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with the constant region of a human IgG1&#44; is one of the therapeutic alternatives approved for the induction phase in both GPA and MPA&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In recent years&#44; a number of studies have evaluated the use of RTX as maintenance therapy in these vasculitides&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In this review&#44; we examine in detail the available information on the efficacy of RTX in maintaining remission in AAV&#46; For this purpose&#44; we conducted a search in the database of the United States National Library of Medicine &#40;PubMed&#41; for articles in English or Spanish published between January 2001 and January 2015&#46; The terms&#44; included in both languages&#44; were&#58; ANCA&#44; vasculitis&#44; granulomatosis with polyangiitis&#44; microscopic polyangiitis and Wegener&#39;s granulomatosis in combination with rituximab&#44; anti-CD&#44; maintenance therapy and biological therapy&#46; The relevant articles were obtained in their complete version and were reviewed and analyzed by both authors&#46; We also identified noteworthy information in the abstracts of international rheumatology meetings held over the last 5 years&#46; This report does not include the use of RTX in EGPA&#44; which was recently reviewed in this journal&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Maintenance Therapy for Vasculitides Associated With Antibodies Against Neutrophil Cytoplasmic Antigens</span><p id="par0020" class="elsevierStylePara elsevierViewall">The treatment of GPA and MPA consists of two different stages&#44; an induction phase &#40;with intensive immunosuppression&#41; and a maintenance phase&#46; The purpose of the latter is to prevent relapses and limit drug toxicity&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Despite the fact that initial treatment with cyclophosphamide &#40;CPM&#41;&#44; RTX or methotrexate &#40;MTX&#41; in combination with high-dose glucocorticoids &#40;GC&#41; achieves partial or complete remission in 75&#37;&#8211;90&#37; of the patients with AAV&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> 11&#37;&#8211;57&#37; of them have relapses while they are being treated with azathioprine &#40;AZA&#41; or MTX alone&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8</span></a> Although the majority are mild&#44; some can be severe&#44; and may provoke additional organ damage&#44; permanent functional sequelae or even death&#46; In addition to the complications inherent to the disease&#44; 40&#37; of the patients develop adverse effects related directly to the therapy employed&#44; for example&#44; osteoporosis or cardiovascular complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">With this scenario&#44; the need to improve certain aspects of maintenance therapy is evident&#46; Especially important among the unresolved matters are&#58; &#40;1&#41; optimization of dose reduction and duration of therapy with the drugs employed&#44; as most of the relapses occur during the tapering of GC and&#47;or immunosuppressive agents &#40;IS&#41; or once they have been discontinued<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#59; &#40;2&#41; early identification of patients at high risk for relapse&#44; for example&#44; those with GPA&#44; upper respiratory tract disease&#44; PR3-ANCA positivity&#44; nasal colonization by <span class="elsevierStyleItalic">Staphylococcus aureus</span> or persistence of ANCA when AZA is initiated<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#8211;16</span></a>&#59; &#40;3&#41; development of individualized treatments in which not only the clinical and ethnical differences are taken into account&#44; but the histological&#44; serological and genetic associations as well<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;17</span></a>&#59; and &#40;4&#41; evaluation of new drugs&#44; such as abatacept &#40;clinicaltrials&#46;gov&#44; <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02108860">NCT02108860</a>&#41;&#44; belimumab &#40;BREVAS study&#44; <a id="intr0015" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01663623">NCT01663623</a>&#41; or RTX&#44; the drug being evaluated here&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">The Basis for the Use of Rituximab in Vasculitides Associated With Antibodies Directed Against Neutrophil Cytoplasmic Antigen</span><p id="par0035" class="elsevierStylePara elsevierViewall">The evidence at different levels indicates that the B lymphocytes play a very important role in AAV&#58; &#40;1&#41; the number of activated B cells is associated with the disease activity and severity<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#59; &#40;2&#41; ANCA&#44; antibodies possibly involved in the pathogenesis of these vasculitides&#44; are produced by B lymphocytes<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a>&#59; &#40;3&#41; in nasal&#44; lung and orbital biopsies from patients with GPA&#44; self-reactive B cells have been identified&#44; adjacent to PR3-ANCA-positive cells&#44; which form structures similar to lymphoid follicles that disappear after treatment with RTX<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#8211;24</span></a>&#59; and &#40;4&#41; B lymphocytes are the main target of CPM&#44; a drug that is essential in the treatment of these vasculitides&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The binding of RTX to CD20 provokes the rapid and sustained depletion of premature and mature B lymphocytes &#40;reducing the plasma cell precursors&#41; through diverse mechanisms&#44; which include antibody-mediated cellular cytotoxicity &#40;mediated by macrophages and natural killer cells&#41;&#44; complement-mediated lysis&#44; induction of apoptosis and sensitization to GC and cytotoxic agents&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Moreover&#44; the drug is capable of inhibiting the interaction between self-reactive B and T cells and increasing the regulatory T lymphocyte population&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#8211;30</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Rituximab as Maintenance Therapy</span><p id="par0045" class="elsevierStylePara elsevierViewall">Information on the use of RTX as maintenance therapy derives from the MAINRITSAN &#40;Maintenance of Remission using Rituximab in Systemic ANCA-associated vasculitis&#41; trial&#44; a recent randomized clinical trial&#44; as well as from certain observational studies &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Clinical Trials</span><p id="par0050" class="elsevierStylePara elsevierViewall">MAINRITSAN is the first and only randomized study to compare RTX and AZA as maintenance therapy in patients with GPA &#40;n<span class="elsevierStyleMonospace">&#61;</span>87&#41;&#44; MPA &#40;n<span class="elsevierStyleMonospace">&#61;</span>23&#41; or renal-limited vasculitis &#40;n<span class="elsevierStyleMonospace">&#61;</span>5&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> The study &#40;controlled&#44; open and multicenter&#41; included 115 patients &#40;80&#37; with new diagnosis&#44; 20&#37; with recurrent disease&#41; in complete remission after induction therapy with GC and CPM&#46; The maintenance protocol was based on the administration of prednisone &#40;approximately 5<span class="elsevierStyleHsp" style=""></span>mg&#47;day for at least 18 months&#41; in combination with AZA &#40;n<span class="elsevierStyleMonospace">&#61;</span>58&#44; 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for 1 year&#44; 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for 6 months and 1&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for the last 4 months&#41; or RTX &#40;n<span class="elsevierStyleMonospace">&#61;</span>57&#44; 500<span class="elsevierStyleHsp" style=""></span>mg initially on days 0 and 14 and&#44; thereafter&#44; every 6 months&#44; for a total of 5 applications&#41;&#46; The percentage of patients with severe relapses &#40;recurrence or worsening of the vasculitis with manifestations that were life-threatening or affected an essential organ&#44; like the brain or heart&#41; after 28 months of follow-up &#40;primary endpoint&#41; was 5&#37; &#40;n<span class="elsevierStyleMonospace">&#61;</span>3&#41; among patients treated with RTX and 29&#37; &#40;n<span class="elsevierStyleMonospace">&#61;</span>17&#41; among those treated with AZA&#44; demonstrating a clear superiority of the monoclonal antibody &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41;&#46; Among the patients who relapsed with AZA&#44; in 8 it occurred during the first year&#59; in 2&#44; between months 12 and 22&#59; and in 7&#44; after the complete discontinuation of the medication &#40;months 24&#8211;28&#41;&#46; In the case of RTX&#44; there was 1 relapse per month in months 8&#44; 22 and 24&#46; With respect to minor relapses&#44; there were no significant differences between the two groups in terms of the rate of adverse events or the incidence of infections&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although the results of the study with RTX are very promising&#44; with one of the lowest rates of relapse reported in these vasculitides&#44; it strikes us as interesting that 41&#37; of the flares recorded in the AZA group occurred when the patients were no longer receiving the medication&#44; possibly causing the therapeutic effect of the drug to be underestimated&#46; However&#44; the protocol for maintenance with AZA is similar to that utilized previously in two large-scale clinical trials involving the same type of patients&#44; and the results of which are similar to those observed in the MAINRITSAN trial&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;8</span></a> As occurs with other IS&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> treatment with AZA or RTX for a longer period of time than that evaluated in the MAINRITSAN trial could be related to a higher rate of sustained remissions&#44; a possibility that should be examined in clinical trials with longer follow-up times&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In short&#44; the MAINRITSAN trial showed that the combination of low doses of GC and RTX at fixed intervals &#40;every 6 months&#44; which is the average duration of the therapeutic effect<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&#41; can be considered a valid&#44; effective and safe alternative for maintenance of remission in patients with AAV&#44; mainly those with newly diagnosed GPA&#46; At the present time&#44; two clinical trials to evaluate RTX as maintenance therapy are being developed&#46; The first&#44; MAINRITSAN 2 &#40;clinicaltrials&#46;gov <a id="intr0020" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01731561">NCT01731561</a>&#41;&#44; will compare two strategies for RTX administration &#40;500<span class="elsevierStyleHsp" style=""></span>mg at fixed intervals of 6 months vs 500<span class="elsevierStyleHsp" style=""></span>mg whenever increases in CD19&#43; lymphocytes or ANCA are detected&#41;&#46; The other study&#44; RITAZAREM &#40;Rituximab Vasculitis Maintenance Study&#41; &#40;<a id="intr0025" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01697267">NCT01697267</a>&#41;&#44; will evaluate patients with refractory AAV receiving RTX &#40;1<span class="elsevierStyleHsp" style=""></span>g every 4 months&#41; or AZA for 2 years&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Observational Studies</span><p id="par0065" class="elsevierStylePara elsevierViewall">The studies that are to be reviewed below disclose certain differences and limitations that should be taken into account for a correct interpretation of the conclusions derived from them&#46; These series evaluated heterogeneous populations&#44; the dose and regimen of RTX administration varied&#44; and there are differences in the reported maintenance protocols&#44; as the drug was utilized&#58; &#40;1&#41; at fixed intervals in a so-called <span class="elsevierStyleItalic">prevention</span> strategy&#59; &#40;2&#41; depending on serological markers&#44; such as an increase in the ANCA level or B lymphocyte reconstitution&#59; or &#40;3&#41; only at the time of relapses&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Rituximab at Fixed Intervals &#40;Preventive&#41;</span><p id="par0070" class="elsevierStylePara elsevierViewall">This strategy has become that most widely used in recent years&#44; and rates of sustained remission &#40;follow-up of 36&#8211;48 months&#41; of 74&#37;&#8211;100&#37; have been reported &#40;in comparison with the 19&#37;&#8211;56&#37; in patients not treated regularly with RTX&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;45</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the features of the major studies&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Although the doses and intervals vary&#44; the administration of 1<span class="elsevierStyleHsp" style=""></span>g every 4&#8211;6 months for 2 years is the regimen that is most frequently used&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;39&#8211;42</span></a> In some protocols&#44; RTX was continued for more than 24 months&#44; meaning that these patients may have received &#8805;10 cycles of the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;40&#44;43</span></a> In contrast to the MAINRITSAN randomized clinical trial&#44; in the great majority of the observational studies&#44; the predominant study population consisted of patients with recurrent or refractory GPA &#40;mean age of 40&#46;5&#8211;52 years&#41;&#44; and the number of newly diagnosed patients was lower&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;41&#44;44</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">With