Rituximab in Lupus Nephritis: A Non-systematic Review

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The prevalence of SLE ranges between 1.4% and 21.9% and the incidence between 7.4 and 159.4 cases per 100000 population.<a class="elsevierStyleCrossRef" href="#bib0150">1</a> It is known that 60% of the SLE patients will develop LN<a class="elsevierStyleCrossRef" href="#bib0155">2</a> and more than 25% of these patients will develop end-stage renal disease 10 years after the onset of renal symptoms.<a class="elsevierStyleCrossRef" href="#bib0150">1</a>The main clinical features are proteinuria and microscopic hematuria. Less common findings are macroscopic hematuria and hypertension.<a class="elsevierStyleCrossRef" href="#bib0155">2</a> Certain histopathological changes can result in different clinical presentations. Thus, although in LN, the histopathological findings obtained from renal biopsy are not necessary for the diagnosis, they are of the utmost importance for the classification of the disease.Different pathophysiological mechanisms have been involved in the development of LN in SLE patients. A combination of genetic, environmental and immunological factors mediate the processes that result in the renal damage.<a class="elsevierStyleCrossRefs" href="#bib0150">1–4</a> Of special importance for the present review is the role of the B cells, which are hyperactive in SLE. The B cells mediate and regulate antibody production, interact with memory T cells and stimulate proinflammatory cytokine production, all of which makes them essential components of the pathophysiology of LN.<a class="elsevierStyleCrossRef" href="#bib0150">1</a> It is for these reasons that the use of rituximab is proposed. Rituximab is a chimeric monoclonal antibody (murine/human) approved by the United States Food and Drug Administration in 1997.<a class="elsevierStyleCrossRef" href="#bib0170">5</a> This monoclonal antibody is directed against CD20, an antigen expressed on the surface of mature and immature B cells. CD20 regulates the initiation of the cell cycle. The binding of the antibody to Fc receptor induces apoptosis and cytotoxicity, mediated by both complement and antibodies.Treatment of LN was based for some years on glucocorticoids. This therapy had the disadvantage of the high morbidity and mortality rates resulting from the high doses administered, as well as its inability to arrest the progression of the renal disease.<a class="elsevierStyleCrossRef" href="#bib0175">6</a> One proposal for solving this problem was the use of immunosuppressive agents, which were evaluated in a landmark clinical trial performed to determine the long-term survival of 107 LN patients. This trial revealed a difference in terms of renal function preservation, but said difference was statistically significant only for the combination of intravenous (IV) cyclophosphamide and low-dose, rather than high-dose, prednisone. No differences in the mortality rate were observed.<a class="elsevierStyleCrossRef" href="#bib0180">7</a>At the present time, therapy for LN consists of an induction phase followed by a maintenance phase. The majority of the patients with active proliferative LN are initially treated with pulsed methylprednisolone for 3 days, followed by a period of oral prednisone at an initial dose that is tapered until it reaches the minimum effective dose. The guidelines for the management of LN of the American College of Rheumatology recommend oral mycophenolate mofetil (2–3g/day) or intravenous cyclophosphamide, together with glucocorticoid therapy as induction therapy for classes III and IV LN (level A evidence).<a class="elsevierStyleCrossRef" href="#bib0185">8</a> In general, high doses of intravenous cyclophosphamide (500–1000mg/m2 each month for 6 months), although the results observed with lower doses of intravenous cyclophosphamide (500mg/m2 every 2 weeks for 6 months) were similar to those of the high-dose regimen.<a class="elsevierStyleCrossRef" href="#bib0190">9</a> The recommendation for maintenance therapy is the use of mycophenolate mofetil or azathioprine. The choice of one or the other should be made on an individual basis.Resistance to standard induction therapy and recurrences during treatment have led to the consideration of new therapeutic strategies that include the use of rituximab as a third line of treatment, especially in focal or diffuse proliferative LN, the clinical courses of which are more aggressive than those of other classes of LN. It is difficult to determine the incidence of resistance to the initial treatment in LN patients simply because it is difficult to determine remission in these individuals, as this concept varies depending on the criteria applied. In general, remission has been confirmed by the presence of inactive urinary sediment, reduced proteinuria and normalization of the serum creatinine level. On the other hand, treatment resistance is defined as the failure to respond after 6 months of glucocorticoid and immunosuppressive therapy.<a class="elsevierStyleCrossRef" href="#bib0185">8</a> The first step in patients who fail to respond to the initial treatment will depend on the immunosuppressive agent being used and will consist in switching to another immunosuppressive medication. Thus, if cyclophosphamide was being administered, it should be replaced by mycophenolate mofetil and vice versa. If this strategy were to fail to achieve remission, the use of rituximab is proposed (level C evidence).<a class="elsevierStyleCrossRef" href="#bib0185">8</a>The LUNAR study (A Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With ISN/RPS Class III or IV Lupus Nephritis)<a class="elsevierStyleCrossRef" href="#bib0195">10</a> is the first randomized, parallel-group, placebo-controlled clinical trial to incorporate rituximab into therapy for LN, in combination with glucocorticoids and mycophenolate mofetil. Its publication in 2012 raised great expectation, as its results would confirm those observed in previous studies.The purpose of the present literature review is to retrieve the most recent publications on the advances and data concerning the use of rituximab in LN, to provide the available information and perform a critical analysis of the limited evidence supporting this information.MethodologyWe conducted a literature search in the MEDLINE and Cochrane databases using the MeSH terms “lupus nephritis/drug therapy” and “rituximab”. We each performed a separate search, using filters so that only those studies defined as “clinical trial”, “multicenter”, “randomized controlled” or “comparative” were retrieved. We also selected observational studies, meta-analyses and/or systematic reviews using search filters. The search in the MEDLINE database yielded 11 studies<a class="elsevierStyleCrossRefs" href="#bib0195">10–20</a> involving humans published between 1 January 2000 and 30 May 2015. Of the 11, 3 were observational (2 prospective<a class="elsevierStyleCrossRefs" href="#bib0200">11,12</a> and 1 retrospective<a class="elsevierStyleCrossRef" href="#bib0210">13</a>). The remaining 8 were clinical trials (7 were open-label<a class="elsevierStyleCrossRefs" href="#bib0215">14–20</a> and only 1, the LUNAR study,<a class="elsevierStyleCrossRef" href="#bib0195">10</a> was randomized, parallel-group and placebo-controlled). We included those observational or experimental studies that involved LN patients—and those involving SLE patients in which a subgroup of LN patients was analyzed—and were designed to evaluate partial and complete remissions in response to treatment with rituximab. One of the open-label clinical trials was excluded because it included only 1 patient.<a class="elsevierStyleCrossRef" href="#bib0220">15</a> We obtained a Cochrane database review.<a class="elsevierStyleCrossRef" href="#bib0250">21</a> The bibliography of each of the selected studies was reviewed in search of other relevant articles; moreover, additional information was sought in the UpToDate™ database using the terms “nefritis lúpica” and “rituximab”. This additional search in the UpToDate™ database yielded no more studies of interest and the information was used as a reference resource for other sections of this review. The exclusion of the article by Fra et al.<a class="elsevierStyleCrossRef" href="#bib0220">15</a> left a total of 10 studies.Rituximab in Observational StudiesThe characteristics of the observational studies retrieved are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>In their retrospective study, Melander et al. included 20 patients who received rituximab as induction therapy for class IV and class V LN, with a follow-up of less than 12 months.<a class="elsevierStyleCrossRef" href="#bib0210">13</a> Remission was finally achieved in 12 patients (60%): 7 complete and 5 partial. Rituximab was administered as first-line treatment in only 2 patients. In this study, the normalization of the glomerular filtration rate was used as a criterion for complete remission (≥60mL/min/1.73m2).In 2010, Terrier et al.<a class="elsevierStyleCrossRef" href="#bib0205">12</a> published a prospective study in France, in which they analyzed the data of the French Autoimmunity and Rituximab Registry. This registry invites the hospitals of France to participate in order to analyze those patients with autoimmune diseases refractory to treatment who are receiving rituximab. In 42 patients with LN (class IV in the great majority), renal response was achieved in 23 of 31 patients with available data for this category. Of these 23 patients, 14 (45%) experienced a complete remission and 9 (29%), partial remission. Proteinuria was markedly reduced, although the serum creatinine level remained stable. However, as the registry is for SLE in general, it does not provide specific data on LN patients (for example, neither the dose nor the protocol for rituximab administration is reported).An observational cohort study in which the purpose was to exclude glucocorticoids from the treatment in patients with LN showed that the combination of rituximab and low-dose intravenous methylprednisolone for induction and mycophenolate mofetil for maintenance, without oral glucocorticoids, is also an effective treatment, as remission was achieved in 60% of the patients.<a class="elsevierStyleCrossRef" href="#bib0200">11</a> For the first time in 60 years, a study showed that oral glucocorticoids can be avoided without compromising treatment efficacy in LN. The randomized controlled clinical trial RITUXILUP (<a href="ctgov:NCT01773616">NCT01773616</a>), which is in the recruitment phase, was designed to evaluate the efficacy of this protocol.Open-label Clinical Trials With RituximabIn 2006, Vigna-Perez et al.