SS within the first 5 years of the disease and who presented moderate-severe skin disorder&#44; recent worsening and high inflammatory markers&#46; It is worth noting that 43&#37; and 51&#37; of the patients assigned to the placebo and TCZ branches&#44; respectively&#44; had previously or concomitantly &#40;the article does not specify&#41; been treated with immunosuppressants&#46; Thirty-nine percent and 49&#37; of the included patients&#44; respectively&#44; were simultaneously treated with corticosteroids&#46; Follow-up was conducted at 24 and 48 weeks&#46; The main objective &#40;variation in the modified Rodnan skin score &#91;mRSS&#93;&#41; was set at 24 weeks&#44; similar to previous studies on rheumatoid arthritis&#46; The open continuation to 96 weeks of the faSScinate study has recently been published&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> The patients who were administered placebo at the start went on to receive TCZ&#44; and the group with the active TCZ treatment maintained it&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The observational study of the Scleroderma Trials and Research Group &#40;EUSTAR&#41; focused on cases with refractory polyarthritis and myopathy associated with SS&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">12</span></a> The patients were prospectively treated with TCZ &#40;arthritis&#41; and Abatacept &#40;arthritis or myopathy&#41;&#46; In the TCZ group&#44; 11 patients maintained their previous glucocorticoid treatment at the start &#40;prednisone &#60;10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#44; and 8 maintained their previous methotrexate treatment&#46; The other studies were heterogeneous case studies&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The main results of these studies are listed below&#44; broken down by type of SS manifestation&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Skin disorder</span><p id="par0065" class="elsevierStylePara elsevierViewall">The primary result of the faSScinate study<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; was a mean mRSS variation of &#8722;2&#46;7 at 24 weeks between the placebo and TCZ groups &#40;95&#37; CI &#8722;5&#46;85 to 0&#46;45&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;09&#41; and &#8722;3&#46;55 at 48 weeks &#40;95&#37; CI &#8722;7&#46;23 to 0&#46;12&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#46; The main objective was therefore not achieved&#46; In the extension to 96 weeks&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> the authors observed that the mean mRSS variation in the placebo group who were administered TCZ between weeks 48 and 96 and that of the patients treated from the start with TCZ were similar&#46; Elhai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">12</span></a> also observed no significant changes in the mRSS in either of the 2 treatment groups&#46; Lastly&#44; the isolated case studies and case series suggested an improvement in the skin disorder&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">12&#44;14&#44;16&#8211;18</span></a> except for 1 patient who did not improve&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pulmonary involvement</span><p id="par0070" class="elsevierStylePara elsevierViewall">The faSScinate clinical trial<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; showed a significantly lower reduction&#44; at 24 weeks of treatment&#44; of the percent forced vital capacity &#40;FVC&#41; in the TCZ group than in the placebo group&#44; with a mean difference of 136<span class="elsevierStyleHsp" style=""></span>mL &#40;95&#37; CI 9&#8211;264&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;03&#41;&#46; These differences were not maintained significantly at 48 weeks &#40;120<span class="elsevierStyleHsp" style=""></span>mL&#59; 95&#37; CI &#8722;23 to 262&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;09&#41;&#46; Worsening of the FVC &#40;&#62;10&#37; of the absolute value&#41; was observed at 24 weeks &#40;3&#37; vs&#46; 19&#37;&#41; and 48 weeks &#40;10&#37; vs&#46; 23&#37;&#41; in fewer patients in the TCZ group than in the placebo group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;009 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;03&#41;&#46; In the study extension&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a> none of the patients showed a &#62;10&#37; reduction in their absolute FVC&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In the European collaborative study&#44; patients with myopathy treated with abatacept shown FVC stability&#59; however&#44; no functional studies were performed on the patients treated with TCZ&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In terms of the case studies &#40;<a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a>&#41;&#44; Shima et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">12</span></a> and Fernandes das Neves<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">14</span></a> both reported similar stability of the interstitial lung disease &#40;ILD&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Joint involvement</span><p id="par0085" class="elsevierStylePara elsevierViewall">The faSScinate study<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> was not designed to assess joint involvement&#46; The EUSTAR observational study<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a> showed a significant reduction in <span class="elsevierStyleItalic">DAS28</span> &#40;disease activity index with a total of 28 joints&#41; from 5&#46;2 to 2&#46;8 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; after 5 months of treatment with TCZ&#46; Glucocorticoid treatment was discontinued for 2 patients and the dosage lowered for 3 patients&#46; Several clinical case series have reported an improvement in the joint inflammatory activity parameters of patients with overlapping syndromes&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">13&#8211;15&#44;18</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Digital ulcers</span><p id="par0090" class="elsevierStylePara elsevierViewall">The faSScinate study<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> observed no statistically significant