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array:24 [ "pii" => "S2173574319301893" "issn" => "21735743" "doi" => "10.1016/j.reumae.2018.11.019" "estado" => "S300" "fechaPublicacion" => "2020-05-01" "aid" => "1311" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología" "copyrightAnyo" => "2018" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Reumatol Clin. 2020;16:195-202" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S1699258X18302651" "issn" => "1699258X" "doi" => "10.1016/j.reuma.2018.11.011" "estado" => "S300" "fechaPublicacion" => "2020-05-01" "aid" => "1311" "copyright" => "Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Reumatol Clin. 2020;16:195-202" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 25 "formatos" => array:2 [ "HTML" => 19 "PDF" => 6 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Artículo especial</span>" "titulo" => "Enfermedad relacionada con IgG4: ¿es el rituximab la mejor estrategia terapéutica en los casos refractarios a terapia convencional? 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"apellidos" => "Díaz-Coronado" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173574319301893" "doi" => "10.1016/j.reumae.2018.11.019" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574319301893?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X18302651?idApp=UINPBA00004M" "url" => "/1699258X/0000001600000003/v1_202006131050/S1699258X18302651/v1_202006131050/es/main.assets" ] ] "itemSiguiente" => array:18 [ "pii" => "S2173574319301042" "issn" => "21735743" "doi" => "10.1016/j.reumae.2018.06.002" "estado" => "S300" "fechaPublicacion" => "2020-05-01" "aid" => "1246" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Reumatol Clin. 2020;16:203-15" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Quality standard for the management of patients with psoriatic arthritis: QUANTUM project" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "203" "paginaFinal" => "215" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Norma de calidad para el manejo del paciente con artritis psoriásica: proyecto QUANTUM" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jesús Sanz Sanz, Emma Beltrán, M. Consuelo Díaz-Miguel Pérez, Cristina Fernández-Carballido, Eva Galíndez, Carlos García Porrua, Jordi Gratacós, Julio Medina, Rubén Queiro, Julio Ramírez, Delia Reina, Carlos Rodríguez Lozano, Fernando José Rodríguez Martínez, Esteban Rubio, Raúl Veroz" "autores" => array:15 [ 0 => array:2 [ "nombre" => "Jesús" "apellidos" => "Sanz Sanz" ] 1 => array:2 [ "nombre" => "Emma" "apellidos" => "Beltrán" ] 2 => array:2 [ "nombre" => "M. 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Results of a systematic review" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "195" "paginaFinal" => "202" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Laura Betancur-Vásquez, Daniel Gonzalez-Hurtado, Daniela Arango-Isaza, Adriana Rojas-Villarraga, Deicy Hernandez-Parra, Samuel Carmona, J.C. Díaz-Coronado" "autores" => array:7 [ 0 => array:4 [ "nombre" => "Laura" "apellidos" => "Betancur-Vásquez" "email" => array:1 [ 0 => "laubet-v@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Daniel" "apellidos" => "Gonzalez-Hurtado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Daniela" "apellidos" => "Arango-Isaza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Adriana" "apellidos" => "Rojas-Villarraga" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 4 => array:3 [ "nombre" => "Deicy" "apellidos" => "Hernandez-Parra" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 5 => array:3 [ "nombre" => "Samuel" "apellidos" => "Carmona" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 6 => array:3 [ "nombre" => "J.C." "apellidos" => "Díaz-Coronado" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Departamento de medicina interna, Universidad CES, Medellín, Colombia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de investigación en medicina, Universidad CES, Medellín, Colombia" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Fundación Universitaria de Ciencias de la Salud (FUCS), Bogotá, Colombia" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Grupo de información clínica, Artmedica IPS, Medellín, Colombia" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Enfermedad relacionada con IgG4: ¿es el rituximab la mejor estrategia terapéutica en los casos refractarios a terapia convencional? Resultados de una revisión sistemática" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2117 "Ancho" => 2083 "Tamanyo" => 175007 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">PRISMA diagram for the selection of papers.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">IgG4-related disease (ER-IgG4) is a fibroinflammatory condition characterised by lymphoplasmacytic infiltration with a predominance of IgG4+ plasma cells, fibrosis and in the majority of cases high levels of IgG4 in serum.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">1</span></a> It may essentially affect any organ, with a variable range of clinical manifestations, the most frequent of which are pancreatic and salivary gland compromise and adenopathies.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Diagnosis is essentially histopathological, with characteristic findings of lymphoplasmacytic infiltration with a >40% proportion of IgG4/IgG, storiform fibrosis and obliterative phlebitis. Other diagnostic tools have also been used, such as imaging and IgG4 serum levels.