<a class="elsevierStyleCrossRef" href="#bib0225">16</a> treated 22 patients with LN with 0.5–1g of rituximab on days 1 and 15 of induction therapy, together with immunosuppressive agents. Most of the patients had disease that was refractory to the previous treatment. Seven patients (31.8%) had a partial remission and 5 (22.7%), complete remission. Moreover, the authors reported improvement in the disease activity index in 90% of the patients, reduced proteinuria as early as day 15 in some, B-cell depletion, and stimulation of the regulatory function of the regulatory T cells (Treg), with no significant adverse effects. Gunnarsson et al.<a class="elsevierStyleCrossRef" href="#bib0230">17</a> reported a change in the histopathological findings in 7 patients with LN in whom biopsies were performed at the start of the study and 6 months later. A change in the histological classification was observed in all the patients. The disease activity index decreased dramatically after 6 months of treatment with rituximab. Complete and partial remissions were achieved in 2 patients and in 1 patient, respectively.In a parallel-group clinical trial,<a class="elsevierStyleCrossRef" href="#bib0235">18</a> treatment with rituximab alone was compared with the combination of rituximab and cyclophosphamide in 19 patients. No significant difference in clinical efficacy was observed between the 2 groups in terms of the rate of remission. Partial and complete remission was achieved in 11 and 4 patients, respectively. On the other hand, in another study,<a class="elsevierStyleCrossRef" href="#bib0240">19</a> with a much longer follow-up period and a larger number of patients, the response to rituximab in combination with cyclophosphamide was evaluated in patients with disease refractory to standard therapy for a mean period of 36 months. Renal and histopathological responses were achieved within the first year, although, in many of the patients, these responses occurred at year 2. Low CD19+ B cell counts and IgM levels were correlated with a shorter time to response, and the duration of B-cell depletion was positively associated with time to response.Davies et al.<a class="elsevierStyleCrossRef" href="#bib0215">14</a> report the rates of remission in 18 patients with disease refractory to standard therapy after 6 months of treatment with rituximab in combination with cyclophosphamide. Eleven patients achieved complete remission and 2, partial remission. We should point out that this study provides information on the patients who showed absolutely no response. The nonresponders experienced considerable renal deterioration, as shown by the histological grade. Class IV-G LN may be particularly associated with a poor response to therapy.The most recent study of Moroni et al.,<a class="elsevierStyleCrossRef" href="#bib0245">20</a> published in 2014, which compared 3 treatments groups, 1 with rituximab, another with scyclophosphamide and a third with mycophenolate mofetil, showed rituximab to be at least as effective as the immunosuppressive agents for induction therapy. As the editorial referring to the aforementioned article indicates, although this study gives us an idea of the role of rituximab in LN, randomized trials with high-level evidence are necessary in order to corroborate these findings.<a class="elsevierStyleCrossRef" href="#bib0255">22</a> The main characteristics of the open-label clinical trials are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>A recent systematic review and meta-analysis,<a class="elsevierStyleCrossRef" href="#bib0260">23</a> which included 30 open-label studies—involving a total of 1242 patients diagnosed with SLE—only 11 of which (201 patients) dealt specifically with LN and rituximab, found an overall rate of renal remission of 72.1% (95% confidence interval [CI], 64.3%–78.8%). The analysis of 10 studies that reported complete and partial remissions demonstrated complete remission in 36.1% (95% CI, 25.2%–48.6%) and partial remission in 37.4% (95% CI, 28.5%–47.3%) of the patients studied. A noteworthy aspect of this review with meta-analysis is the lack of consensus in the evaluation of SLE, as well as the discrepancy between observational studies and clinical trials with respect to the efficacy of rituximab, which we also observed in the present review.Rituximab in a Randomized Placebo-controlled Clinical Trial: the LUNAR StudyThe evidence available up to 2012 supports the use of rituximab as “rescue” therapy rather than initial therapy.<a class="elsevierStyleCrossRef" href="#bib0265">24</a> The LUNAR study is the only parallel-group, placebo-controlled clinical trial that randomized 144 patients with class III or IV LN to receive mycophenolate mofetil, glucocorticoids and rituximab or to receive mycophenolate mofetil, glucocorticoids and placebo. This study included patients from the United States (74%) and from Latin America (26%), and the primary end point was the renal response in terms of complete or partial remission 52 weeks after adding rituximab to the treatment. Despite the fact that the results with rituximab were favorable, they were not statistically significant. In all, 45.8% of the patients in the placebo group achieved remission (either partial or complete). The rate of remission in the rituximab was 56.4%, but the difference was not statistically significant (P=.18). Although no difference could be demonstrated, the authors found that, among black patients, the rate of remission with rituximab was 70% vs 45% in the placebo group. This difference, while not significant (P=.20), indicates both the possible efficacy in this subgroup of patients and the need to undertake a randomized, controlled trial involving only black patients, whose prognosis is poorer than that of other subpopulations.We could attribute this failure, in terms of the statistical difference in the results, to the short follow-up, or even to the small sample size; however, it may be that the response is much more practical and that the addition of rituximab simply is not effective in a therapy that, in itself, is highly effective.There is an interesting difference between the study conducted by Terrier et al. based on the French Autoimmunity and Rituximab Registry and the LUNAR study. The difference in the proportion of patients who were resistant to mycophenolate mofetil and/or cyclophosphamide in the 2 studies is enormous (76% vs 0%). Perhaps this indicates that rituximab is effective when administered to patients who do not respond to standard therapy. A controlled study of patients with LN that is refractory to standard treatment would be highly interesting.A review published by Blüml et al.,<a class="elsevierStyleCrossRef" href="#bib0270">25</a> which details the clinical use of B-cell-targeted therapies, establishes an important principle with the premise that the use of an agent, like mycophenolate mofetil, that interferes with B-cell differentiation can, in a way, mask the effect of rituximab. Mycophenolate mofetil was used in the LUNAR study, a fact that may, in part, explain the results. Another possible hypothesis concerns the mechanism of action of rituximab, as this agent is effective in producing a depletion of circulating B cells without affecting those of the mantle or the marginal zone and, it is thought, that the latter two could continue to mediate inflammation.<a class="elsevierStyleCrossRef" href="#bib0275">26</a> The more we know about the molecular mechanisms of the diseases, the closer we get to knowing the therapeutic objectives. Apparently, the treatment of LN requires a complete understanding of the molecular interactions that mediate its pathogenesis. It is known that B-cell depletion promotes the production of B-cell activating factor; this factor generates new autoreactive B cells. This mechanism could in some way explain the failure of rituximab therapy. The B regulatory cells (Breg) modulate the inflammatory response mediated by the B cells. Studies in mice have shown that rituximab results in the depletion of this B-cell line.<a class="elsevierStyleCrossRef" href="#bib0280">27</a>In a systematic review more recent than the LUNAR study, the clinical efficacy of rituximab is analyzed in 26 reports, including prospective and retrospective studies, case series and case reports.<a class="elsevierStyleCrossRef" href="#bib0285">28</a> The authors found that, of the patients being treated with rituximab, 40% achieved complete remission after 60 weeks and 34% achieved partial remission during the follow-up period. Once again, we observe that rituximab is effective when it is administered after standard therapy has failed and when there is resistance to other drugs. The review details the percentage of patients who respond with rituximab in each LN class. Rituximab is found to be more effective in class III LN (60%). The efficacy of rituximab in refractory LN is being evaluated in the RING study (Rituximab for Lupus Nephritis with Remission as a Goal, <a href="ctgov:NCT01673295">NCT01673295</a>), which includes patients who have no response to standard treatment after 6 months.Despite the lack of conclusive evidence, physicians utilize rituximab in routine clinical practice on the basis of their personal experience and the open-label studies that demonstrate the efficacy of this agent.<a class="elsevierStyleCrossRef" href="#bib0290">29</a> Future studies will probably be able to provide quality evidence that will have an impact on clinical practice, and lead to the reconsideration of the management guidelines concerning the use of rituximab in LN.ConclusionObservational and open-label studies have reported that the monoclonal antibody rituximab has high clinical efficacy in the treatment of LN, which is a serious complication and an indicator of poor prognosis in patients with SLE.A controlled study conducted to confirm its efficacy failed to demonstrate a statistically significant difference attributable to the addition of rituximab to standard therapy in terms of an improvement in the rate of remission in LN patients. These results are discouraging as this nephropathy continues to be associated with high rates of mortality and morbidity due to end-stage renal failure and the severe toxicity and the adverse effects of the drugs that, to date, are being administered for the current treatment of LN. The lack of response observed in controlled studies may be due to the variability of the clinical signs of SLE, as well as to the efficacy of the medications permitted in the study, which could have masked the results.Patients who show resistance to the standard initial treatment usually experience a better response when rituximab is added. This monoclonal antibody may prove to be highly beneficial in those patients, especially in blacks. A randomized, double-blind, controlled study is necessary to confirm its clinical efficacy.At this point, rituximab should not yet be excluded from the group of agents that are to be tested for their potential contribution to the medical management of LN. The target is to be able to discard the glucocorticoids and achieve greater