differences between the placebo arm and the TCZ treatment arm in the number of digital ulcers present at 24 and 48 weeks&#46; The 2 patients with digital ulcers in the study by Fernandes das Neves et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">14</span></a> completely resolved the ulcers at 6 months of starting TCZ&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Side effects</span><p id="par0095" class="elsevierStylePara elsevierViewall">In the faSScinate study&#44;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">9&#44;10</span></a> there were no differences between the 2 groups in the number of adverse effects&#46; The most common effects were infections and gastrointestinal&#44; musculoskeletal and skin symptoms&#46; The onset of severe infectious adverse events was 4&#47;100 patient-years in the placebo group versus 12&#47;100 patient-years in the TCZ group&#46; In the study extension&#44; only those patients who started TCZ for the first time developed infections &#40;6&#47;100 patient-years&#41;&#46; There was a notable onset of digital osteomyelitis in 6 patients&#46; The number of patients who could not finish the study due to adverse effects at 24 and 48 weeks&#44; respectively&#44; was similar in the placebo group &#40;5 patients&#44; 11&#37;&#41; and the TCZ group &#40;6 patients&#44; 14&#37;&#41;&#46; After 48 weeks&#44; 4 patients had died&#44; 3 of them in the TCZ group&#46; Only one death &#40;due to respiratory infection&#41; was directly attributed to the treatment&#46; There were no deaths in the open phase&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The observational EUSTAR study<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">12</span></a> was not designed to assess the drug&#39;s safety&#46; During the follow-up&#44; 1 patient experienced an episode of nausea related to the TCZ infusion&#44; and another patient experienced a transient increase in transaminases&#46; None of the patients discontinued the treatment due to adverse effects&#46; Frech et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">16</span></a> reported 2 cases of patients with SS who were treated with TCZ and who developed &#40;one after an unspecified time and another at 24 months&#41; a worsening of the gastroesophageal reflux and intestinal pseudo-obstruction&#44; respectively&#44; which motivated the discontinuation of the TCZ&#46; The patients improved with antibiotic treatment for the intestinal bacterial overgrowth&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">There are few series that have evaluated TCZ in SS&#46; Nevertheless&#44; the available studies show a modest therapeutic response in both the skin and joints&#46; There is no evidence to support the use of TCZ for the other manifestations&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Only one randomized&#44; double-blind&#44; prospective&#44; phase II clinical trial&#44; one prospective trial and various case studies have been published on the use of TCZ in SS&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The main objective of the faSScinate clinical trial<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> &#40;mRSS variation &#8805;4&#46;7 at 24 weeks&#41; was not achieved&#46; In diffuse SS&#44; an mRSS variation between 3&#46;2 and 5&#46;3 during the first years of disease progression is considered clinically relevant&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">19</span></a> An excessively demanding primary objective and a short time margin could explain the lack of response in this study&#46; As for its open extension&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a> the natural progression of diffuse SS with its tendency to decrease skin thickening over time could also explain part of the improvement in mRSS observed in most patients at 18 and 24 months of the start of the study&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Finally&#44; the results of the observational EUSTAR study<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">12</span></a> and those of various case studies support the potential benefit of TCZ in treating skin induration&#46; To confirm these hypotheses&#44; the results of a phase III study would be of paramount importance &#40;<a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02453256">NCT02453256</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">20</span></a> This study involves a double-blind&#44; randomized&#44; trial with a TCZ treatment branch and a placebo branch&#44; whose main objective is the mRSS variation at 48 weeks&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">With regard to ILD&#44; the worsening of the FVC &#40;&#37;&#41; in the patients treated with TCZ appears to be rare in the faSScinate study&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a> while the cases described by Fernandes das Neves<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">14</span></a> showed stabilization&#46; Documentation of the reduction in biological markers of pulmonary fibrosis such as chemokine CC ligand 18 &#40;typically elevated in patients with ILD&#41; in patients treated with TCZ<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> supports its potential therapeutic effect&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Treatment for arthritis in SS could be another possible indication for TCZ&#46; Arthritis can affect up to 30&#37; of patients with SS&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">21</span></a> Data from the EUSTAR study corresponded to patients with SS who met the criteria for rheumatoid arthritis&#46; In a strategy similar to that for rheumatoid arthritis&#44; the combination of TCZ and methotrexate or corticosteroids could be effective<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a> for the arthritis of SS&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">The safety profile of TCZ appears to be acceptable&#44; with adverse effects very similar to those found in patients with rheumatoid arthritis treated with the drug&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">For patients with digital ulcers due to SS who are treated with TCZ&#44; special attention should be paid to the possibility that