<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">1–4</span></a> There are 2 diagnostic scales (Umehara criteria<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">5</span></a> and Okazaki criteria<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">6</span></a>) and an international consensus<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">7</span></a> that makes it possible to reach the diagnosis. A series of organ-specific criteria have also been established, according to the organ that is involved (pancreatitis, sclerosing cholangitis, dacryoadenitis, ophthalmic, renal and pulmonary criteria associated with IgG4).<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Treatment is a field that has still hardly been explored. Steroids have formed the basis of treatment from the time it was described, although the relapse rate is high at 23–52%, especially when they are suspended.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">9,10</span></a> Disease-modifying anti-rheumatic drugs are not effective in inducing remission, although they may be beneficial in maintenance therapy.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">11</span></a> Recent case reports, series of cases and cohort studies have shown the possible favourable effects of therapy with rituximab (RTX), although the evidence is not conclusive. This systematic review has the aim of evaluating the efficacy and response to treatment with RTX in patients with ER-IgG4 who do not respond to glucocorticoids (GCC) and relapse with other immunomodulating therapies.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Systematic search</span><p id="par0020" class="elsevierStylePara elsevierViewall">A systematic search was conducted in the EMBASE, LILACS, PUBMED and OVID-Cochrane databases of publication until 28 December 2017. The PICO search strategy was followed to construct the question and structure the search (P, Definition of the problem or patient: ER-IgG4; I, Intervention: RTX; C, Intervention of comparison [when applicable]; O, Outcomes<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>Results: all of those reported in the papers to be selected). The following key words were used “IgG4”, “IgG4 related disease”, “igg4-related disease”, “Rituximab”, “cd20 antibody” and “drug therapy”, for the search in English, and “enfermedad relacionada con igg4”, “igg4” and “rituximab” for the search in Spanish in LILACS. Within this strategy the limits were to consider solely papers in English or Spanish. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the search strategies and filters that were applied, together with their respective results according to the different Boolean operators and qualifiers of fields or tags. PRISMA guide methodology was followed (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">12</span></a> to develop the systematic review of the literature.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Selection of studies</span><p id="par0025" class="elsevierStylePara elsevierViewall">The title and abstract of each one of the papers that were selected in the search were evaluated, and the case reports, series of cases, cases and controls, observational studies and clinical trials that compared RTX with any other therapy for ER-IgG4 were selected. Following PICO strategy, the exclusion criteria were applied to papers that covered animal models as well as other subjects or outcomes unrelated to ER-IgG4. Papers in languages other than English or Spanish were excluded. When an observational follow-up study of a cohort study published several papers on the same cohort in different years, only the latest one was kept to prevent over-representation.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Analysis of the information and quality evaluation</span><p id="par0030" class="elsevierStylePara elsevierViewall">The papers selected for review were independently examined by 2 researchers (JD, LB, DG, DA, SC, AR), and differences were resolved by consensus. Variables including average age, sex, clinical manifestations, diagnostic criteria used, therapeutic strategies and response to therapy were extracted from each study. CARE<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">13</span></a> strategy was used to evaluate the quality of case reports and series of cases, while CASP<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">14</span></a> was used for the observational studies and CONSORT<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">15</span></a> was used for the clinical trials. <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> shows the PRISMA<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">12</span></a> flow diagram for the selection of papers.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><p id="par0035" class="elsevierStylePara elsevierViewall">The search criteria recovered 65 results. After applying the inclusion and exclusion criteria and eliminating duplicated papers, 33 studies were selected. 2 studies were then eliminated because they were of duplicated cohorts, so that 31 papers were left for review, and they were subjected to quality analysis. 