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Efficacy and safety of rituximab in the treatment of primary antiphospholipid syndrome: Analysis of 24 cases from the bibliography review
Eficacia y seguridad de rituximab en el tratamiento del síndrome antifosfolipídico primario: análisis de 24 casos a partir de la revisión de la bibliografía
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APS: antiphospholipid syndrome.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Antiphospholipid syndrome (APS) is characterised by the association of thrombosis and/or obstetric morbidity with the persistent presence of plasma circulating antiphospholipid antibodies (APLA), such as lupus anticoagulant (LA), anticardiolipin antibodies (ACA) and/or antibodies targeted against specific proteins, such as β2-glucoprotein I (β2GPI)<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">1</span></a>. The most frequent clinical manifestation is deep venous thrombosis (DVT), while cerebrovascular accident (CVA) is the most prevalent manifestation of arterial thrombosis. Foetal losses (early and late), prematurity and preeclampsia are the most frequent obstetric manifestations<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">2</span></a>.</p><p id="par0010" class="elsevierStylePara elsevierViewall">When APS appears in patients who have no baseline disease, it is called primary APS. Systemic lupus erythematosus (SLE) is the autoimmune disease with which it is most frequently associated.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The treatment of thrombotic APS is based on the control of vascular risk factors, acetylsalicylic acid as primary thromboprofilaxis and long-term anticoagulant treatment as secondary thromboprofilaxis<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">3</span></a>.</p><p id="par0020" class="elsevierStylePara elsevierViewall">There is a series of manifestations not included in the qualifying criteria, such as thrombocytopenia or valvular involvement, the specific treatment of which is unknown; moreover, despite anticoagulant treatment, a group of patients shows thrombotic recurrence. In these cases, various alternative therapeutic strategies have been proposed, among them, rituximab<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a>. This is a human chimeric monoclonal antibody with activity against protein CD20 found in naive, mature and memory B lymphocytes. In the context of autoimmune diseases, the only indication approved by medicine regulatory agencies is rheumatoid arthritis refractory to drugs that modify the disease or anti-tumour necrosis factor α agents<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">5</span></a>.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Two prospective, randomised, double blind studies were unable to show the efficacy of rituximab in patients with moderate SLE<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> or with lupus nephropathy<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a>. Nonetheless, evidence obtained from observational studies supports the role of rituximab in the treatment of patients with serious or refractory lupus<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">8</span></a>.</p><p id="par0030" class="elsevierStylePara elsevierViewall">There is limited experience related to the use of rituximab in the treatment of APS compared to other autoimmune diseases. In cases of primary APS, it is merely anecdotic<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">9–19</span></a>. A review from 2008 included 6 cases of primary APS, 6 cases of APS associated with SLE and one case of catastrophic APS treated with rituximab<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">20</span></a>. A recent Phase <span class="elsevierStyleSmallCaps">ii</span> study has demonstrated its safety and efficacy in the treatment of some clinical manifestations not included in APS qualifying criteria<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a>.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The goal of the present study is to carry out a review of the scientific evidence available about the use of rituximab in primary APS. In addition, a case of primary APS treated with rituximab is described.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and method</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Data collection</span><p id="par0040" class="elsevierStylePara elsevierViewall">A bibliographic search was carried out from the <span class="elsevierStyleItalic">PubMed MEDLINE</span> database up to May 2013 to identify all published cases of primary APS that received rituximab. The key words used were <span class="elsevierStyleItalic">antiphospholipid syndrome</span> and <span class="elsevierStyleItalic">rituximab</span>. Limitations on language and study design were not established, including isolated cases, case series, cohorts and controlled studies.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Articles describing patients with primary APS who received treatment with rituximab were included. The bibliography of the articles included was reviewed to obtain the entire number of cases. Articles written as reviews and those that describe patients with SLE or other associated autoimmune diseases or catastrophic APS were excluded from the study.