this form of administration&#44; the average time between relapses and the first and last doses of the monoclonal antibody was 11&#8211;29 months and 9&#8211;15 months&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;37&#44;42&#8211;45</span></a> Interestingly&#44; a study with an extensive follow-up period &#40;5 years&#41; demonstrated that&#44; after discontinuation of the medication &#40;24 months&#41;&#44; 50&#37; of the patients remained in sustained remission&#44; whereas the remainder relapsed 3 years after the last dose of RTX&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">With regard to drug toxicity&#44; although the cumulative dose of the drug is greater in these patients&#44; the rate of adverse effects &#40;including infections&#41; is similar to that reported in studies in which RTX was administered only during relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;45</span></a> However&#44; it should be stressed that one limitation of preventive maintenance with RTX is the risk of overtreatment of those patients &#40;approximately 40&#37;&#41; who have prolonged remission after a single cycle of induction with RTX&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> Unfortunately&#44; to date there is no way to identify those patients&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Another important datum derived from these studies is that&#44; in the majority of the reported patients&#44; the <span class="elsevierStyleItalic">preventive</span> use of RTX permits the reduction of the prednisone dose &#40;initially 20&#8211;30<span class="elsevierStyleHsp" style=""></span>mg&#47;once daily to &#60;5<span class="elsevierStyleHsp" style=""></span>mg&#47;once daily&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;40&#44;41&#44;43&#44;44</span></a> Moreover&#44; 70&#37;&#8211;90&#37; of the patients treated were able to completely discontinue all other immunosuppressive therapy &#40;mycophenolate mofetil&#44; AZA or MTX&#41; and 21&#37;&#8211;48&#37; were able to discontinue treatment with GC&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;39&#44;41&#44;43&#44;45</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In this respect&#44; it is important to point out the adjuvant role that the classical IS could play in maintenance therapy with RTX&#44; mainly in patients with recurrent or refractory disease&#46; The administration of AZA&#44; MTX&#44; leflunomide or mycophenolate mofetil in combination with RTX as maintenance therapy has been reported in a number of uncontrolled studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;40&#44;44&#44;45&#44;47</span></a> A study with a considerable number of GPA patients &#40;n<span class="elsevierStyleMonospace">&#61;</span>89&#41; reported that&#44; after 2 years of follow-up&#44; those patients treated with AZA or MTX in combination with RTX had a significantly lower rate of relapses than those treated with RTX alone &#40;55&#37; vs 70&#37;&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;04&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> These results contrast with those of the subanalysis of 40 patients from the series of Rhee et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> in which the systematic discontinuation of the IS prior to starting treatment with RTX was not associated with an increased frequency of flares&#46; With respect to the therapeutic complications&#44; some studies have reported that the concomitant use of mycophenolate mofetil and&#44; mainly&#44; CPM is related to a higher predisposition toward severe infections&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> whereas&#44; in other series&#44; there was no increase in the number of adverse events&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> At the present time&#44; the available data do not lead to a clear conclusion about the adjuvant use of IS with RTX&#59; however&#44; it is advisable to avoid the combination of the latter with CPM at full doses&#44; due to the increase in the number of severe adverse events&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Rituximab Based on Biomarker Levels</span><p id="par0100" class="elsevierStylePara elsevierViewall">A retrospective study of GPA patients &#40;n<span class="elsevierStyleMonospace">&#61;</span>53&#41; with refractory disease &#40;40&#37; granulomatous activity&#44; 60&#37; vasculitic&#41; compared the administration of RTX only in the case of new relapse &#40;36&#37;&#41; with an individualized protocol &#40;64&#37;&#41; involving infusion of the drug on the basis of the increase in PR3-ANCA or B lymphocytes in serial measurements&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> At the end of the follow-up period &#40;median 4&#46;4 years&#44; interquartile range 2&#46;7&#8211;6&#46;2&#41;&#44; there were no episodes of reactivation among the patients treated on the basis of the change in ANCA titer or B lymphocyte repopulation &#40;average of 4 cycles of RTX received&#41; in contrast to 32 relapses &#40;relapse rate&#58; 13&#46;8&#47;100 patient years&#41; in the group of patients in which the drug was not administered on a regular basis&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Rituximab in Relapses</span><p id="par0105" class="elsevierStylePara elsevierViewall">The follow-up of the patients treated with a single RTX cycle in the RAVE &#40;Rituximab in ANCA-associated vasculitis&#41; trial demonstrated that&#44; although the results with this approach are similar to those obtained with the CPM&#47;AZA combination&#44; it is not sufficient to maintain prolonged remission&#44; as approximately 60&#37; of the patients will relapse during follow-up &#40;18 months&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;46</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In the light of this evidence&#44; at some centers&#44; retreatment with RTX was adopted as a therapeutic measure only in cases of relapse&#44; and it was observed that the drug &#40;at the dose for lymphoma or rheumatoid arthritis &#91;RA&#93;&#41; is usually equally as effective &#40;and safe&#41; as the initial anti-CD20 therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;36&#44;49</span></a> In the open phase of the RAVE trial&#44;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;50</span></a> 26 patients &#40;92&#37; GPA&#41; received RTX for severe relapses between month 6 and month 18 of the study&#44; and remission was achieved in approximately 90&#37; of the cases &#40;50&#37; were also able to discontinue the concomitant use of GC&#41;&#46; These studies have also shown that RTX is more effective than CPM in maintaining remission in patients with previous recurrent disease&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Although treatment of relapses with RTX appears to be effective&#44; this approach to the administration has the disadvantage that the patients are exposed to the damage derived from the disease&#44; and possibly to higher cumulative doses of prednisone &#40;a drug that is usually increased as an initial measure&#41;&#46; Moreover&#44; given that RTX is usually administered full-dose for induction&#44; this could entail an additional economic cost as compared with single&#44; smaller doses administered once or twice a year&#44; as in the <span class="elsevierStyleItalic">prevention</span> protocols&#46;</p></span></span></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Predictors of Relapses Following Treatment With Rituximab</span><p id="par0120" class="elsevierStylePara elsevierViewall">One persistent question is whether there are biomarkers capable of accurately predicting which patients will relapse during treatment with RTX&#46; Up to now&#44; conclusions based on the evaluation of the two laboratory tests most widely examined &#40;B lymphocyte and ANCA levels&#41; are quite unclear&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;39&#44;45&#44;51</span></a> with publications that argue in favor<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;49&#44;52&#44;53</span></a> and against<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a> their utility&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Determination of Antineutrophil Cytoplasmic Antibodies</span><p id="par0125" class="elsevierStylePara elsevierViewall">In the vast majority of the reported series&#44; it has not been possible to establish a relationship between the change in ANCA levels and the development of recurrence&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;34&#44;36&#44;37&#44;39&#44;41&#44;44&#44;45&#44;50&#44;54&#8211;56</span></a> In these studies&#44; the percentages of patients who became ANCA-positive or in whom the levels increased&#44; and who had relapses or remained in remission ranged from 33&#37; to 77&#37; and from 38&#37; to 66&#37;&#44; respectively&#44; which shows that the sensitivity of this variable is too low to serve as the basis for decisions on maintenance therapy&#46; The only study that found an association between ANCA levels and recurrences reported that seroconversion to ANCA positivity during the post-RTX period was associated with a 7-fold higher risk of having severe relapses&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">With respect to the specificity of ANCA&#44; it has recently been reported that the presence of PR3-ANCA&#44; but not a change in the levels of these antibodies&#44; was related to higher long-term risk of relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;43&#44;46&#44;50</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">One important conclusion derived from the RAVE extension studies is that the possibility of RTX-treated patients having a relapse is extremely low as long as the assays for ANCA are negative and B lymphocytes remain undetectable in peripheral blood&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;50</span></a> In fact&#44; only 1 of the 76 patients included in these studies had a flare while these two markers were below the level of detection&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">B Lymphocytes</span><p id="par0140" class="elsevierStylePara elsevierViewall">As in the case of ANCA&#44; the levels of these cells in peripheral blood have not been shown to be an accurate enough test for the prediction of flares&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;37&#44;39&#44;41&#44;44&#44;56</span></a> Depending on the study analyzed&#44; the reported finding is that approximately 50&#37; of the relapses occur prior to B cell repopulation&#44; that 44&#37;&#8211;88&#37; of the patients who relapse have detectable B lymphocytes&#44; and that between 25&#37; and 66&#37; of those patients in whom normal levels of B lymphocytes are detected do not have relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;34&#44;36&#44;37&#44;45&#44;46</span></a> Moreover&#44; the time between B cell reconstitution and the development of relapses is not constant either&#59; some patients relapse coinciding with lymphocyte repopulation&#44; whereas in others&#44; it may take some time &#40;average 80<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>85 days&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">One of the few series in which a good correlation was found between AAV reactivation and B lymphocyte repopulation reported that the development of flares &#40;n<span class="elsevierStyleMonospace">&#61;</span>32&#41; was always preceded by the detection of these cells in peripheral blood&#44; with a median between the two events of 8&#46;5 months&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Interestingly&#44; in this report&#44; all the recurrences were preceded by or associated with an increase in PR3-ANCA&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">A recent report found that those patients in whom B lymphocytes were detectable within the first year after treatment with RTX had shorter periods of remission than those in whom repopulation took over 12 months&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The possible hypotheses to explain the poor correlation between the number of B lymphocytes and the AAV activity include&#58; &#40;1&#41; the existence of niches or &#8220;sanctuary sites&#8221; for self-reactive B cells in tissues or sites of active inflammation &#40;mainly granulomatous&#41;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&#59; these cell groups would be protected from the pharmacological action of RTX&#44; remaining active before an increase in lymphocytes was observed in peripheral blood<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;58</span></a>&#59; &#40;2&#41; changed dynamics in B cell levels due to a synergic effect between RTX and other conventional IS&#44; such as AZA or CPM&#44; that are frequently administered to patients with resistant or refractory disease<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&#59; &#40;3&#41; racial differences between the populations studied&#44; as the elimination of the B lymphocytes depends not only on the RTX dose&#44; but on polymorphisms in the cell surface receptors &#40;Fc&#947;RIIIa&#41;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a>&#59; and &#40;4&#41; differing definitions from one study to another&#44; with varied absolute values for peripheral blood B cells and diverse phenotypes evaluated &#40;CD19&#43; or CD20&#43;&#41;&#44; as a consequence of the use of detection techniques &#40;flow cytometry&#41; with greater or lesser sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">New Biomarkers</span><p id="par0160" class="elsevierStylePara elsevierViewall">A recent publication stated that the detailed phenotypic analysis of subpopulations of B