4 studies were excluded from the case reports and series of cases<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">16–18</span></a> as they fulfilled fewer than 80% of CARE<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">13</span></a> strategy criteria, while the observational studies met the CASP<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">14</span></a> criteria except for the evaluation of confounding variables, while according to CONSORT<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">15</span></a> the quality evaluation of the clinical trials gave optimum results. Finally 27 papers remained (with a total of 264 patients) for the final review, of which 23 corresponded to case reports and series of cases (105 patients), 3 corresponded to observational follow-up studies of a cohort (129 patients) and there was one clinical trial (30 patients). <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> describes the characteristics of the patients included in the studies, the type of clinical involvement depend on the affected system, previous treatments, type of RTX therapy, response to the same and relapses.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Clinical and sociodemographic characteristics</span><p id="par0040" class="elsevierStylePara elsevierViewall">The age of onset varied from 590 to 70 years old, although there was one case report of a paediatric patient. On average the distribution between the sexes was 75% men. There was a broad and variable range of clinical manifestations, and the majority of organs were involved. Glandular involvement was more frequent in the series of cases and observational studies (pancreas, tear glands, salivary and submandibular glands), lymphatic (ganglia) and involvement of the eye sockets. Involvement was predominantly multiorganic, with an average number of 3.5 organs being affected. The single organ forms were rare and were present in only 3 case reports (with cardiovascular, central nervous system and renal involvement).</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Diagnostic strategies</span><p id="par0045" class="elsevierStylePara elsevierViewall">Diagnosis was a challenge in all of the studies that were included, and in many of them another alternative diagnosis was first considered. The definitive diagnosis was histopathological, with criteria including lymphoplasmacytic infiltrates and associated fibrosis, although other diagnostic tools were used such as imaging techniques, serum levels of IgG4 and, in one case, plasmablasts.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Therapeutic strategies and outcomes</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">First line therapies</span><p id="par0050" class="elsevierStylePara elsevierViewall">27 studies with 264 patients were included, of whom 90% had received a previous treatment other than RTX. Of the previous treatments, GCC were used in 65.5% of cases (172/264 patients) and disease-modifying anti-rheumatic drugs were used in 36.7% (97/264 patients), with a 10% response to these therapeutic strategies. RTX was used in refractory patients. GCC were used as a monotherapy in 10.6%, with a 57% response rate. RTX was used as a first line therapy in 10% of cases, with a 100% response rate.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Rituximab as a second line therapy</span><p id="par0055" class="elsevierStylePara elsevierViewall">RTX was used as a second line therapy in patients, associated in the majority of cases with a steroid; there was a response in 77% of cases. Other therapies such as plasmapherisis and surgery were rarely used, although the latter was frequent in pure vasculitic forms. A higher proportion of patients were found who responded to RTX as a monotherapy or combined therapy than when it was used as a monotherapy with GCC. See <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Treatment regimes</span><p id="par0060" class="elsevierStylePara elsevierViewall">A range of regimes and doses were used, usually decided by the treating doctor. GCC was used in the majority of studies (in pulses in some cases) and with RTX the most frequent regime was 1<span class="elsevierStyleHsp" style=""></span>g in 2 monthly or fortnightly doses.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Response estimation</span><p id="par0065" class="elsevierStylePara elsevierViewall">The response to treatment was not measured in a uniform way in the studies. It was estimated subjectively by the researcher, considering resolution criteria such as clinical or imaging technique parameters, a fall in plasmablast levels or IgG4, fewer relapses or the possibility of ceasing to take GCC.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Clinical response according to type of involvement</span><p id="par0070" class="elsevierStylePara elsevierViewall">There was a greater response to treatment in the patients with a predominance of eye socket, ganglion and glandular (including pancreatic) involvement. The response to treatment in vasculitic and fibrosing forms of the disease was also analysed and compared, without finding any significant differences in the proportions of the same. See <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>.</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">A total of 264 patients were documented, of which only 18 cases had pure vasculitic forms, where the predominant forms of involvement were vasculitis and aortitis with the formation of aneurisms. The primary form of involvement was defined as vessel inflammation as the main result of the disease, while the secondary form of involvement arose due to the effects of the adjacent inflammation. In this presentation it should be emphasised that the majority of these patients required surgery, independently of the use of RTX. Carruthers et al.