</p><p id="par0050" class="elsevierStylePara elsevierViewall">From the articles included, if available, the following data was gathered: demographics, clinical and laboratory data, APLAs and their titre, lymphocytes CD19+ count before and after treatment, previous and concomitant treatments, the line of treatment and dose of rituximab, clinical progress and blood tests, follow-up time, and adverse effects of the treatment. The definition of complete or partial response is described in each article. All the data was entered into a database designed for the study.</p><p id="par0055" class="elsevierStylePara elsevierViewall">As the determination of APLAs in the different studies was made using different commercial tests, the results make reference to their maintenance, negativization or positivization before and after treatment with rituximab.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The results of continuous variables have been presented as means ± standard deviation (SD), and those of categorical variables as percentages.</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Clinical case</span><p id="par0065" class="elsevierStylePara elsevierViewall">A 49-year old female patient with primary APS was diagnosed due to a foetal death during the fourth month of gestation and right pontine ischaemic CVA. The APLAs profile showed double positivity (IgG isotype ACA and LA). Moreover, she had experienced epilepsy during adolescence and autoimmune thrombocytopenia previous to APS diagnosis, which was refractory to corticosteroids and required a splenectomy. Subsequently, she had followed treatment with prednisone 12.5 mg/day, azathioprine 100 mg/day, acenocumarol, calcium, vitamin D and pravastatin.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Her normal platelet counts were around 40 × 10<span class="elsevierStyleSup">9</span>/l. To perform the splenectomy and a uterine prolapse hysterectomy, she received intravenous immunoglobulin (IVIG) as prevention at doses of 25 mg per day for 5 days, without a significant increase in the number of platelets.</p><p id="par0075" class="elsevierStylePara elsevierViewall">During the following months, the patient required 3 hospital admissions due to bleeding diathesis that coincided with a worsening of thrombocytopenia, up to 17 × 10<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a>/l, which did not respond to the increase in the corticosteroids dose or to new IVIG administration. Finally, treatment with rituximab 375 mg/m<span class="elsevierStyleSup">2</span> weekly for 4 weeks was initiated, with no incidence or adverse effects. At the time of rituximab administration, ACAs were negative but the LA continued to be positive. The number of platelets after the first dose of the drug was 9 × 10<span class="elsevierStyleSup">9</span>/l, and after the third dose 24 × 10<span class="elsevierStyleSup">9</span>/l. Once treatment was completed, platelets remained around 15-18 × 10<span class="elsevierStyleSup">9</span>/l for the following 12 months, increasing to 45 × 10<span class="elsevierStyleSup">9</span>/l at 18 months of follow-up. In successive check-ups, the values always remained over 50 × 10<span class="elsevierStyleSup">9</span>/l, and at 96 months follow-up the values were 78 × 10<span class="elsevierStyleSup">9</span>/l. From a clinical standpoint, she has not experienced ecchymosis or macroscopic haemorrhage again, and with the oral anticoagulant treatment she has not had a thrombotic recurrence. The corticosteroid dose was reduced to discontinuation at 36 month treatment with rituximab. The ACAs, which were negative before the administration of rituximab, have remained the same during follow-up. The LA, which was present at the beginning of the treatment with rituximab, was negative 60 months after administration of this drug and has remained negative to date.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Patients</span><p id="par0080" class="elsevierStylePara elsevierViewall">The bibliographic search identified 83 articles that exhibited the above-mentioned conditions. Of those, based on a reading of the abstracts, 34 were discarded because they did not adjust to the screening criteria (lacking reference to APS treatment with rituximab). Using a more thorough analysis of the remaining 49 articles, the 32 cases that included APS treated with rituximab were selected, ruling out 17 of them which were reviews without case descriptions (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>15) or cases that did not receive treatment with rituximab (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Finally, 32 articles with 47 cases of APS treated with rituximab were identified but 15 articles were discarded due to the inclusion of cases only related to associated APS, and 5 that, despite the inclusion of primary APS cases, fulfilled the criteria corresponding to catastrophic APS, which is a disease variation excluded from this review. Of the 12 articles selected, only one was a controlled study, while the rest were case series or descriptions of isolated cases.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">General characteristics and previous manifestations</span><p id="par0085" class="elsevierStylePara elsevierViewall">Finally, 24 patients with primary APS treated with rituximab were identified. Of these, one is the case described in this study, 12 are isolated published cases<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">9–19</span></a> and 11 are part of the study that assessed the safety and efficiency of rituximab in the treatment of some manifestations not included in APS qualifying criteria<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> (RITAPS). The main demographic, clinical and analytical characteristics of patients with primary APS are described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">In 4 patients (16.7%), the clinical symptoms that triggered treatment with rituximab appeared at the beginning of the disease. Thirteen patients (54.2%) had previously experienced thrombotic complications, 3 (12.5%) had had obstetric complications and 4 patients (16.7%) had had both of these. In 2 patients the onset of primary APS satisfied catastrophic APS criteria.