lymphocytes might have the potential to predict relapses&#46; In a study of 54 patients with AAV&#44; it was observed that when &#60;30&#37; of the B lymphocyte repopulation was constituted by CD5&#43; cells &#40;possibly regulatory B cells&#41;&#44; the time to the first recurrence was shorter&#46; This cell subpopulation also correlated negatively with the general disease activity&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Similarly&#44; it has been reported that&#44; when the B lymphocyte reconstitution is composed mainly of memory cells&#44; there is an increased risk of recurrences&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> This is similar to what occurs in systemic lupus erythematosus&#44; in which repopulation with a higher proportion of CD27&#43; B lymphocytes &#40;memory cells&#41; has been related to a higher risk of flares&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">62&#44;63</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Safety</span><p id="par0165" class="elsevierStylePara elsevierViewall">The experience accumulated in the treatment of hematologic neoplasms and RA indicates that RTX has a good margin of safety&#46; The situation in AAV appears to be similar&#44; although the long-term safety of repeated RTX administration has yet to be established&#44; as the majority of the studies have a relatively short follow-up period&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In maintenance studies&#44; anti-CD20&#43; therapy provoked adverse effects in 13&#37;&#8211;60&#37; of the patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;42&#44;43</span></a> with severe infections&#44; hypogammaglobulinemia&#44; severe neutropenia or a lack of efficacy being the main causes of discontinuation&#44; temporary or definitive&#44; of the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44&#44;45</span></a></p><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Reactions Associated With the Administration of Rituximab</span><p id="par0175" class="elsevierStylePara elsevierViewall">Mild allergic reactions are the adverse effect most frequently observed &#40;10&#37;&#8211;50&#37; of the patients&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;64&#44;51</span></a> They usually occur within the first 24<span class="elsevierStyleHsp" style=""></span>h after treatment&#44; and the manifestations are fever&#44; chills&#44; hyper- or hypotension&#44; fatigue&#44; headache&#44; erythema&#44; urticaria&#44; nausea and&#47;or vomiting&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;51</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Infections</span><p id="par0180" class="elsevierStylePara elsevierViewall">These are the most important complications&#44; and mild or severe infections are reported in 7&#37;&#8211;50&#37; of the patients &#40;incidence of 2&#46;6&#8211;15&#46;5&#47;100 patient years&#44; similar to that of CPM&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;36&#44;37&#44;42&#44;46&#44;49&#44;50&#44;56&#44;57&#44;65&#8211;67</span></a> The most common infections are those of the respiratory tract &#40;mainly of viral origin&#41; and the urinary tract&#44; followed by mucocutaneous infections &#40;herpes simplex&#44; herpes zoster and candidiasis&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;36&#44;37&#44;41&#44;46&#44;49&#44;50&#44;65</span></a> Although the majority of these episodes are mild&#44; 14&#37;&#8211;27&#37; are severe and 3&#37;&#8211;29&#37; of the patients develop chronic infections&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;42&#8211;45</span></a> Infections due to opportunistic microorganisms are rare&#44; and RTX is a safe alternative in patients with a history of tuberculosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;39&#44;68</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The reported risk factors for the development of severe infections in these patients are high cumulative doses of CPM and the combination of RTX with other cytotoxic drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;69</span></a> Although the presence of neutropenia or hypogammaglobulinemia could be associated with increased susceptibility to infectious complications&#44; at present&#44; there is no convincing evidence to prove this&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38&#44;44</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Hypogammaglobulinemia</span><p id="par0190" class="elsevierStylePara elsevierViewall">This adverse effect has been reported in 26&#37;&#8211;41&#37; of the patients at some point during maintenance with RTX&#44; but is a transient and self-limiting event in more than 50&#37; of the cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;43&#44;70</span></a></p><p id="par1185" class="elsevierStylePara elsevierViewall">In the majority of the patients&#44; the most marked decrease in the immunoglobulin level was observed during the initial treatment cycles &#40;60&#37; of all the episodes occurring with total doses &#8804;2<span class="elsevierStyleHsp" style=""></span>g and 70&#37; of those with doses &#8804;6<span class="elsevierStyleHsp" style=""></span>g&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Although hypogammaglobulinemia is usually mild to moderate&#44; approximately 7&#37; of the patients have a severe and&#47;or permanent deficiency&#44; requiring discontinuation of the drug and its substitution by intravenous gammaglobulin&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;44&#44;57&#44;51&#44;72</span></a> In this respect&#44; this adverse effect has not been directly related to an increase in the development of severe infections&#44;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38&#44;44</span></a> although it could be a contributing factor in patients with other predisposing conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Among the risk factors that have been associated with the presence of hypogammaglobulinemia&#44; we point out a high cumulative dose of CPM &#40;prior to the initiation of RTX&#41;&#44; low baseline immunoglobulin and CD4&#43; levels&#44; and the concomitant use of the monoclonal antibody with cytotoxic drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;70</span></a> Interestingly&#44; some studies have related hypogammaglobulinemia to the number of RTX cycles&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74&#44;75</span></a> However&#44; this finding has not been corroborated in series with longer follow-up periods&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;51&#44;70&#44;71</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Late-onset Neutropenia</span><p id="par0205" class="elsevierStylePara elsevierViewall">This develops in 3&#37;&#8211;5&#37; of the patients and is generally transient&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In the majority of the cases&#44; it has no effect on the patient&#39;s clinical status&#44; although there may be cases in which the use of a colony-stimulating factor is required&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;44&#44;76&#44;77</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Other Adverse Effects</span><p id="par0210" class="elsevierStylePara elsevierViewall">The published literature includes cases of pancytopenia&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;39</span></a> macular edema<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> and severe pulmonary complications &#40;interstitial disease&#41; in patients with AAV&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Moreover&#44; there are reports of progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus and RA&#44;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">79&#44;80</span></a> and a case &#40;unpublished&#41; of this complication in AAV has been detected&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conclusions</span><p id="par0215" class="elsevierStylePara elsevierViewall">Rituximab has been shown to be effective and safe for use as maintenance therapy in AAV&#44; both in recently diagnosed disease and in patients with frequent relapses&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> On the basis of the information published to date&#44; the administration of 500<span class="elsevierStyleHsp" style=""></span>mg at fixed intervals &#40;twice a year&#41; could be the recommended mode of administration&#44; because of its marked efficacy and safety&#46; However&#44; lower doses may also prove to be effective in the maintenance of remission&#44; as has been reported in other diseases&#44;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">81&#44;82</span></a> or at wider intervals between applications&#46; This could be guided with the utilization of more reliable biomarkers&#44; as well as the individual response to the treatment&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">It still remains to be determined whether the drug is more effective in specific groups&#44; for example&#44; in women of childbearing age or patients susceptible to frequent relapses or with a higher risk of infections&#46; The optimal duration of maintenance with RTX should also be studied&#46; In this respect&#44; and by analogy with conventional treatment&#44; a period of between 18 and 24 months is recommended&#44; although&#44; at the present time&#44; there is nothing conclusive regarding this question&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Finally&#44; we still have yet to know what effect cumulative doses can have and the economic impact of different administration protocols&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Ethical Disclosures</span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Protection of human and animal subjects</span><p id="par0225" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Confidentiality of data</span><p id="par0230" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Right to privacy and informed consent</span><p id="par0235" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflicts of Interest</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors declare they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres599026"
          "titulo" => "Abstract"
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              "identificador" => "abst0005"
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        1 => array:2 [
          "identificador" => "xpalclavsec613495"
          "titulo" => "Keywords"
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          "titulo" => "Resumen"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0130"
          "titulo" => "Maintenance Therapy for Vasculitides Associated With Antibodies Against Neutrophil Cytoplasmic Antigens"
        ]
        6 => array:2 [
          "identificador" => "sec0135"
          "titulo" => "The Basis for the Use of Rituximab in Vasculitides Associated With Antibodies Directed Against Neutrophil Cytoplasmic Antigen"
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        7 => array:3 [
          "identificador" => "sec0020"
          "titulo" => "Rituximab as Maintenance Therapy"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Clinical Trials"
            ]
            1 => array:3 [
              "identificador" => "sec0030"
              "titulo" => "Observational Studies"
              "secciones" => array:3 [
                0 => array:2 [
                  "identificador" => "sec0035"
                  "titulo" => "Rituximab at Fixed Intervals &#40;Preventive&#41;"
                ]
                1 => array:2 [
                  "identificador" => "sec0040"
                  "titulo" => "Rituximab Based on Biomarker Levels"
                ]
                2 => array:2 [
                  "identificador" => "sec0045"
                  "titulo" => "Rituximab in Relapses"
                ]
              ]
            ]
          ]
        ]
        8 => array:3 [
          "identificador" => "sec0140"
          "titulo" => "Predictors of Relapses Following Treatment With Rituximab"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Determination of Antineutrophil Cytoplasmic Antibodies"
            ]
            1 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "B Lymphocytes"
            ]
            2 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "New Biomarkers"
            ]
          ]
        ]
        9 => array:3 [
          "identificador" => "sec0070"
          "titulo" => "Safety"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Reactions Associated With the Administration of Rituximab"
            ]
            1 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Infections"
            ]
            2 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Hypogammaglobulinemia"
            ]
            3 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Late-onset Neutropenia"
            ]
            4 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Other Adverse Effects"
            ]
          ]
        ]
        10 => array:2 [
          "identificador" => "sec0100"
          "titulo" => "Conclusions"
        ]
        11 => array:3 [
          "identificador" => "sec0105"
          "titulo" => "Ethical Disclosures"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0110"
              "titulo" => "Protection of human and animal subjects"
            ]
            1 => array:2 [
              "identificador" => "sec0115"
              "titulo" => "Confidentiality of data"
            ]
            2 => array:2 [
              "identificador" => "sec0120"
              "titulo" => "Right to privacy and informed consent"
            ]
          ]
        ]
        12 => array:2 [
          "identificador" => "sec0125"