<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">19</span></a> even report a patient with ER-IgG4 centred at carotid level with a fleeting amaurosis-type manifestation that persisted in spite of RTX and resolved with endarterectomy. Of the patients who were not subjected to surgery, 3 showed an improvement in their vascular images subsequent to RTX.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">20</span></a></p></span></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Although ER-IgG4 was described around the year 2000, it is still an emerging condition. In recent years more publications have appeared in association with the clinical, serological and histopathological characteristics of the disease, although no strong recommendations have been made regarding its first and second line treatment. Although therapy with GCC is considered to be a first-line therapeutic option, the high relapse rate is also known (at 23–52%), especially when they are suspended.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">9,10,21</span></a> Due to this reason the literature describes a large number of immunosuppressor drug combinations, where the use of RTX seems to stand out as a single or combined therapy. It was decided to evaluate the existing evidence for the therapeutic efficacy of using RTX to treat patients with ER-IgG4, with the aim of supporting or rejecting its use in cases refractory to GCC and other therapies.</p><p id="par0085" class="elsevierStylePara elsevierViewall">The International Consensus on the use of ER-IgG4<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">21</span></a> recommends GCC as the first line therapy, with a 94% interexpert agreement on a dose of 30–40<span class="elsevierStyleHsp" style=""></span>mg/day prednisolone during 2–4 weeks, with a gradual levelling off over 3–6 months after starting the treatment. Considering the high rate of recurrence with this treatment and its high toxicity over the medium to long term, the consensus recommends the use of steroid sparing agents, especially when it is impossible to perform appropriate levelling due to the persistence of disease activity or relapses, although interexpert agreement on this point amounts to only 46%. A study of patients with relapsed autoimmune pancreatitis treated with azatioprine, micophenolate or 6 mercaptopurine compared to GCC as a monotherapy, showed no differences in relapse-free survival between the two groups.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">11</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">A systematic review of therapeutic interventions in ER-IgG4 that included 62 studies with 3034 patients found steroid use in 74%, non-pharmacological therapies such as radiotherapy and surgery in 11%, no intervention in 13% and other therapies in 2%. Treatment with steroids as monotherapy attained an efficacy of 97%, although there were 33% of relapses in spite of the short follow-up periods. Relapses were treated with GCC, which attained a response rate of 95%, azatioprine at 81% and RTX in 9 patients with a 100% response rate.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">22</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Given that the majority of patients with ER-IgG4 have to use GCC to remain in remission, other therapeutic options have been used as GCC sparing agents with results that are not very encouraging. In a series of cases of 21 patients with ER-IgG4 the use of sparing agents such as methotrexate, cyclosporine and azatioprine did not attain the goal of levelling off GCC.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">23</span></a> These findings are consistent with those obtained by this systematic review, where 65.4% of the patients included in the papers reviewed received steroids as the initial therapy and in 36% of the studies reviewed sparing agents were included in different protocols. There was a 10% response rate to the latter therapeutic strategies. In patients who were refractory to these strategies RTX was used.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Large series of cases and cohort studies<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">24,45,47</span></a> have shown a high response rate to RTX associated with fewer relapses of the disease and a major possibility of levelling off GCC over the long term. The results of the review confirm the benefits of therapy with RTX as the second line in patients who are refractory to other treatments such as GCC and disease-modifying antirheumatic drugs, among others, emphasising the response rate of 90.7% when it is used as a second line therapy. Analysis of the total number of cases reported even showed that 10% of patients were treated with RTX as the first line therapy, obtaining a response in 100% of the patients. This finding means that it is now possible to think of using RTX from early phases after diagnosis.</p><p id="par0105" class="elsevierStylePara elsevierViewall">Few of the studies analysed in the review reported relapses with RTX, although it should be underlined that the short periods of follow-up may influence this finding. This contrasts with the proportions described in the literature, in ranges that run from 10% to 41%.