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Indications and doses of rituximab and concomitant drugs</span><p id="par0095" class="elsevierStylePara elsevierViewall">The general indications for the use of rituximab are described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and reported specifically for each patient in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. The most frequent clinical indications were thrombocytopenia with haemorrhagic diathesis in 10 (41.7%) patients and skin involvement in 8 (33.3%). Skin involvement accounted for 6 cases of skin ulcerations/necrosis and 4 cases of livedo reticularis/livedoid vasculitis (in 2 patients, both types of injuries coexisted). Neurological involvement was the cause of treatment in 3 (12.5%) patients, in the form of cognitive deterioration. Three patients (12.5%) had cardiac valvular involvement, with data available for 2 of them, one with aortic vegetation and mitral valve thickening and the other with mitral valve thickening. In 2 (8.3%) patients, the treatment indication was thrombotic complications, one case of temporary CVA despite correct anticoagulant treatment and a patient with bilateral thrombosis of the cerebral venous sigmoid sinuses, with secondary bilateral papilledema. Two (8.3%) patients had symptomatic autoimmune haemolytic anaemia with haemoglobin values of 2.8 and 6.3 g/l, one of them associated with thrombocytopenia (Evans's syndrome). Pulmonary involvement, in the form of alveolar haemorrhage and haemoptysis, and renal involvement, in nephrotic syndrome and acute renal failure, were present in one patient (4.2%) each.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> describes the administration guidelines for rituximab, the drugs previously used, and the concomitant treatment. In 7 (29.2%) patients, rituximab was part of the first line of treatment, 2 cases of skin involvement (one of them had previously responded to rituximab 6 months before), 2 cases of cardiac valvular involvement, 2 cases of thrombotic involvement and one case of cognitive alteration. Out of the remaining patients, it was administered as a second line treatment in 11 (45.8%), and in the remaining 6 (25%), it was administered after at least 2 previous lines of treatment.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">The most frequently used guideline was the administration of 2 doses of 1000 mg fortnightly in 13 (54.1%) patients. Of these, 11 were part of the RITAPS<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> study and received 1000 mg of oral paracetamol, 50 mg of oral diphenhydramine and 100 mg of intravenous methylprednisolone about 30-60 minutes before each infusion, as per protocol. The twelfth patient received 500 mg of intravenous methylprednisolone the day before each infusion. Only one patient (4.2%) received 8 weekly doses of 375 mg/m<span class="elsevierStyleSup">2</span> and the remaining 10 (41.7%) received 4 weekly doses of 375 mg/m<span class="elsevierStyleSup">2</span>. Of the last patients, 2 received supplementary doses. One of them received 2 monthly doses of 375 mg/m<span class="elsevierStyleSup">2</span>, as per the protocol used in mixed cryoglobulinaemia, and the other one received 2 doses of 1000 mg fortnightly after 3 months, due to the increase in the ACAs titres of IgG and IgM isotypes, even if they did not show symptoms. Likewise, one patient treated with 4 weekly doses of 375 mg/m<span class="elsevierStyleSup">2</span> received coadjuvant methylprednisolone.</p><p id="par0110" class="elsevierStylePara elsevierViewall">As treatments previous to the indication that triggered the use of rituximab, 4 (16.7%) patients (2 with skin involvement, one with cognitive alteration and another one with haemolytic anaemia) received only corticosteroids treatment. One (4.2%) patient with thrombocytopenia and cognitive alteration received corticosteroids jointly with anti-D gammaglobulin, and another patient (4.2%), with thrombocytopenia and cardiac valvular involvement, received antagonists of the thrombopoietin receptor jointly with corticosteroids. Five (20.8%) patients received corticosteroids and IVIG before rituximab. Of these, 4 had thrombocytopenia (one of them with concomitant cognitive involvement and another one with haemolytic anaemia, who received cyclophosphamide associated to rituximab), and the fifth had ulcerative skin involvement. Apart from the use of corticosteroids and IVIG, one (4.2%) patient also received treatment with azathioprine due to refractory thrombocytopenia. In one (4.2%) patient with skin and renal involvement, plasma exchange was the preferred treatment before rituximab. The 4 remaining cases (16.7%), in which rituximab was not the first line of treatment, received different immunosuppresants. The case of pulmonary involvement was treated with prednisone, azathioprine, methylprednisolone, IVIG, cyclophosphamide and plasma exchange. Three cases of thrombocytopenia received prednisone, azathioprine, methylprednisolone, IVIG, cyclosporine A, vincristine and cyclophosphamide in one of them, plasma exchange, IVIG, cyclophosphamide, vincristine, dexamethasone and azathioprine in another, and corticosteroids, vincristine, IVIG and cyclophosphamide in the third.