osteomyelitis of the phalanges can occur during the early phases of treatment&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The primary limitation of this review is that there are very few studies that have evaluated the use of TCZ in SS&#46; The only randomized clinical trial had few patients&#44; who also had a high risk of progression of the skin disorder&#44; which could have biased the results&#46; The other studies included a small number of patients&#44; the measure of the results was heterogeneous&#44; and the studied manifestations were varied&#46; These results should therefore be interpreted with caution&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">In conclusion&#44; the few available studies indicate that&#44; although TCZ has shown no significant improvement in treating the skin induration of SS&#44; the drug could be effective in treating the inflammatory arthritis associated with this condition&#46; Severe infections are the most significant adverse effect resulting from the use of this drug&#46; We need to wait for the results of future studies to better define the role of TCZ in the therapeutic algorithms of SS&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres1066225"
          "titulo" => "Abstract"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Background"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Material and methods"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Literature review"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Study selection"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Data extraction"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Statistical analysis"
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        6 => array:3 [
          "identificador" => "sec0035"
          "titulo" => "Results"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Skin disorder"
            ]
            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Pulmonary involvement"
            ]
            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Joint involvement"
            ]
            3 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Digital ulcers"
            ]
            4 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Side effects"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Discussion"
        ]
        8 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Conflict of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2017-12-23"
    "fechaAceptado" => "2018-02-17"
    "PalabrasClave" => array:2 [
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1014100"
          "palabras" => array:3 [
            0 => "Systemic sclerosis"
            1 => "Tocilizumab"
            2 => "Treatment"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1014101"
          "palabras" => array:3 [
            0 => "Esclerosis sist&#233;mica"
            1 => "Tocilizumab"
            2 => "Tratamiento"
          ]
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      ]
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The available treatments for systemic sclerosis &#40;SS&#41; have limited effectiveness&#46; Treatment with tocilizumab &#40;TCZ&#41;&#44; a biological drug that inhibits interleukin 6 &#40;IL-6&#41;&#44; has recently been proposed&#46; In this study&#44; we conducted a literature review to assess the safety and efficacy of TCZ in SS&#46; We found 52 articles&#44; 10 of which we selected after evaluating the articles&#46; In a randomized clinical trial&#44; TCZ showed a nonsignificant improvement in the degree of skin induration&#44; while another observational study showed neutral results&#46; In this same clinical trial&#44; the functional respiratory parameters showed a certain degree of stabilization&#46; The safety profile of TCZ is acceptable&#59; however&#44; the current evidence regarding treatment of SS with TCZ is highly limited&#44; although the drug could have a beneficial effect in skin disorder&#46; New clinical trials are needed to determine the usefulness of TCZ in SS&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los tratamientos disponibles para la esclerosis sist&#233;mica &#40;ES&#41; tienen una efectividad limitada&#46; Recientemente se ha propuesto el tratamiento con tocilizumab &#40;TCZ&#41;&#44; un f&#225;rmaco biol&#243;gico que inhibe la interleucina 6 &#40;IL6&#41;&#46; En este trabajo se realiza una revisi&#243;n de la literatura para evaluar la eficacia y seguridad de TCZ en ES&#46; Se han encontrado 52 art&#237;culos&#44; de los que&#44; tras su evaluaci&#243;n&#44; se han seleccionado solo 10&#46; En un ensayo cl&#237;nico aleatorizado TCZ demostr&#243; una mejor&#237;a no significativa del grado de induraci&#243;n cut&#225;nea&#44; mientras que en un estudio observacional los resultados fueron neutros&#46; En dicho ensayo cl&#237;nico&#44; los par&#225;metros funcionales respiratorios mostraron cierto grado de estabilizaci&#243;n&#46; El perfil de seguridad de TCZ es aceptable&#46; La evidencia actual en cuanto al tratamiento de la ES con TCZ es muy limitada&#44; aunque el f&#225;rmaco podr&#237;a tener un efecto beneficioso en la afectaci&#243;n cut&#225;nea&#46; Se requieren nuevos ensayos cl&#237;nicos para comprobar su utilidad en ES&#46;</p></span>"
      ]
    ]
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The other coauthors of the VII Master&#39;s final workgroup on the Clinical Management of Systemic Autoimmune Diseases of the Spanish Society of Internal Medicine are&#58; Mar&#237;a Fontecha Ortega &#40;Department of Internal Medicine&#44; University Hospital of Getafe&#44; Getafe&#44; Spain&#41;&#44; Mar&#237;a Jos&#233; Forner &#40;Department of Internal Medicine&#44; University Clinic Hospital&#44; Valencia&#44; Spaina&#41;&#44; Inmaculada Fern&#225;ndez-Galante &#40;Department of Internal Medicine&#44; Healthcare Complex of Segovia&#44; Segovia&#44; Spain&#41;&#44; Carmen Pilar Sime&#243;n-Aznar &#40;Systemic Autoimmune Diseases Unit&#44; Department of Internal Medicine&#44; University Hospital Vall d&#8217;Hebron&#44; Barcelona&#44; Spain&#41;&#46;</p>"
        "identificador" => "fn0005"