efficacy in terms of the rate of complete remissions. Therapy targeting B-cell depletion will probably consist in much more than the administration of a single drug; in view of the immune mechanisms that play a role in the pathogenesis of LN, it would be necessary to establish a strategy to block the compensatory mechanisms and inhibit the unwanted effects of rituximab, in order to optimize therapy involving this drug. At this time, there is no conclusive evidence (systematic reviews with or without meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0250">21,23,28</a>) that supports the use of rituximab as part of the first-line therapy in LN, and the recommendation for the use of this agent as third-line therapy comes from open-label studies with low statistical power, as has been detailed in this review. It will be necessary to perform randomized, double-blind, placebo-controlled clinical trials that preferentially utilize the so-called adaptive randomization, in which patient allocation varies in favor of the group showing the best outcome over the course of data collection. Likewise, the subgroup of black patients is of special interest as this subpopulation showed a difference, although not statistically significant, indicating the potential benefit of a clinical trial designed to confirm the benefit of rituximab particularly in this group.Ethical DisclosuresProtection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this study.Confidentiality of dataThe authors declare that no patient data appear in this article.Right to privacy and informed consentThe authors declare that no patient data appear in this article.Conflicts of InterestThe authors declare they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres824577" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec821057" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres824578" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec821056" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methodology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Rituximab in Observational Studies" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Open-label Clinical Trials With Rituximab" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Rituximab in a Randomized Placebo-controlled Clinical Trial: the LUNAR Study" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusion" ] 10 => array:3 [ "identificador" => "sec0035" "titulo" => "Ethical Disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Right to privacy and informed consent" ] ] ] 11 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of Interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-07-14" "fechaAceptado" => "2016-01-15" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec821057" "palabras" => array:3 [ 0 => "Rituximab" 1 => "Nephritis" 2 => "Lupus" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec821056" "palabras" => array:3 [ 0 => "Rituximab" 1 => "Nefritis" 2 => "Lupus" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Lupus nephritis (LN) is a common and severe complication in patients with lupus. Current therapy is based on immunosuppressive drugs and glucocorticoids. Recently, rituximab has been proposed as an alternative treatment for LN. Rituximab is a monoclonal antibody directed against the CD20 antigen receptor on B cells. The aim of this review is to summarize all the available information about rituximab in LN. Eleven studies were found; three of them were observational studies (2 prospective and 1 retrospective) and eight were clinical trials (7 open-label studies and only 1 randomized controlled trial [RCT]). The evidence is insufficient to establish the role of rituximab in the treatment of LN. Results from the only RCT, which were negative, suggest a clinical benefit in black people. Further studies must confirm this hypothesis. Controlled clinical trials involving adaptive randomization are required to establish the real benefit of rituximab in LN." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La nefritis lúpica (NL) es una complicación común y grave del lupus. En la actualidad, la terapia está basada en inmunosupresores y glucocorticoides. Recientemente se ha planteado como posible tratamiento al rituximab, un anticuerpo monoclonal dirigido contra el antígeno CD20 de los linfocitos B. El objetivo de la presente revisión es recopilar la información disponible hasta el momento acerca del uso de rituximab en NL. Se encontraron 11 estudios, 3 observacionales (2 prospectivos y uno retrospectivo) y 8 ensayos clínicos (7 abiertos y solo uno aleatorizado controlado). La evidencia es insuficiente para establecer el papel del rituximab en la terapia de la NL. Resultados del único ensayo clínico aleatorizado y controlado, el cual falló en demostrar una mejoría clínica significativa, indican un posible beneficio en pacientes de raza negra. Futuros estudios deben confirmar dicha hipótesis. Se proponen ensayos clínicos controlados, con aleatorización adaptativa, para establecer el verdadero beneficio con rituximab en NL." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Zurita Gavilanes L, Costa Valarezo A. Rituximab en nefritis lúpica: una revisión no sistemática. Reumatol Clin. 2016;12:210–215." ] ] "multimedia" => array:2 [ 0 => 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:3 [ "leyenda" => "CR, complete remission; GFR, glomerular filtration rate; LN, lupus nephritis; MPS, methylprednisolone; PR, partial remission; RTX, rituximab; SLE, systemic lupus erythematosus; UPC, urinary protein to creatine; W, women." "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">Population \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">No. of patients (mean age [years]) \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-naïve patients (%) \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">Protocol of RTX administration \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">Mean follow-up period \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">Main outcomes (P value) \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">Melander et al.<a class="elsevierStyleCrossRef" href="#bib0210">13</a> 2009<a class="elsevierStyleCrossRefs" href="#tblfn0005">a,b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III-V LN according to biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20; 95% W (25.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">375mg/m2×4 in 90% of patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 35%; PR: 25% \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">Terrier et al.<a class="elsevierStyleCrossRef" href="#bib0205">12</a> 2010<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SLE, 31% con LN; 19% class iii and 52.4% class iv (95% biopsy) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dose in LN patients of the registry not reported \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16.6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 45% (.0001); PR: 29% (.004) \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">Condon et al.<a class="elsevierStyleCrossRef" href="#bib0200">11</a> 2013<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III-V LN according to biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50; 78% W (45) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1g×2 (with 0.5g MPS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40.75 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 72%; PR: 18% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1386301.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Retrospective observational study." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "PR, 24-h proteinuria >50% and stabilization of the GFR; CR, proteinuria <0.5g/day, absence of hematuria and GFR≥60mL/min/1.73m2 or improvement of 50% over the basal GFR value." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "PR, improvement by 50% in all the renal parameters (serum creatinine and proteinuria); CR, decrease in proteinuria to 0.5g/day, disappearance of hematuria and normalization of GFR." ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "CR, combination of a UPC ratio less than 50mg/mmol and serum creatinine no greater than 15% of baseline level; PC, UPC ratio <300mg/mmol with a reduction >50% with respect to the baseline level and an increase in serum creatine no greater than 15% over the baseline level." ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of the Observational Studies With Rituximab." ] ] 1 => 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" => "Cr, serum creatinine; CR, complete remission; CYC, cyclophosphamide; IST, immunosuppressive therapy; LN, lupus nephritis; MMF, mycophenolate mofetil; PC, partial remission; PCB, placebo; RTX, rituximab; SLICC, Systemic Lupus International Collaborating Clinics; UPC, urinary protein to creatinine; W, women." "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">LN classification (%) \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">Response to treatment at the time of RTX therapy \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">No. of patients (mean age in years) \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">Comparator \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">RTX administration protocol \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">Evaluation time points \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">Results \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">Vigna-Perez et al.<a class="elsevierStyleCrossRef" href="#bib0225">16</a> 2006<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III (9.1); IV (81.8); V (9.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Disease refractory to treatment Recurrence (9.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22; W 86.4% (29) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RTX+IST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">0.5–1g day×2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Days 30, 60 and 90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 31.8%; PR: 22.7% \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">Gunnarsson et al.<a class="elsevierStyleCrossRef" href="#bib0230">17</a> 2007<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III (14.3); IV (85.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Disease refractory to treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7; W 100% (30) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RTX+IST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">375mg/m2×4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 42.9%; PR: 14.3% \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">Li et al.<a class="elsevierStyleCrossRef" href="#bib0235">18</a> 2009<a class="elsevierStyleCrossRef" href="#tblfn0035">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III (10.5); IV (15.8); III+ IV (5.3); III +V (63.2); IV+V (5.