          "titulo" => "Conflicts of Interest"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2015-04-05"
    "fechaAceptado" => "2015-06-07"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec613495"
          "palabras" => array:6 [
            0 => "Rituximab"
            1 => "Anti-neutrophil cytoplasmic antibodies"
            2 => "Treatment"
            3 => "Maintenance"
            4 => "Granulomatosis with polyangiitis"
            5 => "Microscopic polyangiitis"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec613494"
          "palabras" => array:6 [
            0 => "Rituximab"
            1 => "Anticuerpos anticitoplasma de neutr&#243;filo"
            2 => "Tratamiento"
            3 => "Mantenimiento"
            4 => "Granulomatosis con poliangitis"
            5 => "Poliangitis microsc&#243;pica"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">ANCA-associated vasculitides &#40;AAV&#41; are chronic autoimmune diseases characterized by inflammation and destruction of small vessels&#46; Rituximab is now licensed for use as a remission-induction agent in the treatment of these disorders&#46; During recent years&#44; several non-controlled studies have suggested that rituximab may be of value in maintaining disease remission in AAV&#46; In these series&#44; 3 techniques have been tried&#58; &#8220;watch-and-wait&#8221;&#44; repeated cycles in fixed intervals&#44; or administration based on proposed biomarkers&#46; More importantly&#44; the results of the MAINRITSAN trial showed that this anti-CD20 agent is superior to azathioprine for preventing major relapses in AAV&#46; This review summarizes current information regarding the effectiveness&#44; timing&#44; dosing&#44; duration and safety of rituximab as a valid option for remission maintenance&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Las vasculitis asociadas a ANCA son enfermedades autoinmunes cr&#243;nicas que se caracterizan por inflamaci&#243;n y destrucci&#243;n de vasos de peque&#241;o tama&#241;o&#46; El rituximab es un tratamiento efectivo para la fase de inducci&#243;n de estas patolog&#237;as&#46; Durante los &#250;ltimos a&#241;os&#44; varios estudios no controlados han reportado que tambi&#233;n es eficaz durante la fase de mantenimiento terap&#233;utico&#46; En estas series&#44; el f&#225;rmaco se administr&#243; solo durante las reca&#237;das&#44; a intervalos fijos o sobre la base en cambios en algunos biomarcadores&#46; Los resultados del estudio MAINRITSAN mostraron que el rituximab es superior a la azatioprina como terapia de mantenimiento en estas enfermedades&#46; Este trabajo de revisi&#243;n resume la informaci&#243;n m&#225;s reciente sobre el uso de rituximab como opci&#243;n para la fase de mantenimiento de las vasculitis asociadas a ANCA&#44; detallando su efectividad&#44; los diversos protocolos de administraci&#243;n&#44; el perfil de seguridad y el uso potencial de biomarcadores para guiar el tratamiento&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Alba MA&#44; Flores-Su&#225;rez LF&#46; Rituximab como terapia de mantenimiento en las vasculitis asociadas a ANCA&#58; &#191;c&#243;mo&#44; cu&#225;ndo y por qu&#233;&#63; Reumatol Clin&#46; 2016&#59;12&#58;39&#8211;46&#46;</p>"
      ]
    ]
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      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">All the reported series are observational cohorts from a single center&#44; except &#40;9&#41; &#40;multicenter retrospective&#41;&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">AE&#58; adverse events&#59; CPM&#58; cyclophosphamide&#59; Dx&#58; diagnosis&#59; GC&#58; glucocorticoids&#59; GPA&#58; granulomatosis with polyangiitis&#59; IS&#58; immunosuppressive agents&#59; MPA&#58; microscopic polyangiitis&#59; MTX&#58; methotrexate&#59; Rec&#47;Ref&#58; recurrent&#47;refractory&#59; Ref&#58; reference&#59; RTX&#58; rituximab&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Modified from Keogh et al&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> and McAdoo and Pusey&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a></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">Reference-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">Follow-up &#40;months&#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">Study 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">Induction<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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 maintenance regimen<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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">Relapses&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">Safety&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">Comment&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" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> 2010&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 &#40;n<span class="elsevierStyleMonospace">&#61;</span>39&#41;24 months &#40;n<span class="elsevierStyleMonospace">&#61;</span>20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPA&#47;MPARec&#47;Ref&#40;n<span class="elsevierStyleMonospace">&#61;</span>39&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or 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 every 4 months for 2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;6&#37;Relapse rate&#58; 5&#46;0&#47;100 patient-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#37; severe AE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Decrease of 87&#37; in 30&#37; of patients with IS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38 &#40;21&#8211;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPA &#40;85&#37;&#41;&#47;MPARec&#47;Ref &#40;90&#37;&#41;New Dx &#40;10&#37;&#41;&#40;n<span class="elsevierStyleMonospace">&#61;</span>28&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or RTX or MTX&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> every 6 months &#40;n<span class="elsevierStyleMonospace">&#61;</span>13&#41;1<span class="elsevierStyleHsp" style=""></span>g biannual &#40;n<span class="elsevierStyleMonospace">&#61;</span>4&#41;1<span class="elsevierStyleHsp" style=""></span>g every 12 months &#40;n<span class="elsevierStyleMonospace">&#61;</span>3&#41;Other regimens &#40;n<span class="elsevierStyleMonospace">&#61;</span>8&#41;Average infusions&#58; 4 &#40;2&#8211;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#37;Relapse rate&#58; 2&#46;0&#47;100 patient-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 severe AE &#40;infection&#41;3 patients with mild infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Concomitant use of IS in more than 50&#37; of the patients treated with RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52&#46;8 &#40;32&#46;4&#8211;74&#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">GPARec&#47;Ref&#40;n<span class="elsevierStyleMonospace">&#61;</span>53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or RTX&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>&#47;week<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4 &#40;90&#37;&#41; or 1<span class="elsevierStyleHsp" style=""></span>g every 2 weeks<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 &#40;10&#37;&#41; when there was reconstitution of B lymphocytes or increase in PR3-ANCA vs RTX only in relapses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#37; patients treated according to a <span class="elsevierStyleItalic">preventive</span> strategy vs 32 relapses in patients not managed by protocol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 infections &#40;9 in respiratory tract&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment based on biomarkersAll the flares preceded by increase in ANCA or B lymphocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">55 &#40;19&#8211;62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPA&#47;MPARec&#47;Ref&#40;n<span class="elsevierStyleMonospace">&#61;</span>73&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multiple&#44; including biologic&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 every 6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 years &#40;n<span class="elsevierStyleMonospace">&#61;</span>45&#41; vs RTX only in relapses &#40;n<span class="elsevierStyleMonospace">&#61;</span>28&#41;Cumulative dose in patients treated regularly&#58; 6 &#40;2&#8211;11&#41; g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#37; in patients treated according to a <span class="elsevierStyleItalic">preventive</span> strategy vs 72&#37; not managed by protocol at 24 months &#40;26&#37; vs 81&#37; at 48 months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe AE 47&#37; RTX vs 32&#37; non-RTX &#40;severe infections 27&#37; vs 21&#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">Considerable decrease in GC&#44; 38&#37; discontinue completelyIS are discontinued in 95&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> 2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">47 &#40;2&#8211;88&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPARec&#47;Ref &#40;80&#37;&#41;New Dx &#40;20&#37;&#41;&#40;n<span class="elsevierStyleMonospace">&#61;</span>35&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">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 every 15 days once a year1<span class="elsevierStyleHsp" style=""></span>g biannualCumulative dose&#58; 8 &#40;2&#8211;13&#41; g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23&#37;Relapse rate&#58; 6&#46;6&#47;100 patient-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#37; severe infections37&#37; discontinue RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GC reduced from 22<span class="elsevierStyleHsp" style=""></span>mg to 5<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; 21&#37; discontinue completely&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">34&#46;2 &#40;8&#8211;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPARec&#47;Ref &#40;95&#37;&#41;New Dx &#40;5&#37;&#41; &#40;n<span class="elsevierStyleMonospace">&#61;</span>66&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">500<span class="elsevierStyleHsp" style=""></span>mg every 6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>1&#46;5 yearsCumulative dose&#58; 4&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;7<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#37;Relapse rate&#58; 11&#46;2&#47;100 patient-yearsOnly 5 patients relapsed in the first 2 years of treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21 severe AE13&#46;6&#37; of the patients develop infections&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; develop granulomatous diseaseConsiderable reduction in GC with treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">59 &#40;44&#46;5&#8211;73&#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">GPA &#40;90&#37;&#41;&#47;MPARec&#47;Ref &#40;97&#37;&#41;New Dx &#40;3&#37;&#41;&#40;n<span class="elsevierStyleMonospace">&#61;</span>69&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or 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 every 6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 yearsCumulative dose&#58; 6<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#37;40&#37; after complete discontinuation of RTX &#40;34 months average continuous remission&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">93 severe AE in 36 patients29&#37; severe infections &#40;57&#37; in respiratory tract&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">90&#37; of the patients are able to discontinue IS and 48&#37; GCIncludes patients from series &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">84 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPA &#40;43&#37;&#41;&#47;MPARec&#47;Ref and new Dx&#40;n<span class="elsevierStyleMonospace">&#61;</span>172&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or 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 every 4 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#37; &#40;severe relapses 5&#37;&#41;Average in remission&#58; 2&#46;1 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#37; severe infections &#40;36&#37; pulmonary&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Survival comparable to general populationIncludes patients from series &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18 &#40;12&#8211;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">GPA &#40;88&#37;&#41;&#47;MPARec&#47;Ref&#40;n<span class="elsevierStyleMonospace">&#61;</span>80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multiple&#44; including RTX&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> every 6 months &#40;26&#37;&#41;500<span class="elsevierStyleHsp" style=""></span>mg every 6 months &#40;14&#37;&#41;1<span class="elsevierStyleHsp" style=""></span>g every 6 months &#40;11&#37;&#41;Others&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#37; treated with RTX vs 44&#37; without the drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 severe AE15&#37; infections5&#37; patients died&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Demonstrates the wide variability in RTX administration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Studies Related to Maintenance Therapy With Rituximab &#40;Fixed Intervals&#41;&#46;</p>"
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    "bibliografia" => array:2 [
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Review article
Rituximab as Maintenance Therapy for ANCA Associated Vasculitis: How, When and Why?
Rituximab como terapia de mantenimiento en las vasculitis asociadas a ANCA: ¿cómo, cuándo y por qué?
Marco A. Alba, Luis Felipe Flores-Suárez
Corresponding author
felipe98@prodigy.net.mx

Corresponding author.