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      1 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Fern&#225;ndez-Codina A&#44; Fern&#225;ndez-Fern&#225;ndez J&#44; Fern&#225;ndez-Pantiga A&#44; en nombre del grupo vii de trabajo de final de m&#225;ster en Manejo Cl&#237;nico de Enfermedades Autoinmunes Sist&#233;micas de la Sociedad Espa&#241;ola de Medicina Interna&#46; Utilizaci&#243;n de tocilizumab en la esclerosis sist&#233;mica&#58; breve revisi&#243;n de la literatura&#46; Rev Clin Esp&#46; 2018&#59;218&#58;298&#8211;304&#46;</p>"
      ]
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of the literature review&#46;</p>"
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ACA&#44; anticentromere antibodies&#59; ACPA&#44; anticitrullinated peptide antibodies&#59; AMA&#44; antimitochondrial antibodies&#59; ANA&#44; antinuclear antibodies&#59; anti-PM&#47;Scl 100&#44; anti-PM&#47;Scl 100 antibodies&#59; anti-RNAP III&#44; anti-RNA polymerase III antibodies&#59; anti-Scl-70&#44; antitopoisomerase antibodies&#59; dSSc&#44; diffuse systemic sclerosis&#59; DU&#44; digital ulcers&#59; ILD&#44; interstitial lung disease&#59; iv&#44; intravenous&#59; MTX&#44; methotrexate&#59; ND&#44; no data&#59; N-TCZ&#44; number of patients treated with tocilizumab&#59; PAH&#44; pulmonary arterial hypertension&#59; PBO&#44; placebo&#59; RF&#44; rheumatoid factor&#59; sc&#44; subcutaneous&#59; SRC&#44; scleroderma renal crisis&#59; TCZ&#44; tocilizumab&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author&#47;year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span> &#40;treated with TCZ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Women&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">dSSc&#44; <span class="elsevierStyleItalic">N</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Autoantibodies&#44; <span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Noncutaneous manifestations&#44; <span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Elhai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational prospective multicenter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TCZ 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg a month sc vs&#46; abatacept 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg a month sc&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20<span class="elsevierStyleHsp" style=""></span>weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27 &#40;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">23 &#40;85&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 &#40;51&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-Scl-70 14 &#40;52&#41;<br>ACA 5 &#40;19&#41;<br>RF 7 &#40;26&#41;<br>ACPA 7 &#40;26&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arthritis &#40;18&#41;<br>Myopathy &#40;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Frech et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-RNAP III 1 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arthritis &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fernandes das Neves et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">14</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TCZ 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg at 1<span class="elsevierStyleHsp" style=""></span>month&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24<span class="elsevierStyleHsp" style=""></span>weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;66&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-Scl-70 2 &#40;67&#41;<br>Anti-PM&#47;Scl-100 1 &#40;33&#41;<br>RF 1 &#40;33&#41;<br>ACPA 1 &#40;33&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DU &#40;2&#41;<br>Arthritis &#40;1&#41;<br>ILD &#40;3&#41;<br>Intestinal &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Khanna et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; double-blind phase II clinical trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TCZ 162<span class="elsevierStyleHsp" style=""></span>mg weekly sc vs&#46; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48<span class="elsevierStyleHsp" style=""></span>weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">87 &#40;43&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">67 &#40;77&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">87 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-RNAP III 30 &#40;34&#41;<br>Anti-Scl-70 28 &#40;32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Khanna et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; open&#44; phase II clinical trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TCZ 162<span class="elsevierStyleHsp" style=""></span>mg weekly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">96<span class="elsevierStyleHsp" style=""></span>weeks initial TCZ group&#47;48<span class="elsevierStyleHsp" style=""></span>weeks initial PBO group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">61 &#40;61&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">49 &#40;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">61 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kondo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">15</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TCZ 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 14 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">28<span class="elsevierStyleHsp" style=""></span>weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ANA<br>RF<br>ACPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Myopathy<br>Arthritis<br>DU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kono et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TCZ 162<span class="elsevierStyleHsp" style=""></span>mg every 2<span class="elsevierStyleHsp" style=""></span>weeks sc&#59; TCZ 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg a month iv&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54 and 108<span class="elsevierStyleHsp" style=""></span>weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ACPA 2 &#40;100&#41;<br>Anti-Scl-70 1 &#40;50&#41;<br>U1-RNP 1 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arthritis &#40;2&#41;<br>ILD &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Saito et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TCZ 600<span