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not reported \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RTX: 9 (40.3); RTX+CYC: 10 (39.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RTX vs RTX+CYC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1g×2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Every month for 6 months, every 2 months thereafter for 48 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 21%; PR: 58% \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">Davies et al.<a class="elsevierStyleCrossRef" href="#bib0215">14</a> 2013<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III (27.8); IV (27.8); V (11.1); IV +V (22.2); III +V (11.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Disease refractory to treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18; W (−) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RTX+CYC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1g×2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 61.1%; PR: 11.1% \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">Jónsdóttir et al.<a class="elsevierStyleCrossRef" href="#bib0240">19</a> 2013<a class="elsevierStyleCrossRef" href="#tblfn0040">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III or IV (60); V (36). \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Most patients with disease refractory to treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25; W 92% (34.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RTX+CYC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">375mg/m2×4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Every 2–3 months the first year, every 6 months thereafter. Mean follow-up 36 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 64%; PR: 24% \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">Moroni et al.<a class="elsevierStyleCrossRef" href="#bib0245">20</a> 2014<a class="elsevierStyleCrossRef" href="#tblfn0045">e</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III (16.6); IV (48.1); V (3.7); III +V (9.3); IV+V (18.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50% no treatment, 40.7% recurrence and 9.3% disease refractory to treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MMF: 17 (32.4); RTX: 17 (31.1); CYC: 20 (31) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RTX vs CYC vs MMF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1g×2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 70.6%; PR: 29.4% \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">Rovin et al.<a class="elsevierStyleCrossRef" href="#bib0195">10</a> 2012 LUNAR<a class="elsevierStyleCrossRef" href="#tblfn0050">f</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RTX: III (34.7); IV (65.3); V alone or in combination (36.1). PCB: III (33.3); IV (66.7); V alone or in combination (31.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No treatment for LN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RTX: 72; W 87.5% (31.8). PCB: 72; W 93.1% (29.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes (PCB) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MMF+PCB vs MMF+RTX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1g×4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Response at 52 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR: 26.4%; PR, 30.6%. P=.55 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1386300.png" ] ] ] "notaPie" => array:6 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "CR, normal Cr, inactive urinary sediment, proteinuria <0.5g/day; PR, improvement >40% in renal parameters compared to the beginning of the study." ] 1 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "b" "nota" => "CR, normal Cr, normal serum albumin, inactive urinary sediment, albuminuria <0.5g/day; PR, improvement ≥50% in renal parameters compared to the beginning of the study." ] 2 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "c" "nota" => "CR, if the baseline SLICC disease activity index was >0 and was reduced to 0 after follow-up; PR, if the baseline SLICC disease activity index was higher than the index after follow-up, but the latter was not equal to 0." ] 3 => array:3 [ "identificador" => "tblfn0040" "etiqueta" => "d" "nota" => "Response to treatment (CR and PR), defined in accordance with the 2009 European Consensus Statement on LN." ] 4 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "e" "nota" => "CR, Cr<1.2mg/dL (or return to the baseline value in patients with chronic kidney disease) and proteinuria <0.5g/day and <5 urinary red blood cells/high power field; PR, Cr<1.2mg/dL (or return to the baseline value in patients with chronic kidney disease) and proteinuria of 0.5–2g/day." ] 5 => array:3 [ "identificador" => "tblfn0050" "etiqueta" => "f" "nota" => "CR, normal Cr if it was abnormal at the beginning of the study, or a Cr level ≤115% of baseline if it was normal at the beginning of the study; inactive urinary sediment (<5 red blood cells/high power field and absence of red blood cell casts), and UPC ratio <0.5; PR, Cr≤115% of baseline, urinary red blood cells/high power field ≤50% above baseline and no red blood cell casts, and a decrease of at least 50% in the UPC ratio to <1.0 (if the baseline UPC ratio was ≤3.0) or to ≤3.0 (if the baseline UPC ratio was >3.0)." ] ] ] "descripcion" => array:1 [ "en" => "Characteristics of the Clinical Trials With Rituximab." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0150" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lupus nephritis: an overview of recent findings" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. 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Rituximab in Lupus Nephritis: A Non-systematic Review

Rituximab en nefritis lúpica: una revisión no sistemática

Luis Zurita Gavilanesa,b, Aldo Costa Valarezob,

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aldocosva_01@hotmail.com

Corresponding author.

a Unidad de Enfermedades Reumáticas y Autoinmunes (UNERA), Guayaquil, Ecuador

b Facultad de Ciencias Médicas, Universidad Espíritu Santo, Guayaquil, Ecuador

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Lupus nephritis &#40;LN&#41; is a common but serious complication of systemic lupus erythematosus &#40;SLE&#41;&#46; The prevalence of SLE ranges between 1&#46;4&#37; and 21&#46;9&#37; and the incidence between 7&#46;4 and 159&#46;4 cases per 100<span class="elsevierStyleHsp" style=""></span>000 population&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> It is known that 60&#37; of the SLE patients will develop LN<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> and more than 25&#37; of these patients will develop end-stage renal disease 10 years after the onset of renal symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The main clinical features are proteinuria and microscopic hematuria&#46; Less common findings are macroscopic hematuria and hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> Certain histopathological changes can result in different clinical presentations&#46; Thus&#44; although in LN&#44; the histopathological findings obtained from renal biopsy are not necessary for the diagnosis&#44; they are of the utmost importance for the classification of the disease&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Different pathophysiological mechanisms have been involved in the development of LN in SLE patients&#46; A combination of genetic&#44; environmental and immunological factors mediate the processes that result in the renal damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">1&#8211;4</span></a> Of special importance for the present review is the role of the B cells&#44; which are hyperactive in SLE&#46; The B cells mediate and regulate antibody production&#44; interact with memory T cells and stimulate proinflammatory cytokine production&#44; all of which makes them essential components of the pathophysiology of LN&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> It is for these reasons that the use of rituximab is proposed&#46; Rituximab is a chimeric monoclonal antibody &#40;murine&#47;human&#41; approved by the United States Food and Drug Administration in 1997&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> This monoclonal antibody is directed against CD20&#44; an antigen expressed on the surface of mature and immature B cells&#46; CD20 regulates the initiation of the cell cycle&#46; The binding of the antibody to Fc receptor induces apoptosis and cytotoxicity&#44; mediated by both complement and antibodies&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Treatment of LN was based for some years on glucocorticoids&#46; This therapy had the disadvantage of the high morbidity and mortality rates resulting from the high doses administered&#44; as well as its inability to arrest the progression of the renal disease&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a> One proposal for solving this problem was the use of immunosuppressive agents&#44; which were evaluated in a landmark clinical trial performed to determine the long-term survival of 107 LN patients&#46; This trial revealed a difference in terms of renal function preservation&#44; but said difference was statistically significant only for the combination of intravenous &#40;IV&#41; cyclophosphamide and low-dose&#44; rather than high-dose&#44; prednisone&#46; No differences in the mortality rate were observed&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">At the present time&#44; therapy for LN consists of an induction phase followed by a maintenance phase&#46; The majority of the patients with active proliferative LN are initially treated with pulsed methylprednisolone for 3 days&#44; followed by a period of oral prednisone at an initial dose that is tapered until it reaches the minimum effective dose&#46; The guidelines for the management of LN of the American College of Rheumatology recommend oral mycophenolate mofetil &#40;2&#8211;3<span class="elsevierStyleHsp" style=""></span>g&#47;day&#41; or intravenous cyclophosphamide&#44; together with glucocorticoid therapy as induction therapy for classes III and IV LN &#40;level A evidence&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">8</span></a> In general&#44; high doses of intravenous cyclophosphamide &#40;500&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> each month for 6 months&#41;&#44; although the results observed with lower doses of intravenous cyclophosphamide &#40;500<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> every 2 weeks for 6 months&#41; were similar to those of the high-dose regimen&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a> The recommendation for maintenance therapy is the use of mycophenolate mofetil or azathioprine&#46; The choice of one or the other should be made on an individual basis&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Resistance to standard induction therapy