<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">19,24,27</span></a> Some factors have been found to be associated with the risk of relapse, including high concentrations in serum of IgG4, IgE and eosynophiles, the absence of regular doses of the medication and most especially a response rate index in ER-IGG4<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>9 prior to the use of RTX.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">27</span></a> This index was only applied and reported in 3 of the 27 studies included in the review.</p><p id="par0110" class="elsevierStylePara elsevierViewall">A multicentre study undertaken in France found that the patients who received treatment, not necessarily associated with relapses, achieved greater survival free of the same (41 vs 21 months).<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">27</span></a> Although the data of the present study do not make it possible to evaluate the effectiveness of RTX in terms of relapse-free time, it would be important to answer this question in a future work within the context of long-term maintenance.</p><p id="par0115" class="elsevierStylePara elsevierViewall">The systematic review analysed the response to treatment with RTX depending on the form of presentation of the disease. Eye socket involvement was found in 30% of cases, glandular involvement in 53% and ganglion involvement in 32.5% of all the patients, and this is similar to the finding of other series.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">28</span></a> Although a high proportion of patients with these clinical manifestations responded to treatment, as they are the most common forms of presentation of the disease it is not possible to conclude that RTX has a greater effect in this group. A comparative analysis was also performed between pure vasculitic forms, in which similar response rates were found. Nevertheless, it is not possible to categorically conclude that primary vasculitic forms respond to treatment with RTX, as the majority of cases had received previous or concomitant surgery and therapies with GCC before or during the administration of RTX for severe vascular complications such as aneurisms. However, the good response to this multimodal approach in the majority of cases stands out.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Although it was not a research aim, it is important to mention the heterogeneity that was found in how the different authors defined improvement or remission after treatment with GCC, RTX or other therapies, together with the absence of objective measurements of therapeutic response throughout the studies. This was shown by the fact that the ER-IgG4 response index was only applied in 2 observational cohort follow-up studies and in one clinical trial. This instrument was designed to evaluate disease activity, and it considers the organs which are potentially involved and the levels of IgG4 in mg/dl. To validate this index it was applied retrospectively to a registry of 15 patients in Massachusetts Hospital, obtaining a Pearson coefficient of 0.93 between the 2 evaluating rheumatologists.<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">29</span></a> Including IgG4 levels in the score has led to debate, given that the pathological role of the said molecule has not been clearly established, and that it seems to behave as an epiphenomenon of the disease, so that it could be explained by an unknown primary inflammatory stimulus.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">1</span></a> It is therefore necessary to generalise the detection of the response, especially in future clinical trials, to give results that make it possible make comparisons and draw more precise conclusions.</p><p id="par0125" class="elsevierStylePara elsevierViewall">It may be concluded from this review that therapy with RTX in patients with ER-IgG4 who have relapsed with while using GCC or other disease-modifying therapies has benefits in terms of the therapeutic response. Its effect on relapses is less clear due to the duration of follow-up in the studies, although over the mid-term it gave better results than other therapies. It has also been shown to be effective as a first line therapy.</p><p id="par0130" class="elsevierStylePara elsevierViewall">Randomised controlled clinical trials are required that make it possible to confirm what has been reported to date in the literature. Therapy with anti-CD20 seems to be one of the best therapeutic strategies in ER-IgG4, not only for recurrent and refractory disease, but also as the initial treatment, given the potential benefits in terms of therapeutic response, reducing the number of relapses and lowering GCC treatment toxicity.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1348436" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Materials and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1240514" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1348437" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Materiales y métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1240513" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Systematic search" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Selection of studies" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Analysis of the information and quality evaluation" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Clinical and sociodemographic characteristics" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Diagnostic strategies" ] 2 => array:3 [ "identificador" => "sec0045" "titulo" => "Therapeutic strategies