class="elsevierStyleHsp" style=""></span>mg a month sc<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX 6<span class="elsevierStyleHsp" style=""></span>mg weekly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36<span class="elsevierStyleHsp" style=""></span>weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ACA<br>RF<br>ACPA<br>AMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arthritis<br>Primary biliary cirrhosis<br>Adenopathies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shima et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tocilizumab 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg a month&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24<span class="elsevierStyleHsp" style=""></span>weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ANA 2 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SRC &#40;1&#41;<br>ILD &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shima et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">TCZ 8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg a month sc<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>methylprednisolone 8<span class="elsevierStyleHsp" style=""></span>mg a day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64<span class="elsevierStyleHsp" style=""></span>weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-RNAP III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SRC<br>Gastrointestinal<br>PAH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Design and epidemiological and clinical characteristics of the reviewed studies that included patients with systemic scleroderma treated with tocilizumab&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; FVC&#44; forced vital capacity&#59; &#916; mRSS&#44; variation on the modified Rodnan skin score&#59; NS&#44; no significant&#59; ND&#44; no data&#59; TCZ&#44; tocilizumab&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author&#47;year&#47;study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline mRSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Final mRSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#916; mRSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Result&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline FVC &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Final FVC &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#916; FVC &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Result&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Elhai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Observational&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonsignificant improvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Frech et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&#47;27&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&#47;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sustained improvement in a patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fernandes das Neves et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">14</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#47;41&#47;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#47;25&#47;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;7&#47;&#8722;16&#47;&#8722;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Improvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DLCO stability in 2 patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Khanna et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; phase II clinical trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#46;6&#47;26&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;2&#46;77&#47;&#8722;6&#46;33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonsignificant improvement in mRSS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">82&#47;80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;6&#46;3&#47;&#8722;2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;037&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Less decrease in FVC &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Khanna et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">10</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Randomized&#44; continuation&#44; open&#44; phase II clinical trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24&#46;6&#47;25&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;9&#46;4&#47;&#8722;9&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Maintained response in initial TCZ and similar response in initial placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80&#47;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No significant worsening &#40;&#62;10&#37;&#41; of the FVC &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kondo et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">15</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kono et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#47;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#47;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;17&#47;&#8722;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Improvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Saito et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The sclerodactyly did not improve&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shima et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">12</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case series&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27&#47;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#47;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#47;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Improvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&#47;71&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&#47;69&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SD&#47;&#8722;1&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No improvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Shima et al&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Case report&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Improved joint range of motion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2018.02.010

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