Clínica de Vasculitis Sistémicas Primarias, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
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    "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>"
    "titulo" => "Rituximab as Maintenance Therapy for ANCA Associated Vasculitis&#58; How&#44; When and Why&#63;"
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        "autoresLista" => "Marco A&#46; Alba, Luis Felipe Flores-Su&#225;rez"
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      "es" => array:1 [
        "titulo" => "Rituximab como terapia de mantenimiento en las vasculitis asociadas a ANCA&#58; &#191;c&#243;mo&#44; cu&#225;ndo y por qu&#233;&#63;"
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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">Vasculitides associated with antineutrophil cytoplasmic antibodies &#40;ANCA&#41; are a group of multisystemic diseases characterized by necrotizing inflammation of small vessels&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The term ANCA-associated vasculitides &#40;AAV&#41; includes granulomatosis with polyangiitis &#40;GPA&#44; Wegener&#39;s granulomatosis&#41;&#44; microscopic polyangiitis &#40;MPA&#41; and eosinophilic granulomatosis with polyangiitis &#40;EGPA&#44; Churg-Strauss syndrome&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Rituximab &#40;RTX&#41;&#44; a chimeric monoclonal antibody that integrates the anti-CD20 variable region of a murine immunoglobulin &#40;Ig&#41; with the constant region of a human IgG1&#44; is one of the therapeutic alternatives approved for the induction phase in both GPA and MPA&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In recent years&#44; a number of studies have evaluated the use of RTX as maintenance therapy in these vasculitides&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In this review&#44; we examine in detail the available information on the efficacy of RTX in maintaining remission in AAV&#46; For this purpose&#44; we conducted a search in the database of the United States National Library of Medicine &#40;PubMed&#41; for articles in English or Spanish published between January 2001 and January 2015&#46; The terms&#44; included in both languages&#44; were&#58; ANCA&#44; vasculitis&#44; granulomatosis with polyangiitis&#44; microscopic polyangiitis and Wegener&#39;s granulomatosis in combination with rituximab&#44; anti-CD&#44; maintenance therapy and biological therapy&#46; The relevant articles were obtained in their complete version and were reviewed and analyzed by both authors&#46; We also identified noteworthy information in the abstracts of international rheumatology meetings held over the last 5 years&#46; This report does not include the use of RTX in EGPA&#44; which was recently reviewed in this journal&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Maintenance Therapy for Vasculitides Associated With Antibodies Against Neutrophil Cytoplasmic Antigens</span><p id="par0020" class="elsevierStylePara elsevierViewall">The treatment of GPA and MPA consists of two different stages&#44; an induction phase &#40;with intensive immunosuppression&#41; and a maintenance phase&#46; The purpose of the latter is to prevent relapses and limit drug toxicity&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Despite the fact that initial treatment with cyclophosphamide &#40;CPM&#41;&#44; RTX or methotrexate &#40;MTX&#41; in combination with high-dose glucocorticoids &#40;GC&#41; achieves partial or complete remission in 75&#37;&#8211;90&#37; of the patients with AAV&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> 11&#37;&#8211;57&#37; of them have relapses while they are being treated with azathioprine &#40;AZA&#41; or MTX alone&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8</span></a> Although the majority are mild&#44; some can be severe&#44; and may provoke additional organ damage&#44; permanent functional sequelae or even death&#46; In addition to the complications inherent to the disease&#44; 40&#37; of the patients develop adverse effects related directly to the therapy employed&#44; for example&#44; osteoporosis or cardiovascular complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">With this scenario&#44; the need to improve certain aspects of maintenance therapy is evident&#46; Especially important among the unresolved matters are&#58; &#40;1&#41; optimization of dose reduction and duration of therapy with the drugs employed&#44; as most of the relapses occur during the tapering of GC and&#47;or immunosuppressive agents &#40;IS&#41; or once they have been discontinued<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#59; &#40;2&#41; early identification of patients at high risk for relapse&#44; for example&#44; those with GPA&#44; upper respiratory tract disease&#44; PR3-ANCA positivity&#44; nasal colonization by <span class="elsevierStyleItalic">Staphylococcus aureus</span> or persistence of ANCA when AZA is initiated<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#8211;16</span></a>&#59; &#40;3&#41; development of individualized treatments in which not only the clinical and ethnical differences are taken into account&#44; but the histological&#44; serological and genetic associations as well<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;17</span></a>&#59; and &#40;4&#41; evaluation of new drugs&#44; such as abatacept &#40;clinicaltrials&#46;gov&#44; <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02108860">NCT02108860</a>&#41;&#44; belimumab &#40;BREVAS study&#44; <a id="intr0015" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01663623">NCT01663623</a>&#41; or RTX&#44; the drug being evaluated here&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">The Basis for the Use of Rituximab in Vasculitides Associated With Antibodies Directed Against Neutrophil Cytoplasmic Antigen</span><p id="par0035" class="elsevierStylePara elsevierViewall">The evidence at different levels indicates that the B lymphocytes play a very important role in AAV&#58; &#40;1&#41; the number of activated B cells is associated with the disease activity and severity<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#59; &#40;2&#41; ANCA&#44; antibodies possibly involved in the pathogenesis of these vasculitides&#44; are produced by B lymphocytes<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a>&#59; &#40;3&#41; in nasal&#44; lung and orbital biopsies from patients with GPA&#44; self-reactive B cells have been identified&#44; adjacent to PR3-ANCA-positive cells&#44; which form structures similar to lymphoid follicles that disappear after treatment with RTX<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#8211;24</span></a>&#59; and &#40;4&#41; B lymphocytes are the main target of CPM&#44; a drug that is essential in the treatment of these vasculitides&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The binding of RTX to CD20 provokes the rapid and sustained depletion of premature and mature B lymphocytes &#40;reducing the plasma cell precursors&#41; through diverse mechanisms&#44; which include antibody-mediated cellular cytotoxicity &#40;mediated by macrophages and natural killer cells&#41;&#44; complement-mediated lysis&#44; induction of apoptosis and sensitization to GC and cytotoxic agents&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Moreover&#44; the drug is capable of inhibiting the interaction between self-reactive B and T cells and increasing the regulatory T lymphocyte population&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#8211;30</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Rituximab as Maintenance Therapy</span><p id="par0045" class="elsevierStylePara elsevierViewall">Information on the use of RTX as maintenance therapy derives from the MAINRITSAN &#40;Maintenance of Remission using Rituximab in Systemic ANCA-associated vasculitis&#41; trial&#44; a recent randomized clinical trial&#44; as well as from certain observational studies &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Clinical Trials</span><p id="par0050" class="elsevierStylePara elsevierViewall">MAINRITSAN is the first and only randomized study to compare RTX and AZA as maintenance therapy in patients with GPA &#40;n<span class="elsevierStyleMonospace">&#61;</span>87&#41;&#44; MPA &#40;n<span class="elsevierStyleMonospace">&#61;</span>23&#41; or renal-limited vasculitis &#40;n<span class="elsevierStyleMonospace">&#61;</span>5&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> The study &#40;controlled&#44; open and multicenter&#41; included 115 patients &#40;80&#37; with new diagnosis&#44; 20&#37; with recurrent disease&#41; in complete remission after induction therapy with GC and CPM&#46; The maintenance protocol was based on the administration of prednisone &#40;approximately 5<span class="elsevierStyleHsp" style=""></span>mg&#47;day for at least 18 months&#41; in combination with AZA &#40;n<span class="elsevierStyleMonospace">&#61;</span>58&#44; 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for 1 year&#44; 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for 6 months and 1&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for the last 4 months&#41; or RTX &#40;n<span class="elsevierStyleMonospace">&#61;</span>57&#44; 500<span class="elsevierStyleHsp" style=""></span>mg initially on days 0 and 14 and&#44; thereafter&#44; every 6 months&#44; for a total of 5 applications&#41;&#46; The percentage of patients with severe relapses &#40;recurrence or worsening of the vasculitis with manifestations that were life-threatening or affected an essential organ&#44; like the brain or heart&#41; after 28 months of follow-up &#40;primary endpoint&#41; was 5&#37; &#40;n<span class="elsevierStyleMonospace">&#61;</span>3&#41; among patients treated with RTX and 29&#37; &#40;n<span class="elsevierStyleMonospace">&#61;</span>17&#41; among those treated with AZA&#44; demonstrating a clear superiority of the monoclonal antibody &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41;&#46; Among the patients who relapsed with AZA&#44; in 8 it occurred during the first year&#59; in 2&#44; between months 12 and 22&#59; and in 7&#44; after the complete discontinuation of the medication &#40;months 24&#8211;28&#41;&#46; In the case of RTX&#44; there was 1 relapse per month in months 8&#44; 22 and 24&#46; With respect to minor relapses&#44; there were no significant differences between the two groups in terms of the rate of adverse events or the incidence of infections&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although the results of the study with RTX are very promising&#44; with one of the lowest rates of relapse reported in these vasculitides&#44; it strikes us as interesting that 41&#37; of the flares recorded in the AZA group occurred when the patients were no longer receiving the medication&#44; possibly causing the therapeutic effect of the drug to be underestimated&#46; However&#44; the protocol for maintenance with AZA is similar to that utilized previously in two large-scale clinical trials involving the same type of patients&#44; and the results of which are similar to those observed in the MAINRITSAN trial&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;8</span></a> As occurs with other IS&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> treatment with AZA or RTX for a longer period of time than that evaluated in the MAINRITSAN trial could be related to a higher rate of sustained remissions&#44; a possibility that should be examined in clinical trials with longer follow-up times&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">In short&#44; the MAINRITSAN trial showed that the combination of low doses of GC and RTX at fixed intervals &#40;every 6 months&#44; which is the average duration of the therapeutic effect<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&#41; can be considered a valid&#44; effective and safe alternative for maintenance of remission in patients with AAV&#44; mainly those with newly diagnosed GPA&#46; At the present time&#44; two clinical trials to evaluate RTX as maintenance therapy are being developed&#46; The first&#44; MAINRITSAN 2 &#40;clinicaltrials&#46;gov <a id="intr0020" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01731561">NCT01731561</a>&#41;&#44; will compare two strategies for RTX administration &#40;500<span class="elsevierStyleHsp" style=""></span>mg at fixed intervals of 6 months vs 500<span class="elsevierStyleHsp" style=""></span>mg whenever increases in CD19&#43; lymphocytes or ANCA are detected&#41;&#46; The other study&#44; RITAZAREM &#40;Rituximab Vasculitis Maintenance Study&#41; &#40;<a id="intr0025" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01697267">NCT01697267</a>&#41;&#44; will evaluate patients with refractory AAV receiving RTX &#40;1<span class="elsevierStyleHsp" style=""></span>g every 4 months&#41; or AZA for 2 years&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Observational Studies</span><p id="par0065" class="elsevierStylePara elsevierViewall">The studies that are to be reviewed below disclose certain differences and limitations that should be taken into account for a correct interpretation of the conclusions derived from them&#46; These series evaluated heterogeneous populations&#44; the dose and regimen of RTX administration varied&#44; and there are differences in the reported maintenance protocols&#44; as the drug was utilized&#58; &#40;1&#41; at fixed intervals in a so-called <span class="elsevierStyleItalic">prevention</span> strategy&#59; &#40;2&#41; depending on serological markers&#44; such as an increase in the ANCA level or B lymphocyte reconstitution&#59; or &#40;3&#41; only at the time of relapses&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Rituximab at Fixed Intervals &#40;Preventive&#41;</span><p id="par0070" class="elsevierStylePara elsevierViewall">This strategy has become that most widely used in recent years&#44; and rates of sustained remission &#40;follow-up of 36&#8211;48 months&#41; of 74&#37;&#8211;100&#37; have