and outcomes" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "First line therapies" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Rituximab as a second line therapy" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Treatment regimes" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Response estimation" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Clinical response according to type of involvement" ] ] ] ] ] 7 => array:2 [ "identificador" => "sec0075" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflict of interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-07-16" "fechaAceptado" => "2018-11-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1240514" "palabras" => array:4 [ 0 => "IgG4" 1 => "IgG4 related disease" 2 => "Rituximab" 3 => "CD20 antibody" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1240513" "palabras" => array:4 [ 0 => "IgG4" 1 => "Enfermedad relacionada con IgG4" 2 => "Rituximab" 3 => "Antígeno CD20" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">IgG4 related disease is a fibroinflammatory condition characterised by lymphoplasmocytic infiltration with predominance of IgG4+ plasma cells, fibrosis, and in most cases elevated IgG4 serum levels. It can affect any organ and result in varying clinical manifestations. Steroids are the cornerstone of treatment, however there is a high percentage of relapse. Recent studies have demonstrated favourable effects with rituximab.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To evaluate effectiveness related to the response to treatment with rituximab in patients with IgG4 related disease refractory to steroids and other immunosuppressant therapies.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Materials and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We undertook a systematic search of the specialist databases EMBASE, LILACS, PUBMED and OVID-Cochrane for publications up until December 2017.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">After the quality analysis, we selected 27 articles (264 patients in total) for the final review, of which 23 were case reports and case series (105 patients), 3 were observational follow-up cohort studies (129 patients), and there was one clinical trial (30 patients). IgG4 related disease presents predominantly in male patients aged between 50 and 70 years on average. Multiple organs are compromised with an average of 3.5 compromised organs. Orbital, glandular and lymph-node compromise is most frequent. Patients in the different studies we included had received various treatments prior to starting rituximab, including glucocorticoids and disease-modifying anti-rheumatic drugs. There was 90.7% response in the cases where rituximab was used as second line therapy; rituximab was used as first line treatment for 10% of the patients with a 100% response rate.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The use of rituximab for patients refractory to first-line treatments was associated with a high response percentage and less dependence on glucocorticoids.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Materials and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducción</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La enfermedad relacionada con IgG4 es una condición fibroinflamatoria caracterizada por infiltración linfoplasmocítica con predominio de células plasmáticas IgG4+, fibrosis y en la mayoría de los casos niveles séricos elevados de IgG4. Puede afectar cualquier órgano y llevar a manifestaciones clínicas variables. El tratamiento con esteroides es la piedra angular, sin embargo, el porcentaje de recidivas es alto. Estudios recientes han mostrado efectos favorables con rituximab.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Evaluar la efectividad relacionada con la respuesta al tratamiento con rituximab en los pacientes con enfermedad relacionada con IgG4 refractarios a uso de esteroides y otras terapias inmunosupresoras.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Materiales y métodos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se realizó una búsqueda sistemática en bases de datos especializadas EMBASE, LILACS, PUBMED y OVID-Cochrane de publicaciones hasta diciembre de 2017.</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Posteriormente al análisis de calidad se seleccionaron 27 artículos (264 pacientes en total) para la revisión final de los cuales 23 correspondían a reportes de caso y series de caso (105 pacientes), 3 a estudios observacionales de seguimiento a una cohorte (129 pacientes) y un ensayo clínico (30 pacientes). La enfermedad relacionada con IgG4 se presenta predominantemente en pacientes de sexo masculino con una edad promedio entre 50 y 70 años. El compromiso orgánico es múltiple con un promedio de 3,5 órganos comprometidos, siendo lo más frecuente el compromiso orbitario, glandular y ganglionar. Los pacientes de los diferentes estudios incluidos recibieron diversos tratamientos previo al inicio de rituximab, entre ellos glucocorticoides y fármacos antirreumáticos modificadores de la enfermedad. El porcentaje de respuesta en aquellos casos donde el rituximab se empleó como terapia de segunda línea fue del 90,7%; en el 10% de los pacientes se empleó rituximab como primera línea con un porcentaje de respuesta del 100%.</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusión</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">El uso de rituximab en pacientes refractarios a terapias de primera línea se asocia a un alto porcentaje de respuesta y a menor dependencia a glucocorticoides.