and recurrences during treatment have led to the consideration of new therapeutic strategies that include the use of rituximab as a third line of treatment&#44; especially in focal or diffuse proliferative LN&#44; the clinical courses of which are more aggressive than those of other classes of LN&#46; It is difficult to determine the incidence of resistance to the initial treatment in LN patients simply because it is difficult to determine remission in these individuals&#44; as this concept varies depending on the criteria applied&#46; In general&#44; remission has been confirmed by the presence of inactive urinary sediment&#44; reduced proteinuria and normalization of the serum creatinine level&#46; On the other hand&#44; treatment resistance is defined as the failure to respond after 6 months of glucocorticoid and immunosuppressive therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">8</span></a> The first step in patients who fail to respond to the initial treatment will depend on the immunosuppressive agent being used and will consist in switching to another immunosuppressive medication&#46; Thus&#44; if cyclophosphamide was being administered&#44; it should be replaced by mycophenolate mofetil and vice versa&#46; If this strategy were to fail to achieve remission&#44; the use of rituximab is proposed &#40;level C evidence&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">8</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The LUNAR study &#40;A Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With ISN&#47;RPS Class III or IV Lupus Nephritis&#41;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> is the first randomized&#44; parallel-group&#44; placebo-controlled clinical trial to incorporate rituximab into therapy for LN&#44; in combination with glucocorticoids and mycophenolate mofetil&#46; Its publication in 2012 raised great expectation&#44; as its results would confirm those observed in previous studies&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The purpose of the present literature review is to retrieve the most recent publications on the advances and data concerning the use of rituximab in LN&#44; to provide the available information and perform a critical analysis of the limited evidence supporting this information&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methodology</span><p id="par0045" class="elsevierStylePara elsevierViewall">We conducted a literature search in the MEDLINE and Cochrane databases using the MeSH terms &#8220;lupus nephritis&#47;drug therapy&#8221; and &#8220;rituximab&#8221;&#46; We each performed a separate search&#44; using filters so that only those studies defined as &#8220;clinical trial&#8221;&#44; &#8220;multicenter&#8221;&#44; &#8220;randomized controlled&#8221; or &#8220;comparative&#8221; were retrieved&#46; We also selected observational studies&#44; meta-analyses and&#47;or systematic reviews using search filters&#46; The search in the MEDLINE database yielded 11 studies<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">10&#8211;20</span></a> involving humans published between 1 January 2000 and 30 May 2015&#46; Of the 11&#44; 3 were observational &#40;2 prospective<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">11&#44;12</span></a> and 1 retrospective<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a>&#41;&#46; The remaining 8 were clinical trials &#40;7 were open-label<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">14&#8211;20</span></a> and only 1&#44; the LUNAR study&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> was randomized&#44; parallel-group and placebo-controlled&#41;&#46; We included those observational or experimental studies that involved LN patients&#8212;and those involving SLE patients in which a subgroup of LN patients was analyzed&#8212;and were designed to evaluate partial and complete remissions in response to treatment with rituximab&#46; One of the open-label clinical trials was excluded because it included only 1 patient&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a> We obtained a Cochrane database review&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> The bibliography of each of the selected studies was reviewed in search of other relevant articles&#59; moreover&#44; additional information was sought in the UpToDate&#8482; database using the terms &#8220;nefritis l&#250;pica&#8221; and &#8220;rituximab&#8221;&#46; This additional search in the UpToDate&#8482; database yielded no more studies of interest and the information was used as a reference resource for other sections of this review&#46; The exclusion of the article by Fra et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a> left a total of 10 studies&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Rituximab in Observational Studies</span><p id="par0050" class="elsevierStylePara elsevierViewall">The characteristics of the observational studies retrieved are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">In their retrospective study&#44; Melander et al&#46; included 20 patients who received rituximab as induction therapy for class IV and class V LN&#44; with a follow-up of less than 12 months&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> Remission was finally achieved in 12 patients &#40;60&#37;&#41;&#58; 7 complete and 5 partial&#46; Rituximab was administered as first-line treatment in only 2 patients&#46; In this study&#44; the normalization of the glomerular filtration rate was used as a criterion for complete remission &#40;&#8805;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In 2010&#44; Terrier et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> published a prospective study in France&#44; in which they analyzed the data of the French Autoimmunity and Rituximab Registry&#46; This registry invites the hospitals of France to participate in order to analyze those patients with autoimmune diseases refractory to treatment who are receiving rituximab&#46; In 42 patients with LN &#40;class IV in the great majority&#41;&#44; renal response was achieved in 23 of 31 patients with available data for this category&#46; Of these 23 patients&#44; 14 &#40;45&#37;&#41; experienced a complete remission and 9 &#40;29&#37;&#41;&#44; partial remission&#46; Proteinuria was markedly reduced&#44; although the serum creatinine level remained stable&#46; However&#44; as the registry is for SLE in general&#44; it does not provide specific data on LN patients &#40;for example&#44; neither the dose nor the protocol for rituximab administration is reported&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">An observational cohort study in which the purpose was to exclude glucocorticoids from the treatment in patients with LN showed that the combination of rituximab and low-dose intravenous methylprednisolone for induction and mycophenolate mofetil for maintenance&#44; without oral glucocorticoids&#44; is also an effective treatment&#44; as remission was achieved in 60&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> For the first time in 60 years&#44; a study showed that oral glucocorticoids can be avoided without compromising treatment efficacy in LN&#46; The randomized controlled clinical trial RITUXILUP &#40;<a href="ctgov:NCT01773616">NCT01773616</a>&#41;&#44; which is in the recruitment phase&#44; was designed to evaluate the efficacy of this protocol&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Open-label Clinical Trials With Rituximab</span><p id="par0070" class="elsevierStylePara elsevierViewall">In 2006&#44; Vigna-Perez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> treated 22 patients with LN with 0&#46;5&#8211;1<span class="elsevierStyleHsp" style=""></span>g of rituximab on days 1 and 15 of induction therapy&#44; together with immunosuppressive agents&#46; Most of the patients had disease that was refractory to the previous treatment&#46; Seven patients &#40;31&#46;8&#37;&#41; had a partial remission and 5 &#40;22&#46;7&#37;&#41;&#44; complete remission&#46; Moreover&#44; the authors reported improvement in the disease activity index in 90&#37; of the patients&#44; reduced proteinuria as early as day 15 in some&#44; B-cell depletion&#44; and stimulation of the regulatory function of the regulatory T cells &#40;Treg&#41;&#44; with no significant adverse effects&#46; Gunnarsson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> reported a change in the histopathological findings in 7 patients with LN in whom biopsies were performed at the start of the study and 6 months later&#46; A change in the histological classification was observed in all the patients&#46; The disease activity index decreased dramatically after 6 months of treatment with rituximab&#46; Complete and partial remissions were achieved in 2 patients and in 1 patient&#44; respectively&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In a parallel-group clinical trial&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a> treatment with rituximab alone was compared with the combination of rituximab and cyclophosphamide in 19 patients&#46; No significant difference in clinical efficacy was observed between the 2 groups in terms of the rate of remission&#46; Partial and complete remission was achieved in 11 and 4 patients&#44; respectively&#46; On the other hand&#44; in another study&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a> with a much longer follow-up period and a larger number of patients&#44; the response to rituximab in combination with cyclophosphamide was evaluated in patients with disease refractory to standard therapy for a mean period of 36 months&#46; Renal and histopathological responses were achieved within the first year&#44; although&#44; in many of the patients&#44; these responses occurred at year 2&#46; Low CD19&#43; B cell counts and IgM levels were correlated with a shorter time to response&#44; and the duration of B-cell depletion was positively associated with time to response&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Davies et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a> report the rates of remission in 18 patients with disease refractory to standard therapy after 6 months of treatment with rituximab in combination with cyclophosphamide&#46; Eleven patients achieved complete remission and 2&#44; partial remission&#46; We should point out that this study provides information on the patients who showed absolutely no response&#46; The nonresponders experienced considerable renal deterioration&#44; as shown by the histological grade&#46; Class IV-G LN may be particularly associated with a poor response to therapy&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The most recent study of Moroni et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> published in 2014&#44; which compared 3 treatments groups&#44; 1 with rituximab&#44; another with scyclophosphamide and a third with