been reported &#40;in comparison with the 19&#37;&#8211;56&#37; in patients not treated regularly with RTX&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;45</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the features of the major studies&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Although the doses and intervals vary&#44; the administration of 1<span class="elsevierStyleHsp" style=""></span>g every 4&#8211;6 months for 2 years is the regimen that is most frequently used&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;39&#8211;42</span></a> In some protocols&#44; RTX was continued for more than 24 months&#44; meaning that these patients may have received &#8805;10 cycles of the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;40&#44;43</span></a> In contrast to the MAINRITSAN randomized clinical trial&#44; in the great majority of the observational studies&#44; the predominant study population consisted of patients with recurrent or refractory GPA &#40;mean age of 40&#46;5&#8211;52 years&#41;&#44; and the number of newly diagnosed patients was lower&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;41&#44;44</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">With this form of administration&#44; the average time between relapses and the first and last doses of the monoclonal antibody was 11&#8211;29 months and 9&#8211;15 months&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;37&#44;42&#8211;45</span></a> Interestingly&#44; a study with an extensive follow-up period &#40;5 years&#41; demonstrated that&#44; after discontinuation of the medication &#40;24 months&#41;&#44; 50&#37; of the patients remained in sustained remission&#44; whereas the remainder relapsed 3 years after the last dose of RTX&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">With regard to drug toxicity&#44; although the cumulative dose of the drug is greater in these patients&#44; the rate of adverse effects &#40;including infections&#41; is similar to that reported in studies in which RTX was administered only during relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;45</span></a> However&#44; it should be stressed that one limitation of preventive maintenance with RTX is the risk of overtreatment of those patients &#40;approximately 40&#37;&#41; who have prolonged remission after a single cycle of induction with RTX&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> Unfortunately&#44; to date there is no way to identify those patients&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Another important datum derived from these studies is that&#44; in the majority of the reported patients&#44; the <span class="elsevierStyleItalic">preventive</span> use of RTX permits the reduction of the prednisone dose &#40;initially 20&#8211;30<span class="elsevierStyleHsp" style=""></span>mg&#47;once daily to &#60;5<span class="elsevierStyleHsp" style=""></span>mg&#47;once daily&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;40&#44;41&#44;43&#44;44</span></a> Moreover&#44; 70&#37;&#8211;90&#37; of the patients treated were able to completely discontinue all other immunosuppressive therapy &#40;mycophenolate mofetil&#44; AZA or MTX&#41; and 21&#37;&#8211;48&#37; were able to discontinue treatment with GC&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;39&#44;41&#44;43&#44;45</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In this respect&#44; it is important to point out the adjuvant role that the classical IS could play in maintenance therapy with RTX&#44; mainly in patients with recurrent or refractory disease&#46; The administration of AZA&#44; MTX&#44; leflunomide or mycophenolate mofetil in combination with RTX as maintenance therapy has been reported in a number of uncontrolled studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;40&#44;44&#44;45&#44;47</span></a> A study with a considerable number of GPA patients &#40;n<span class="elsevierStyleMonospace">&#61;</span>89&#41; reported that&#44; after 2 years of follow-up&#44; those patients treated with AZA or MTX in combination with RTX had a significantly lower rate of relapses than those treated with RTX alone &#40;55&#37; vs 70&#37;&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;04&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> These results contrast with those of the subanalysis of 40 patients from the series of Rhee et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> in which the systematic discontinuation of the IS prior to starting treatment with RTX was not associated with an increased frequency of flares&#46; With respect to the therapeutic complications&#44; some studies have reported that the concomitant use of mycophenolate mofetil and&#44; mainly&#44; CPM is related to a higher predisposition toward severe infections&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> whereas&#44; in other series&#44; there was no increase in the number of adverse events&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> At the present time&#44; the available data do not lead to a clear conclusion about the adjuvant use of IS with RTX&#59; however&#44; it is advisable to avoid the combination of the latter with CPM at full doses&#44; due to the increase in the number of severe adverse events&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Rituximab Based on Biomarker Levels</span><p id="par0100" class="elsevierStylePara elsevierViewall">A retrospective study of GPA patients &#40;n<span class="elsevierStyleMonospace">&#61;</span>53&#41; with refractory disease &#40;40&#37; granulomatous activity&#44; 60&#37; vasculitic&#41; compared the administration of RTX only in the case of new relapse &#40;36&#37;&#41; with an individualized protocol &#40;64&#37;&#41; involving infusion of the drug on the basis of the increase in PR3-ANCA or B lymphocytes in serial measurements&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> At the end of the follow-up period &#40;median 4&#46;4 years&#44; interquartile range 2&#46;7&#8211;6&#46;2&#41;&#44; there were no episodes of reactivation among the patients treated on the basis of the change in ANCA titer or B lymphocyte repopulation &#40;average of 4 cycles of RTX received&#41; in contrast to 32 relapses &#40;relapse rate&#58; 13&#46;8&#47;100 patient years&#41; in the group of patients in which the drug was not administered on a regular basis&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Rituximab in Relapses</span><p id="par0105" class="elsevierStylePara elsevierViewall">The follow-up of the patients treated with a single RTX cycle in the RAVE &#40;Rituximab in ANCA-associated vasculitis&#41; trial demonstrated that&#44; although the results with this approach are similar to those obtained with the CPM&#47;AZA combination&#44; it is not sufficient to maintain prolonged remission&#44; as approximately 60&#37; of the patients will relapse during follow-up &#40;18 months&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;46</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In the light of this evidence&#44; at some centers&#44; retreatment with RTX was adopted as a therapeutic measure only in cases of relapse&#44; and it was observed that the drug &#40;at the dose for lymphoma or rheumatoid arthritis &#91;RA&#93;&#41; is usually equally as effective &#40;and safe&#41; as the initial anti-CD20 therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;36&#44;49</span></a> In the open phase of the RAVE trial&#44;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;50</span></a> 26 patients &#40;92&#37; GPA&#41; received RTX for severe relapses between month 6 and month 18 of the study&#44; and remission was achieved in approximately 90&#37; of the cases &#40;50&#37; were also able to discontinue the concomitant use of GC&#41;&#46; These studies have also shown that RTX is more effective than CPM in maintaining remission in patients with previous recurrent disease&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Although treatment of relapses with RTX appears to be effective&#44; this approach to the administration has the disadvantage that the patients are exposed to the damage derived from the disease&#44; and possibly to higher cumulative doses of prednisone &#40;a drug that is usually increased as an initial measure&#41;&#46; Moreover&#44; given that RTX is usually administered full-dose for induction&#44; this could entail an additional economic cost as compared with single&#44; smaller doses administered once or twice a year&#44; as in the <span class="elsevierStyleItalic">prevention</span> protocols&#46;</p></span></span></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Predictors of Relapses Following Treatment With Rituximab</span><p id="par0120" class="elsevierStylePara elsevierViewall">One persistent question is whether there are biomarkers capable of accurately predicting which patients will relapse during treatment with RTX&#46; Up to now&#44; conclusions based on the evaluation of the two laboratory tests most widely examined &#40;B lymphocyte and ANCA levels&#41; are quite unclear&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;39&#44;45&#44;51</span></a> with publications that argue in favor<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;49&#44;52&#44;53</span></a> and against<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a> their utility&#46;</p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Determination of Antineutrophil Cytoplasmic Antibodies</span><p id="par0125" class="elsevierStylePara elsevierViewall">In the vast majority of the reported series&#44; it has not been possible to establish a relationship between the change in ANCA levels and the development of recurrence&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;34&#44;36&#44;37&#44;39&#44;41&#44;44&#44;45&#44;50&#44;54&#8211;56</span></a> In these studies&#44; the percentages of patients who became ANCA-positive or in whom the levels increased&#44; and who had relapses or remained in remission ranged from 33&#37; to 77&#37; and from 38&#37; to 66&#37;&#44; respectively&#44; which shows that the sensitivity of this variable is too low to serve as the basis for decisions on maintenance therapy&#46; The only study that found an association between ANCA levels and recurrences reported that seroconversion to ANCA positivity during the post-RTX period was associated with a 7-fold higher risk of having severe relapses&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">With respect to the specificity of ANCA&#44; it has recently been reported that the presence of PR3-ANCA&#44; but not a change in the levels of these antibodies&#44; was related to higher long-term risk of relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;43&#44;46&#44;50</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">One important conclusion derived from the RAVE extension studies is that the possibility of RTX-treated patients having a relapse is extremely low as long as the assays for ANCA are negative and B lymphocytes remain undetectable in peripheral blood&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;50</span></a> In fact&#44; only 1 of the 76 patients included in these studies had a flare while these two markers were below the level of detection&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">B Lymphocytes</span><p id="par0140" class="elsevierStylePara elsevierViewall">As in the case of ANCA&#44; the levels of these cells in peripheral blood have not been shown to be an accurate enough test for the prediction of flares&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;37&#44;39&#44;41&#44;44&#44;56</span></a> Depending on the study analyzed&#44; the reported finding is that approximately 50&#37; of the relapses occur prior to B cell repopulation&#44; that 44&#37;&#8211;88&#37; of the patients who relapse have detectable B lymphocytes&#44; and that between 25&#37; and 66&#37; of those patients in whom normal levels of B lymphocytes are detected do not have relapses&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;34&#44;36&#44;37&#44;45&#44;46</span></a> Moreover&#44; the time between B cell reconstitution and the development of relapses is not constant either&#59; some patients relapse coinciding with lymphocyte repopulation&#44; whereas in others&#44; it may take some time &#40;average 80<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>85 days&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">One of the few series in which a good correlation was found between AAV reactivation and B lymphocyte repopulation reported that the development of flares &#40;n<span class="elsevierStyleMonospace">&#61;</span>32&#41; was always preceded by the detection of these cells in peripheral blood&#44; with a median between the two events of 8&#46;5 months&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Interestingly&#44; in this report&#44; all the recurrences were preceded by or associated with an increase in PR3-ANCA&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">A recent report found that those patients in whom B lymphocytes were detectable within the first year after treatment with RTX had shorter periods of remission than those in whom repopulation took over 12 months&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The possible hypotheses to explain the poor correlation between the number of B lymphocytes and the AAV activity include&#58; &#40;1&#41; the existence of niches or &#8220;sanctuary sites&#8221; for self-reactive B cells in tissues or sites of active inflammation &#40;mainly granulomatous&#41;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a>&#59; these cell groups would be protected from the pharmacological action of RTX&#44; remaining active before an increase in lymphocytes was observed in peripheral blood<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;58</span></a>&#59; &#40;2&#41; changed dynamics in B cell levels due to a synergic effect between RTX and other conventional IS&#44; such as AZA or CPM&#44; that are frequently