</p><p id="par0115" class="elsevierStylePara elsevierViewall">As antithrombotic treatment, 13 (54.2%) patients received anticoagulant medication, 4 (16.7%) antiaggregation and 4 (16.7%) a combination of both. One case was under treatment with oral prednisone and tacrolimus due to a previous renal transplant.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Clinical response to rituximab and follow-up</span><p id="par0120" class="elsevierStylePara elsevierViewall">The progress of patients based on the clinical manifestations that triggered the use of rituximab and the follow-up period are described in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. The mean follow-up was 72.0<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>71.7 weeks (interval 24-356 weeks).</p><p id="par0125" class="elsevierStylePara elsevierViewall">Overall, and in line with the criteria of the authors of each article, 13 (54.2%) patients achieved a complete clinical response with the treatment with rituximab. In detail, there were 4 patients with skin involvement in the form of necrosis, livedoid vasculitis and/or pyoderma gangrenosum, who presented total resolution of the injuries. Of these, one experienced clinical recurrence with the same involvement during week 36 of follow-up. Another patient with temporary CVA also experienced a complete response despite the anticoagulant treatment without new thrombotic symptoms during follow-up, and as did one case of renal involvement and normalisation of urine protein values. The resolution of sigmoid sinus thrombosis with recovery of visual acuity in one patient, the resolution of cognitive alteration in another case, and the increase in the number of platelets >150 × 10<span class="elsevierStyleSup">9</span>/l in 3 patients with thrombocytopenia are other cases of complete clinical response. Two cases of cardiac valvular involvement corresponding to the study by Erkan et al<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> stand out: no changes were observed on completion of the 52 weeks of the study follow-up, but both cases achieved complete resolution in weeks 82 and 120, respectively.</p><p id="par0130" class="elsevierStylePara elsevierViewall">Seven (29.2%) patients showed partial response to rituximab treatment. Four of them, with thrombocytopenia, maintained a platelet count between 50 and 150 × 10<span class="elsevierStyleSup">9</span>/l, y 2, with haemolytic anaemia and haemoglobin values between 9 and 12 g/l. A patient with skin involvement in the form of pyoderma gangrenosum experienced partial improvement of his injuries. Finally, the patient with alveolar haemorrhage and serious haemoptysis experienced a partial response, without any new episodes of diffuse alveolar haemorrhage but with episodes of mild haemoptysis.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Four (16.7%) patients did not experience any significant change with administration of the treatment. There were 3 cases of thrombocytopenia in which, after treatment, platelets remained under 50 × 10<span class="elsevierStyleSup">9</span>/l, and one case of cognitive alteration.</p><p id="par0140" class="elsevierStylePara elsevierViewall">The response percentage based on treatment indication was highly varied. Complete response was 100% in the 2 cases treated due to thrombotic complications, while in the case of skin involvement 5 (62.5%) patients had a complete response and 3 (37.5%) a partial clinical response. There was high variability in the neurological involvement response: one (33.3%) case with complete response, another (33.3%) with partial response and a third (33.3%) without response. In the long-term follow-up of the 3 cases with cardiac valvular involvement, one (33.3%) patient did not respond and 2 (66.7%) showed complete response. The only case with pulmonary involvement showed partial response and the patient with renal involvement showed complete response. The 2 patients with haemolytic anaemia experienced a partial response (100%), and in the case of thrombocytopenia, 3 (30%) patients experienced a complete response, 4 (40%) a partial response, and the other 3 (30%) did not show a significant response.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Behaviour of antiphospholipid antibodies with rituximab</span><p id="par0145" class="elsevierStylePara elsevierViewall">The evolution of APLAs before and after rituximab is described in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>. The titration of APLAs at the time of rituximab treatment has only been obtained from data derived from different studies in 11 out of the 24 patients for LA, 12 for ACA IgG and 11 for ACA IgM, and only in 5 patients for anti-β2GPI. Before rituximab administration, LA was positive in 8 (72.7%) patients, ACA IgG in 9 (75%) and ACA IgM in 5 (45.4%). The positivity for anti-β2GPI IgG and IgM was confirmed in 4 (80%) of the 5 patients who were determined to have it.