mycophenolate mofetil&#44; showed rituximab to be at least as effective as the immunosuppressive agents for induction therapy&#46; As the editorial referring to the aforementioned article indicates&#44; although this study gives us an idea of the role of rituximab in LN&#44; randomized trials with high-level evidence are necessary in order to corroborate these findings&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a> The main characteristics of the open-label clinical trials are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">A recent systematic review and meta-analysis&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">23</span></a> which included 30 open-label studies&#8212;involving a total of 1242 patients diagnosed with SLE&#8212;only 11 of which &#40;201 patients&#41; dealt specifically with LN and rituximab&#44; found an overall rate of renal remission of 72&#46;1&#37; &#40;95&#37; confidence interval &#91;CI&#93;&#44; 64&#46;3&#37;&#8211;78&#46;8&#37;&#41;&#46; The analysis of 10 studies that reported complete and partial remissions demonstrated complete remission in 36&#46;1&#37; &#40;95&#37; CI&#44; 25&#46;2&#37;&#8211;48&#46;6&#37;&#41; and partial remission in 37&#46;4&#37; &#40;95&#37; CI&#44; 28&#46;5&#37;&#8211;47&#46;3&#37;&#41; of the patients studied&#46; A noteworthy aspect of this review with meta-analysis is the lack of consensus in the evaluation of SLE&#44; as well as the discrepancy between observational studies and clinical trials with respect to the efficacy of rituximab&#44; which we also observed in the present review&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Rituximab in a Randomized Placebo-controlled Clinical Trial&#58; the LUNAR Study</span><p id="par0095" class="elsevierStylePara elsevierViewall">The evidence available up to 2012 supports the use of rituximab as &#8220;rescue&#8221; therapy rather than initial therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">24</span></a> The LUNAR study is the only parallel-group&#44; placebo-controlled clinical trial that randomized 144 patients with class III or IV LN to receive mycophenolate mofetil&#44; glucocorticoids and rituximab or to receive mycophenolate mofetil&#44; glucocorticoids and placebo&#46; This study included patients from the United States &#40;74&#37;&#41; and from Latin America &#40;26&#37;&#41;&#44; and the primary end point was the renal response in terms of complete or partial remission 52 weeks after adding rituximab to the treatment&#46; Despite the fact that the results with rituximab were favorable&#44; they were not statistically significant&#46; In all&#44; 45&#46;8&#37; of the patients in the placebo group achieved remission &#40;either partial or complete&#41;&#46; The rate of remission in the rituximab was 56&#46;4&#37;&#44; but the difference was not statistically significant &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;18&#41;&#46; Although no difference could be demonstrated&#44; the authors found that&#44; among black patients&#44; the rate of remission with rituximab was 70&#37; vs 45&#37; in the placebo group&#46; This difference&#44; while not significant &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;20&#41;&#44; indicates both the possible efficacy in this subgroup of patients and the need to undertake a randomized&#44; controlled trial involving only black patients&#44; whose prognosis is poorer than that of other subpopulations&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">We could attribute this failure&#44; in terms of the statistical difference in the results&#44; to the short follow-up&#44; or even to the small sample size&#59; however&#44; it may be that the response is much more practical and that the addition of rituximab simply is not effective in a therapy that&#44; in itself&#44; is highly effective&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">There is an interesting difference between the study conducted by Terrier et al&#46; based on the French Autoimmunity and Rituximab Registry and the LUNAR study&#46; The difference in the proportion of patients who were resistant to mycophenolate mofetil and&#47;or cyclophosphamide in the 2 studies is enormous &#40;76&#37; vs 0&#37;&#41;&#46; Perhaps this indicates that rituximab is effective when administered to patients who do not respond to standard therapy&#46; A controlled study of patients with LN that is refractory to standard treatment would be highly interesting&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">A review published by Bl&#252;ml et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> which details the clinical use of B-cell-targeted therapies&#44; establishes an important principle with the premise that the use of an agent&#44; like mycophenolate mofetil&#44; that interferes with B-cell differentiation can&#44; in a way&#44; mask the effect of rituximab&#46; Mycophenolate mofetil was used in the LUNAR study&#44; a fact that may&#44; in part&#44; explain the results&#46; Another possible hypothesis concerns the mechanism of action of rituximab&#44; as this agent is effective in producing a depletion of circulating B cells without affecting those of the mantle or the marginal zone and&#44; it is thought&#44; that the latter two could continue to mediate inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a> The more we know about the molecular mechanisms of the diseases&#44; the closer we get to knowing the therapeutic objectives&#46; Apparently&#44; the treatment of LN requires a complete understanding of the molecular interactions that mediate its pathogenesis&#46; It is known that B-cell depletion promotes the production of B-cell activating factor&#59; this factor generates new autoreactive B cells&#46; This mechanism could in some way explain the failure of rituximab therapy&#46; The B regulatory cells &#40;Breg&#41; modulate the inflammatory response mediated by the B cells&#46; Studies in mice have shown that rituximab results in the depletion of this B-cell line&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In a systematic review more recent than the LUNAR study&#44; the clinical efficacy of rituximab is analyzed in 26 reports&#44; including prospective and retrospective studies&#44; case series and case reports&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a> The authors found that&#44; of the patients being treated with rituximab&#44; 40&#37; achieved complete remission after 60 weeks and 34&#37; achieved partial remission during the follow-up period&#46; Once again&#44; we observe that rituximab is effective when it is administered after standard therapy has failed and when there is resistance to other drugs&#46; The review details the percentage of patients who respond with rituximab in each LN class&#46; Rituximab is found to be more effective in class III LN &#40;60&#37;&#41;&#46; The efficacy of rituximab in refractory LN is being evaluated in the RING study &#40;Rituximab for Lupus Nephritis with Remission as a Goal&#44; <a href="ctgov:NCT01673295">NCT01673295</a>&#41;&#44; which includes patients who have no response to standard treatment after 6 months&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Despite the lack of conclusive evidence&#44; physicians utilize rituximab in routine clinical practice on the basis of their personal experience and the open-label studies that demonstrate the efficacy of this agent&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a> Future studies will probably be able to provide quality evidence that will have an impact on clinical practice&#44; and lead to the reconsideration of the management guidelines concerning the use of rituximab in LN&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusion</span><p id="par0125" class="elsevierStylePara elsevierViewall">Observational and open-label studies have reported that the monoclonal antibody rituximab has high clinical efficacy in the treatment of LN&#44; which is a serious complication and an indicator of poor prognosis in patients with SLE&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">A controlled study conducted to confirm its efficacy failed to demonstrate a statistically significant difference attributable to the addition of rituximab to standard therapy in terms of an improvement in the rate of remission in LN patients&#46; These results are discouraging as this nephropathy continues to be associated with high rates of mortality and morbidity due to end-stage renal failure and the severe toxicity and the adverse effects of the drugs that&#44; to date&#44; are being administered for the current treatment of LN&#46; The lack of response observed in controlled studies may be due to the variability of the clinical signs of SLE&#44; as well as to the efficacy of the medications permitted in the study&#44; which could have masked the results&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Patients who show resistance to the standard initial treatment usually experience a better response when rituximab is added&#46; This monoclonal antibody may prove to be highly beneficial in those patients&#44; especially in blacks&#46; A randomized&#44; double-blind&#44; controlled study is necessary to confirm its clinical efficacy&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">At this point&#44; rituximab should not yet be excluded from the group of agents that are to be tested for their potential contribution to the medical management of LN&#46; The target is to be able to discard the glucocorticoids and achieve greater efficacy in terms of the rate of complete remissions&#46; Therapy targeting B-cell depletion will probably consist in much more than the administration of a single drug&#59; in view of the immune mechanisms that play a role in the pathogenesis of LN&#44; it would be necessary to establish a strategy to block the compensatory mechanisms and inhibit the unwanted effects of rituximab&#44; in order to optimize therapy involving this drug&#46; At this time&#44; there is no conclusive evidence &#40;systematic reviews with or without meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">21&#44;23&#44;28</span></a>&#41; that supports the use of rituximab as part of the first-line therapy in LN&#44; and the recommendation for the use of this agent as third-line therapy comes from open-label studies with low statistical power&#44; as has been detailed in this review&#46; It will be necessary to perform randomized&#44; double-blind&#44; placebo-controlled clinical trials that preferentially utilize the so-called adaptive randomization&#44; in which patient allocation varies in favor of the group showing the best outcome over the course of data collection&#46; Likewise&#44; the subgroup of black patients is of special interest as this subpopulation showed a difference&#44; although not statistically significant&#44; indicating the potential benefit of a clinical trial designed to confirm the benefit of rituximab particularly in this group&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Ethical Disclosures</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Protection of human and animal subjects</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Confidentiality of data</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Right to privacy and informed consent</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of Interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres824577"