administered to patients with resistant or refractory disease<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&#59; &#40;3&#41; racial differences between the populations studied&#44; as the elimination of the B lymphocytes depends not only on the RTX dose&#44; but on polymorphisms in the cell surface receptors &#40;Fc&#947;RIIIa&#41;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a>&#59; and &#40;4&#41; differing definitions from one study to another&#44; with varied absolute values for peripheral blood B cells and diverse phenotypes evaluated &#40;CD19&#43; or CD20&#43;&#41;&#44; as a consequence of the use of detection techniques &#40;flow cytometry&#41; with greater or lesser sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">New Biomarkers</span><p id="par0160" class="elsevierStylePara elsevierViewall">A recent publication stated that the detailed phenotypic analysis of subpopulations of B lymphocytes might have the potential to predict relapses&#46; In a study of 54 patients with AAV&#44; it was observed that when &#60;30&#37; of the B lymphocyte repopulation was constituted by CD5&#43; cells &#40;possibly regulatory B cells&#41;&#44; the time to the first recurrence was shorter&#46; This cell subpopulation also correlated negatively with the general disease activity&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Similarly&#44; it has been reported that&#44; when the B lymphocyte reconstitution is composed mainly of memory cells&#44; there is an increased risk of recurrences&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> This is similar to what occurs in systemic lupus erythematosus&#44; in which repopulation with a higher proportion of CD27&#43; B lymphocytes &#40;memory cells&#41; has been related to a higher risk of flares&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">62&#44;63</span></a></p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Safety</span><p id="par0165" class="elsevierStylePara elsevierViewall">The experience accumulated in the treatment of hematologic neoplasms and RA indicates that RTX has a good margin of safety&#46; The situation in AAV appears to be similar&#44; although the long-term safety of repeated RTX administration has yet to be established&#44; as the majority of the studies have a relatively short follow-up period&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In maintenance studies&#44; anti-CD20&#43; therapy provoked adverse effects in 13&#37;&#8211;60&#37; of the patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;42&#44;43</span></a> with severe infections&#44; hypogammaglobulinemia&#44; severe neutropenia or a lack of efficacy being the main causes of discontinuation&#44; temporary or definitive&#44; of the drug&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44&#44;45</span></a></p><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Reactions Associated With the Administration of Rituximab</span><p id="par0175" class="elsevierStylePara elsevierViewall">Mild allergic reactions are the adverse effect most frequently observed &#40;10&#37;&#8211;50&#37; of the patients&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;64&#44;51</span></a> They usually occur within the first 24<span class="elsevierStyleHsp" style=""></span>h after treatment&#44; and the manifestations are fever&#44; chills&#44; hyper- or hypotension&#44; fatigue&#44; headache&#44; erythema&#44; urticaria&#44; nausea and&#47;or vomiting&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;51</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Infections</span><p id="par0180" class="elsevierStylePara elsevierViewall">These are the most important complications&#44; and mild or severe infections are reported in 7&#37;&#8211;50&#37; of the patients &#40;incidence of 2&#46;6&#8211;15&#46;5&#47;100 patient years&#44; similar to that of CPM&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;36&#44;37&#44;42&#44;46&#44;49&#44;50&#44;56&#44;57&#44;65&#8211;67</span></a> The most common infections are those of the respiratory tract &#40;mainly of viral origin&#41; and the urinary tract&#44; followed by mucocutaneous infections &#40;herpes simplex&#44; herpes zoster and candidiasis&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;36&#44;37&#44;41&#44;46&#44;49&#44;50&#44;65</span></a> Although the majority of these episodes are mild&#44; 14&#37;&#8211;27&#37; are severe and 3&#37;&#8211;29&#37; of the patients develop chronic infections&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;42&#8211;45</span></a> Infections due to opportunistic microorganisms are rare&#44; and RTX is a safe alternative in patients with a history of tuberculosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;39&#44;68</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The reported risk factors for the development of severe infections in these patients are high cumulative doses of CPM and the combination of RTX with other cytotoxic drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;69</span></a> Although the presence of neutropenia or hypogammaglobulinemia could be associated with increased susceptibility to infectious complications&#44; at present&#44; there is no convincing evidence to prove this&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38&#44;44</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Hypogammaglobulinemia</span><p id="par0190" class="elsevierStylePara elsevierViewall">This adverse effect has been reported in 26&#37;&#8211;41&#37; of the patients at some point during maintenance with RTX&#44; but is a transient and self-limiting event in more than 50&#37; of the cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;43&#44;70</span></a></p><p id="par1185" class="elsevierStylePara elsevierViewall">In the majority of the patients&#44; the most marked decrease in the immunoglobulin level was observed during the initial treatment cycles &#40;60&#37; of all the episodes occurring with total doses &#8804;2<span class="elsevierStyleHsp" style=""></span>g and 70&#37; of those with doses &#8804;6<span class="elsevierStyleHsp" style=""></span>g&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Although hypogammaglobulinemia is usually mild to moderate&#44; approximately 7&#37; of the patients have a severe and&#47;or permanent deficiency&#44; requiring discontinuation of the drug and its substitution by intravenous gammaglobulin&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;44&#44;57&#44;51&#44;72</span></a> In this respect&#44; this adverse effect has not been directly related to an increase in the development of severe infections&#44;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38&#44;44</span></a> although it could be a contributing factor in patients with other predisposing conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Among the risk factors that have been associated with the presence of hypogammaglobulinemia&#44; we point out a high cumulative dose of CPM &#40;prior to the initiation of RTX&#41;&#44; low baseline immunoglobulin and CD4&#43; levels&#44; and the concomitant use of the monoclonal antibody with cytotoxic drugs&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;70</span></a> Interestingly&#44; some studies have related hypogammaglobulinemia to the number of RTX cycles&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74&#44;75</span></a> However&#44; this finding has not been corroborated in series with longer follow-up periods&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">57&#44;51&#44;70&#44;71</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Late-onset Neutropenia</span><p id="par0205" class="elsevierStylePara elsevierViewall">This develops in 3&#37;&#8211;5&#37; of the patients and is generally transient&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In the majority of the cases&#44; it has no effect on the patient&#39;s clinical status&#44; although there may be cases in which the use of a colony-stimulating factor is required&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;44&#44;76&#44;77</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Other Adverse Effects</span><p id="par0210" class="elsevierStylePara elsevierViewall">The published literature includes cases of pancytopenia&#44;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;39</span></a> macular edema<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> and severe pulmonary complications &#40;interstitial disease&#41; in patients with AAV&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Moreover&#44; there are reports of progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus and RA&#44;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">79&#44;80</span></a> and a case &#40;unpublished&#41; of this complication in AAV has been detected&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conclusions</span><p id="par0215" class="elsevierStylePara elsevierViewall">Rituximab has been shown to be effective and safe for use as maintenance therapy in AAV&#44; both in recently diagnosed disease and in patients with frequent relapses&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> On the basis of the information published to date&#44; the administration of 500<span class="elsevierStyleHsp" style=""></span>mg at fixed intervals &#40;twice a year&#41; could be the recommended mode of administration&#44; because of its marked efficacy and safety&#46; However&#44; lower doses may also prove to be effective in the maintenance of remission&#44; as has been reported in other diseases&#44;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">81&#44;82</span></a> or at wider intervals between applications&#46; This could be guided with the utilization of more reliable biomarkers&#44; as well as the individual response to the treatment&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">It still remains to be determined whether the drug is more effective in specific groups&#44; for example&#44; in women of childbearing age or patients susceptible to frequent relapses or with a higher risk of infections&#46; The optimal duration of maintenance with RTX should also be studied&#46; In this respect&#44; and by analogy with conventional treatment&#44; a period of between 18 and 24 months is recommended&#44; although&#44; at the present time&#44; there is nothing conclusive regarding this question&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> Finally&#44; we still have yet to know what effect cumulative doses can have and the economic impact of different administration protocols&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Ethical Disclosures</span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Protection of human and animal subjects</span><p id="par0225" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Confidentiality of data</span><p id="par0230" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Right to privacy and informed consent</span><p id="par0235" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflicts of Interest</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors declare they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Introduction"
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        5 => array:2 [
          "identificador" => "sec0130"
          "titulo" => "Maintenance Therapy for Vasculitides Associated With Antibodies Against Neutrophil Cytoplasmic Antigens"
        ]
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          "titulo" => "The Basis for the Use of Rituximab in Vasculitides Associated With Antibodies Directed Against Neutrophil Cytoplasmic Antigen"
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          "identificador" => "sec0020"
          "titulo" => "Rituximab as Maintenance Therapy"
          "secciones" => array:2 [
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              "identificador" => "sec0025"
              "titulo" => "Clinical Trials"
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            1 => array:3 [
              "identificador" => "sec0030"
              "titulo" => "Observational Studies"
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                0 => array:2 [
                  "identificador" => "sec0035"
                  "titulo" => "Rituximab at Fixed Intervals &#40;Preventive&#41;"
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                  "titulo" => "Rituximab Based on Biomarker Levels"
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                  "titulo" => "Rituximab in Relapses"
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          "identificador" => "sec0140"
          "titulo" => "Predictors of Relapses Following Treatment With Rituximab"
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            0 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Determination of Antineutrophil Cytoplasmic Antibodies"
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            1 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "B Lymphocytes"
            ]
            2 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "New Biomarkers"
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          "titulo" => "Safety"
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              "titulo" => "Reactions Associated With the Administration of Rituximab"
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              "titulo" => "Infections"
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            2 => array:2 [
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              "titulo" => "Hypogammaglobulinemia"
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              "titulo" => "Late-onset Neutropenia"
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          "titulo" => "Conclusions"
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              "identificador" => "sec0110"
              "titulo" => "Protection of human and animal subjects"
            ]
            1 => array:2 [
              "identificador" => "sec0115"