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Materiales y métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Betancur-Vásquez L, Gonzalez-Hurtado D, Arango-Isaza D, Rojas-Villarraga A, Hernandez-Parra D, Carmona S, et al. Enfermedad relacionada con IgG4: ¿es el rituximab la mejor estrategia terapéutica en los casos refractarios a terapia convencional? Resultados de una revisión sistemática. Reumatol Clin. 2020;16:195–202.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2117 "Ancho" => 2083 "Tamanyo" => 175007 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">PRISMA diagram for the selection of papers.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Database \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Search strategy \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Filters \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Results \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EMBASE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">((“IGG4”) OR “igg4 related disease”) OR “igg4-related disease”) AND “Rituximab”[Mesh]) OR “cd20 antibody”) AND “Drug therapy”[subheading]) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LILACS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">w:(tw:((ti:(enfermedad relacionada con igg4)) OR (ti:(igg4)) AND (tw:(rituximab))) AND (instance:“regional”)) AND (instance:“regional”) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PUBMED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">w:(tw:((ti:(enfermedad relacionada con igg4)) OR (ti:(igg4)) AND (tw:(rituximab))) AND (instance:“regional”)) AND (instance:“regional”) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical trials, meta-analysis, multicentre study, systematic reviews and case report \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OVID-Cochrane \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(“IGG4” or “igg4 related disease” or “igg4-related disease”).ti. and (“Rituximab” or “cd20 antibody”).ab. and “therapy”.af \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Articles \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">65 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2314072.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Search methodology.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">AZA: azatioprine; CFM: cyclophosphamide; CX: surgery; DXM: dextromethorphan; ER-IgG4: IgG4-related disease; F: female; GCC: glucocorticoid; INFa2a: interferon alpha 2a subtype; M: male; MFM: micophenolate; MPDN: methylprednisolone; MTX: methotrexate; PDN: prednisolone; PLX: plasmapheresis, RC: case report; RT: radiotherapy; RTX: rituximab; R-CHOP: rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone; R-CHVP: rituximab-cyclophosphamide-adriamycin-etoposide-prednisolone; SC: series of cases; ND: no data; CNS: central nervous system; PNS: peripheral nervous system.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author<span class="elsevierStyleSup">ref</span> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study type \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age, sex \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of compromise \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Previous treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Previous use of GCC as monotherapy \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of RTX therapy \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Successful treatment according to author (number of patients) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No response (number of patients) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Response time \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Relapse \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Jindal et al.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">30</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72 years old/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Glandular, hepatobiliar, renal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. PDN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wallace et al.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">31</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56 years old/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eye sockets and trigeminal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. PDN<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MTX2. MFM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 wks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wong et al.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">32</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 years old/M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eye sockets, glandular, cardiovascular and haematological \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. PDN, DXM2. PDN<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>AZA<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>INFalpha2a<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>CFM<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>PLX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 wks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chen et al.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">33</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n