          "titulo" => "Abstract"
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              "identificador" => "abst0005"
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        1 => array:2 [
          "identificador" => "xpalclavsec821057"
          "titulo" => "Keywords"
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          "identificador" => "xres824578"
          "titulo" => "Resumen"
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              "identificador" => "abst0010"
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        3 => array:2 [
          "identificador" => "xpalclavsec821056"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Methodology"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Rituximab in Observational Studies"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Open-label Clinical Trials With Rituximab"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Rituximab in a Randomized Placebo-controlled Clinical Trial&#58; the LUNAR Study"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Conclusion"
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        10 => array:3 [
          "identificador" => "sec0035"
          "titulo" => "Ethical Disclosures"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Protection of human and animal subjects"
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            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Confidentiality of data"
            ]
            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Right to privacy and informed consent"
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          ]
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        11 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conflicts of Interest"
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        12 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2015-07-14"
    "fechaAceptado" => "2016-01-15"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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          "palabras" => array:3 [
            0 => "Rituximab"
            1 => "Nephritis"
            2 => "Lupus"
          ]
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      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec821056"
          "palabras" => array:3 [
            0 => "Rituximab"
            1 => "Nefritis"
            2 => "Lupus"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Lupus nephritis &#40;LN&#41; is a common and severe complication in patients with lupus&#46; Current therapy is based on immunosuppressive drugs and glucocorticoids&#46; Recently&#44; rituximab has been proposed as an alternative treatment for LN&#46; Rituximab is a monoclonal antibody directed against the CD20 antigen receptor on B cells&#46; The aim of this review is to summarize all the available information about rituximab in LN&#46; Eleven studies were found&#59; three of them were observational studies &#40;2 prospective and 1 retrospective&#41; and eight were clinical trials &#40;7 open-label studies and only 1 randomized controlled trial &#91;RCT&#93;&#41;&#46; The evidence is insufficient to establish the role of rituximab in the treatment of LN&#46; Results from the only RCT&#44; which were negative&#44; suggest a clinical benefit in black people&#46; Further studies must confirm this hypothesis&#46; Controlled clinical trials involving adaptive randomization are required to establish the real benefit of rituximab in LN&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La nefritis l&#250;pica &#40;NL&#41; es una complicaci&#243;n com&#250;n y grave del lupus&#46; En la actualidad&#44; la terapia est&#225; basada en inmunosupresores y glucocorticoides&#46; Recientemente se ha planteado como posible tratamiento al rituximab&#44; un anticuerpo monoclonal dirigido contra el ant&#237;geno CD20 de los linfocitos B&#46; El objetivo de la presente revisi&#243;n es recopilar la informaci&#243;n disponible hasta el momento acerca del uso de rituximab en NL&#46; Se encontraron 11 estudios&#44; 3 observacionales &#40;2 prospectivos y uno retrospectivo&#41; y 8 ensayos cl&#237;nicos &#40;7 abiertos y solo uno aleatorizado controlado&#41;&#46; La evidencia es insuficiente para establecer el papel del rituximab en la terapia de la NL&#46; Resultados del &#250;nico ensayo cl&#237;nico aleatorizado y controlado&#44; el cual fall&#243; en demostrar una mejor&#237;a cl&#237;nica significativa&#44; indican un posible beneficio en pacientes de raza negra&#46; Futuros estudios deben confirmar dicha hip&#243;tesis&#46; Se proponen ensayos cl&#237;nicos controlados&#44; con aleatorizaci&#243;n adaptativa&#44; para establecer el verdadero beneficio con rituximab en NL&#46;</p></span>"
      ]
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0055">Please cite this article as&#58; Zurita Gavilanes L&#44; Costa Valarezo A&#46; Rituximab en nefritis l&#250;pica&#58; una revisi&#243;n no sistem&#225;tica&#46; Reumatol Clin&#46; 2016&#59;12&#58;210&#8211;215&#46;</p>"
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        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">CR&#44; complete remission&#59; GFR&#44; glomerular filtration rate&#59; LN&#44; lupus nephritis&#59; MPS&#44; methylprednisolone&#59; PR&#44; partial remission&#59; RTX&#44; rituximab&#59; SLE&#44; systemic lupus erythematosus&#59; UPC&#44; urinary protein to creatine&#59; W&#44; women&#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">Population&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">No&#46; of patients &#40;mean age &#91;years&#93;&#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">Treatment-na&#239;ve patients &#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">Protocol of RTX administration&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">Mean follow-up period&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">Main outcomes &#40;<span class="elsevierStyleItalic">P</span> value&#41;&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">Melander et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> 2009<a class="elsevierStyleCrossRefs" href="#tblfn0005"><span class="elsevierStyleSup">a&#44;b</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">III-V LN according to biopsy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#59; 95&#37; W &#40;25&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4 in 90&#37; of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 35&#37;&#59; PR&#58; 25&#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">Terrier et al&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> 2010<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</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">SLE&#44; 31&#37; con LN&#59; 19&#37; class <span class="elsevierStyleSmallCaps">iii</span> and 52&#46;4&#37; class <span class="elsevierStyleSmallCaps">iv</span> &#40;95&#37; biopsy&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dose in LN patients of the registry not reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#46;6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 45&#37; &#40;&#46;0001&#41;&#59; PR&#58; 29&#37; &#40;&#46;004&#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">Condon et al&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> 2013<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</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">III-V LN according to biopsy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#59; 78&#37; W &#40;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 &#40;with 0&#46;5<span class="elsevierStyleHsp" style=""></span>g MPS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40&#46;75 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 72&#37;&#59; PR&#58; 18&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Retrospective observational study&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">PR&#44; 24-h proteinuria &#62;50&#37; and stabilization of the GFR&#59; CR&#44; proteinuria &#60;0&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;day&#44; absence of hematuria and GFR<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> or improvement of 50&#37; over the basal GFR value&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">PR&#44; improvement by 50&#37; in all the renal parameters &#40;serum creatinine and proteinuria&#41;&#59; CR&#44; decrease in proteinuria to 0&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;day&#44; disappearance of hematuria and normalization of GFR&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">CR&#44; combination of a UPC ratio less than 50<span class="elsevierStyleHsp" style=""></span>mg&#47;mmol and serum creatinine no greater than 15&#37; of baseline level&#59; PC&#44; UPC ratio &#60;300<span class="elsevierStyleHsp" style=""></span>mg&#47;mmol with a reduction &#62;50&#37; with respect to the baseline level and an increase in serum creatine no greater than 15&#37; over the baseline level&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Characteristics of the Observational Studies With Rituximab&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Cr&#44; serum creatinine&#59; CR&#44; complete remission&#59; CYC&#44; cyclophosphamide&#59; IST&#44; immunosuppressive therapy&#59; LN&#44; lupus nephritis&#59; MMF&#44; mycophenolate mofetil&#59; PC&#44; partial remission&#59; PCB&#44; placebo&#59; RTX&#44; rituximab&#59; SLICC&#44; Systemic Lupus International Collaborating Clinics&#59; UPC&#44; urinary protein to creatinine&#59; W&#44; women&#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">LN classification &#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">Response to treatment at the time of RTX therapy&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">No&#46; of patients &#40;mean age in years&#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">Comparator&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">RTX administration protocol&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">Evaluation time points&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">Results&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">Vigna-Perez et al&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> 2006<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</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">III &#40;9&#46;1&#41;&#59; IV &#40;81&#46;8&#41;&#59; V &#40;9&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Disease refractory to treatment Recurrence &#40;9&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&#59; W 86&#46;4&#37; &#40;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IST&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;5&#8211;1<span class="elsevierStyleHsp" style=""></span>g day<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Days 30&#44; 60 and 90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 31&#46;8&#37;&#59; PR&#58; 22&#46;7&#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">Gunnarsson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> 2007<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</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">III &#40;14&#46;3&#41;&#59; IV &#40;85&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Disease refractory to treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#59; W 100&#37; &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 42&#46;9&#37;&#59; PR&#58; 14&#46;3&#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">Li et al&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a> 2009<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">c</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">III &#40;10&#46;5&#41;&#59; IV &#40;15&#46;8&#41;&#59; III<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span> IV &#40;5&#46;3&#41;&#59; III <span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>V &#40;63&#46;2&#41;&#59; IV<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>V &#40;5&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&#58; 9 &#40;40&#46;3&#41;&#59; RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CYC&#58; 10 &#40;39&#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">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX vs RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CYC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Every month for 6 months&#44; every 2 months thereafter for 48 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 21&#37;&#59; PR&#58; 58&#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">Davies et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a> 2013<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</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">III &#40;27&#46;8&#41;&#59; IV &#40;27&#46;8&#41;&#59; V &#40;11&#46;1&#41;&#59; IV <span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>V &#40;22&#46;2&#41;&#59; III <span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>V &#40;11&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Disease refractory to treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#59; W &#40;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CYC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 61&#46;1&#37;&#59; PR&#58; 11&#46;1&#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">J&#243;nsd&#243;ttir et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a> 2013<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">d</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">III or IV &#40;60&#41;&#59; V &#40;36&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Most patients with disease refractory to treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25&#59; W 92&#37; &#40;34&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CYC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Every 2&#8211;3 months the first year&#44; every 6 months thereafter&#46; Mean follow-up 36 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 64&#37;&#59; PR&#58; 24&#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">Moroni et al&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> 2014<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">e</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">III &#40;16&#46;6&#41;&#59; IV &#40;48&#46;1&#41;&#59; V &#40;3&#46;7&#41;&#59; III <span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>V &#40;9&#46;3&#41;&#59; IV<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>V &#40;18&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#37; no treatment&#44; 40&#46;7&#37; recurrence and 9&#46;3&#37; disease refractory to treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MMF&#58; 17 &#40;32&#46;4&#41;&#59; RTX&#58; 17 &#40;31&#46;1&#41;&#59; CYC&#58; 20 &#40;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX vs CYC vs MMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 70&#46;6&#37;&#59; PR&#58; 29&#46;4&#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">Rovin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> 2012 LUNAR<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">f</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">RTX&#58; III &#40;34&#46;7&#41;&#59; IV &#40;65&#46;3&#41;&#59; V alone or in combination &#40;36&#46;1&#41;&#46; PCB&#58; III &#40;33&#46;3&#41;&#59; IV &#40;66&#46;7&#41;&#59; V alone or in combination &#40;31&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No treatment for LN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&#58; 72&#59; W 87&#46;5&#37; &#40;31&#46;8&#41;&#46; PCB&#58; 72&#59; W 93&#46;1&#37; &#40;29&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;PCB&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MMF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PCB vs MMF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>g<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Response at 52 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&#58; 26&#46;4&#37;&#59; PR&#44; 30&#46;6&#37;&#46; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;55&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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            0 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">CR&#44; normal Cr&#44; inactive urinary sediment&#44; proteinuria &#60;0&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;day&#59; PR&#44; improvement &#62;40&#37; in renal parameters compared to the beginning of the study&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">CR&#44; normal Cr&#44; normal serum albumin&#44; inactive urinary sediment&#44; albuminuria &#60;0&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;day&#59; PR&#44; improvement &#8805;50&#37; in renal parameters compared to the beginning of the study&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0035">CR&#44; if the baseline SLICC disease activity index was &#62;0 and was reduced to 0 after follow-up&#59; PR&#44; if the baseline SLICC disease activity index was higher than the index after follow-up&#44; but the latter was not equal to 0&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0040">Response to treatment &#40;CR and PR&#41;&#44; defined in accordance with the 2009 European Consensus Statement on LN&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0045"
              "etiqueta" => "e"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0045">CR&#44; Cr<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>1&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;dL &#40;or return to the baseline value in patients with chronic kidney disease&#41; and proteinuria &#60;0&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;day and &#60;5 urinary red blood cells&#47;high power field&#59; PR&#44; Cr<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>1&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;dL &#40;or return to the baseline value in patients with chronic kidney disease&#41; and proteinuria of 0&#46;5&#8211;2<span class="elsevierStyleHsp" style=""></span>g&#47;day&#46;</p>"
            ]
            5 => array:3 [
              "identificador" => "tblfn0050"
              "etiqueta" => "f"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0050">CR&#44; normal Cr if it was abnormal at the beginning of the study&#44; or a Cr level &#8804;115&#37; of baseline if it was normal at the beginning of the study&#59; inactive urinary sediment &#40;&#60;5 red blood cells&#47;high power field and absence of red blood cell casts&#41;&#44; and UPC ratio &#60;0&#46;5&#59; PR&#44; Cr<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>115&#37; of baseline&#44; urinary red blood cells&#47;high power field &#8804;50&#37; above baseline and no red blood cell casts&#44; and a decrease of at least 50&#37; in the UPC ratio to &#60;1&#46;0 &#40;if the baseline UPC ratio was &#8804;3&#46;0&#41; or to &#8804;3&#46;0 &#40;if the baseline UPC ratio was &#62;3&#46;0&#41;&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Characteristics of the Clinical Trials With Rituximab&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:29 [
            0 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lupus nephritis&#58; an overview of recent findings"
                      "autores" => array:1 [
                        0 => array:2 [
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Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2016.01.001

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	21	20	41
2024 October	100	51	151
2024 September	137	57	194
2024 August	151	85	236
2024 July	215	83	298
2024 June	138	82	220
2024 May	138	64	202
2024 April	115	44	159
2024 March	86	52	138
2024 February	61	42	103
2024 January	70	47	117
2023 December	63	46	109
2023 November	71	36	107
2023 October	79	49	128
2023 September	157	55	212
2023 August	90	31	121
2023 July	75	42	117
2023 June	96	38	134
2023 May	83	36	119
2023 April	63	16	79
2023 March	108	57	165
2023 February	88	31	119
2023 January	97	41	138
2022 December	85	37	122
2022 November	72	33	105
2022 October	81	55	136
2022 September	85	36	121
2022 August	60	47	107
2022 July	46	36	82
2022 June	52	21	73
2022 May	71	45	116
2022 April	59	41	100
2022 March	96	45	141
2022 February	98	39	137
2022 January	92	44	136
2021 December	59	58	117
2021 November	81	49	130
2021 October	160	71	231
2021 September	65	51	116
2021 August	60	55	115
2021 July	92	35	127
2021 June	162	64	226
2021 May	79	72	151
2021 April	208	185	393
2021 March	127	53	180
2021 February	95	44	139
2021 January	71	50	121
2020 December	70	42	112
2020 November	59	30	89
2020 October	52	27	79
2020 September	60	37	97
2020 August	33	26	59
2020 July	35	26	61
2020 June	52	37	89
2020 May	40	20	60
2020 April	29	15	44
2020 March	18	4	22
2020 February	1	0	1
2018 May	4	1	5
2018 April	48	16	64
2018 March	73	13	86
2018 February	35	7	42
2018 January	30	11	41
2017 December	29	13	42
2017 November	34	19	53
2017 October	49	13	62
2017 September	54	16	70
2017 August	38	10	48
2017 July	53	24	77
2017 June	76	25	101
2017 May	72	19	91
2017 April	45	15	60
2017 March	37	25	62
2017 February	32	27	59
2017 January	33	22	55
2016 December	63	49	112
2016 November	63	45	108
2016 October	65	69	134
2016 September	79	43	122
2016 August	135	32	167
2016 July	80	53	133

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