              "titulo" => "Confidentiality of data"
            ]
            2 => array:2 [
              "identificador" => "sec0120"
              "titulo" => "Right to privacy and informed consent"
            ]
          ]
        ]
        12 => array:2 [
          "identificador" => "sec0125"
          "titulo" => "Conflicts of Interest"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2015-04-05"
    "fechaAceptado" => "2015-06-07"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec613495"
          "palabras" => array:6 [
            0 => "Rituximab"
            1 => "Anti-neutrophil cytoplasmic antibodies"
            2 => "Treatment"
            3 => "Maintenance"
            4 => "Granulomatosis with polyangiitis"
            5 => "Microscopic polyangiitis"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec613494"
          "palabras" => array:6 [
            0 => "Rituximab"
            1 => "Anticuerpos anticitoplasma de neutr&#243;filo"
            2 => "Tratamiento"
            3 => "Mantenimiento"
            4 => "Granulomatosis con poliangitis"
            5 => "Poliangitis microsc&#243;pica"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">ANCA-associated vasculitides &#40;AAV&#41; are chronic autoimmune diseases characterized by inflammation and destruction of small vessels&#46; Rituximab is now licensed for use as a remission-induction agent in the treatment of these disorders&#46; During recent years&#44; several non-controlled studies have suggested that rituximab may be of value in maintaining disease remission in AAV&#46; In these series&#44; 3 techniques have been tried&#58; &#8220;watch-and-wait&#8221;&#44; repeated cycles in fixed intervals&#44; or administration based on proposed biomarkers&#46; More importantly&#44; the results of the MAINRITSAN trial showed that this anti-CD20 agent is superior to azathioprine for preventing major relapses in AAV&#46; This review summarizes current information regarding the effectiveness&#44; timing&#44; dosing&#44; duration and safety of rituximab as a valid option for remission maintenance&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Las vasculitis asociadas a ANCA son enfermedades autoinmunes cr&#243;nicas que se caracterizan por inflamaci&#243;n y destrucci&#243;n de vasos de peque&#241;o tama&#241;o&#46; El rituximab es un tratamiento efectivo para la fase de inducci&#243;n de estas patolog&#237;as&#46; Durante los &#250;ltimos a&#241;os&#44; varios estudios no controlados han reportado que tambi&#233;n es eficaz durante la fase de mantenimiento terap&#233;utico&#46; En estas series&#44; el f&#225;rmaco se administr&#243; solo durante las reca&#237;das&#44; a intervalos fijos o sobre la base en cambios en algunos biomarcadores&#46; Los resultados del estudio MAINRITSAN mostraron que el rituximab es superior a la azatioprina como terapia de mantenimiento en estas enfermedades&#46; Este trabajo de revisi&#243;n resume la informaci&#243;n m&#225;s reciente sobre el uso de rituximab como opci&#243;n para la fase de mantenimiento de las vasculitis asociadas a ANCA&#44; detallando su efectividad&#44; los diversos protocolos de administraci&#243;n&#44; el perfil de seguridad y el uso potencial de biomarcadores para guiar el tratamiento&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Alba MA&#44; Flores-Su&#225;rez LF&#46; Rituximab como terapia de mantenimiento en las vasculitis asociadas a ANCA&#58; &#191;c&#243;mo&#44; cu&#225;ndo y por qu&#233;&#63; Reumatol Clin&#46; 2016&#59;12&#58;39&#8211;46&#46;</p>"
      ]
    ]
    "multimedia" => array:1 [
      0 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">All the reported series are observational cohorts from a single center&#44; except &#40;9&#41; &#40;multicenter retrospective&#41;&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">AE&#58; adverse events&#59; CPM&#58; cyclophosphamide&#59; Dx&#58; diagnosis&#59; GC&#58; glucocorticoids&#59; GPA&#58; granulomatosis with polyangiitis&#59; IS&#58; immunosuppressive agents&#59; MPA&#58; microscopic polyangiitis&#59; MTX&#58; methotrexate&#59; Rec&#47;Ref&#58; recurrent&#47;refractory&#59; Ref&#58; reference&#59; RTX&#58; rituximab&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Modified from Keogh et al&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> and McAdoo and Pusey&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Reference-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">Follow-up &#40;months&#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">Study 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">Induction<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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 maintenance regimen<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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">Relapses&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">Safety&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">Comment&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" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> 2010&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 &#40;n<span class="elsevierStyleMonospace">&#61;</span>39&#41;24 months &#40;n<span class="elsevierStyleMonospace">&#61;</span>20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPA&#47;MPARec&#47;Ref&#40;n<span class="elsevierStyleMonospace">&#61;</span>39&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or 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 every 4 months for 2 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;6&#37;Relapse rate&#58; 5&#46;0&#47;100 patient-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#37; severe AE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Decrease of 87&#37; in 30&#37; of patients with IS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38 &#40;21&#8211;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPA &#40;85&#37;&#41;&#47;MPARec&#47;Ref &#40;90&#37;&#41;New Dx &#40;10&#37;&#41;&#40;n<span class="elsevierStyleMonospace">&#61;</span>28&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or RTX or MTX&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> every 6 months &#40;n<span class="elsevierStyleMonospace">&#61;</span>13&#41;1<span class="elsevierStyleHsp" style=""></span>g biannual &#40;n<span class="elsevierStyleMonospace">&#61;</span>4&#41;1<span class="elsevierStyleHsp" style=""></span>g every 12 months &#40;n<span class="elsevierStyleMonospace">&#61;</span>3&#41;Other regimens &#40;n<span class="elsevierStyleMonospace">&#61;</span>8&#41;Average infusions&#58; 4 &#40;2&#8211;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#37;Relapse rate&#58; 2&#46;0&#47;100 patient-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 severe AE &#40;infection&#41;3 patients with mild infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Concomitant use of IS in more than 50&#37; of the patients treated with RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52&#46;8 &#40;32&#46;4&#8211;74&#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">GPARec&#47;Ref&#40;n<span class="elsevierStyleMonospace">&#61;</span>53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or RTX&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>&#47;week<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4 &#40;90&#37;&#41; or 1<span class="elsevierStyleHsp" style=""></span>g every 2 weeks<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 &#40;10&#37;&#41; when there was reconstitution of B lymphocytes or increase in PR3-ANCA vs RTX only in relapses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#37; patients treated according to a <span class="elsevierStyleItalic">preventive</span> strategy vs 32 relapses in patients not managed by protocol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 infections &#40;9 in respiratory tract&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment based on biomarkersAll the flares preceded by increase in ANCA or B lymphocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">55 &#40;19&#8211;62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPA&#47;MPARec&#47;Ref&#40;n<span class="elsevierStyleMonospace">&#61;</span>73&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multiple&#44; including biologic&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 every 6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 years &#40;n<span class="elsevierStyleMonospace">&#61;</span>45&#41; vs RTX only in relapses &#40;n<span class="elsevierStyleMonospace">&#61;</span>28&#41;Cumulative dose in patients treated regularly&#58; 6 &#40;2&#8211;11&#41; g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#37; in patients treated according to a <span class="elsevierStyleItalic">preventive</span> strategy vs 72&#37; not managed by protocol at 24 months &#40;26&#37; vs 81&#37; at 48 months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Severe AE 47&#37; RTX vs 32&#37; non-RTX &#40;severe infections 27&#37; vs 21&#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">Considerable decrease in GC&#44; 38&#37; discontinue completelyIS are discontinued in 95&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> 2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">47 &#40;2&#8211;88&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPARec&#47;Ref &#40;80&#37;&#41;New Dx &#40;20&#37;&#41;&#40;n<span class="elsevierStyleMonospace">&#61;</span>35&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">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 every 15 days once a year1<span class="elsevierStyleHsp" style=""></span>g biannualCumulative dose&#58; 8 &#40;2&#8211;13&#41; g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23&#37;Relapse rate&#58; 6&#46;6&#47;100 patient-years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#37; severe infections37&#37; discontinue RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GC reduced from 22<span class="elsevierStyleHsp" style=""></span>mg to 5<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; 21&#37; discontinue completely&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">34&#46;2 &#40;8&#8211;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPARec&#47;Ref &#40;95&#37;&#41;New Dx &#40;5&#37;&#41; &#40;n<span class="elsevierStyleMonospace">&#61;</span>66&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RTX&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">500<span class="elsevierStyleHsp" style=""></span>mg every 6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>1&#46;5 yearsCumulative dose&#58; 4&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;7<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#37;Relapse rate&#58; 11&#46;2&#47;100 patient-yearsOnly 5 patients relapsed in the first 2 years of treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21 severe AE13&#46;6&#37; of the patients develop infections&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; develop granulomatous diseaseConsiderable reduction in GC with treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">59 &#40;44&#46;5&#8211;73&#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">GPA &#40;90&#37;&#41;&#47;MPARec&#47;Ref &#40;97&#37;&#41;New Dx &#40;3&#37;&#41;&#40;n<span class="elsevierStyleMonospace">&#61;</span>69&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or 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 every 6 months<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 yearsCumulative dose&#58; 6<span class="elsevierStyleHsp" style=""></span>g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#37;40&#37; after complete discontinuation of RTX &#40;34 months average continuous remission&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">93 severe AE in 36 patients29&#37; severe infections &#40;57&#37; in respiratory tract&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">90&#37; of the patients are able to discontinue IS and 48&#37; GCIncludes patients from series &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">84 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">GPA &#40;43&#37;&#41;&#47;MPARec&#47;Ref and new Dx&#40;n<span class="elsevierStyleMonospace">&#61;</span>172&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CPM or 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 every 4 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#37; &#40;severe relapses 5&#37;&#41;Average in remission&#58; 2&#46;1 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#37; severe infections &#40;36&#37; pulmonary&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Survival comparable to general populationIncludes patients from series &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18 &#40;12&#8211;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">GPA &#40;88&#37;&#41;&#47;MPARec&#47;Ref&#40;n<span class="elsevierStyleMonospace">&#61;</span>80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Multiple&#44; including RTX&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> every 6 months &#40;26&#37;&#41;500<span class="elsevierStyleHsp" style=""></span>mg every 6 months &#40;14&#37;&#41;1<span class="elsevierStyleHsp" style=""></span>g every 6 months &#40;11&#37;&#41;Others&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#37; treated with RTX vs 44&#37; without the drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 severe AE15&#37; infections5&#37; patients died&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Demonstrates the wide variability in RTX administration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information
ISSN: 21735743
Original language: English
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2016 September 130 24 154
2016 August 96 24 120
2016 July 67 26 93
2016 March 1 0 1
2016 February 4 80 84
2016 January 1 64 65
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Reumatología Clínica (English Edition)
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¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?