</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Data on APLAs behaviour after rituximab administration was available for only 9 patients. A first case with negative APLAs and complete clinical response (skin necrosis) did not show variations in the values. The patient with pulmonary involvement had positive APLAs (LA, ACA and anti-β2GPI) from its beginning as catastrophic APS 12 months before; 6 months after the episode, anti-β2GPI normalised but ACAs had substantially increased. One case with previous positivity for LA and isotypes IgG of ACA and anti-β2GPI (since the onset of baseline symptoms, 9 years ago) received rituximab for the treatment of refractory thrombocytopenia, with complete clinical response and decrease in the APLAs titres, without achieving negativization during the 42 weeks of follow-up. The positivity of ACAs in the case with renal involvement experienced a decrease (ACAs IgM become negative) during the first 15 months of follow-up; subsequently, the titres increased without a clinical translation, thus, rituximab treatment was repeated and negativization of both isotypes was achieved 10 days after completion. Despite the anticoagulant treatment, the patient with thrombotic involvement had elevated and persistent ACA IgG titres, which remained elevated after the treatment and a good clinical response. In the patient with thrombocytopenia and haemolytic anaemia who showed anti-β2GPI IgG and IgM, the partial response was accompanied by its negativization at 4 months. In one case of refractory thrombocytopenia, LA and ACA IgG and IgM remained positive. One patient with positivity for LA and the 2 isotypes of ACA and anti-β2GPI received rituximab as treatment for thrombocytopenia; before the treatment, IgM isotypes decreased without a substantial increase in the platelets. Upon completion of the treatment, anti-β2GPI IgG and IgM and ACA IgM became negative; 6 months after treatment, anti-β2GPI was positive again and the ACA IgM remained negative. In the case described, in spite of having recorded positivity before ACA IgM, ACAs were negative when rituximab was administered and remained like that during the follow-up. The LA, which was present at the beginning of the treatment with rituximab, became negative 60 months later and has remained negative to date.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">CD19+ lymphocyte count before and after treatment with rituximab</span><p id="par0155" class="elsevierStylePara elsevierViewall">This information was available for only 2 out of the 24 patients. The first case<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> showed a complete clinical response and CD19+ lymphocytes decreased from 13.7% of the total amount of lymphocytes to 0.1% 2 weeks after the first dose of rituximab, and to 0.0% 2 weeks after the second dose. The second case<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> had no significant clinical response, the initial CD19+ lymphocyte count was 591 × 10<span class="elsevierStyleSup">9</span>/l and followed an erratic behaviour after the administration of the different rituximab doses. They initially decreased (204 × 10<span class="elsevierStyleSup">9</span>/l after the first dose and 160 × 10<span class="elsevierStyleSup">9</span>/l after the second one), and later increased (405 × 10<span class="elsevierStyleSup">9</span>/l after the third dose, 223 × 10<span class="elsevierStyleSup">9</span>/l after the fourth dose of rituximab and 280 × 10<span class="elsevierStyleSup">9</span>/l 6 months after the completion of the treatment).</p><p id="par0160" class="elsevierStylePara elsevierViewall">A similar count was also carried out among the 11 patients of the RITAPS<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> study, but the result is described as a mean ± SD, which also includes the rest of the patients (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8) that were part of the study and did not satisfy the qualifying APS criteria, so we cannot analyse their progress.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Adverse effects of rituximab treatment</span><p id="par0165" class="elsevierStylePara elsevierViewall">Unfortunately, we cannot analyse the side effects of the treatment in the 11 patients of the RITAPS<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> study because they are described jointly with the rest of the patients (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8) that are part of the study and did not satisfy the qualifying APS criteria. Of the remaining 13 patients with primary APS treated with rituximab, only one case with adverse effects after administration is described, which consists of in 2 hospital admissions due to transient neutropenia and pneumonia, respectively.</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0170" class="elsevierStylePara elsevierViewall">Rituximab, used as the first choice drug in one third of the patients, showed a good clinical response in the cases of thrombotic complications, skin and cardiac valvular involvement and, to a lesser extent, in the cases of haemolytic anaemia and thrombocytopenia. Its role in the variation of APLAs titres is more controversial.</p><p id="par0175" class="elsevierStylePara elsevierViewall">The pathogenic role of APLAs has been demonstrated in animal models, where their presence increases the creation of thrombi in arterial and venous circulation<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a>. Moreover, there is evidence on the role of B lymphocytes as being responsible for the production of these autoantibodies. The subpopulation of B lymphocytes expressing CD5 in their surface is associated with the presence of APLAs<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">23</span></a>. In this sense, no studies have been published about the depletion of B lymphocytes with drugs such as rituximab in animal models of APS. However, 2 studies have analysed the modulating treatment of B lymphocytes in murine APS models<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">24,25</span></a>, and a third study has focused on blocking costimulating signals, such as antigen-4 associated to cytotoxic T cell<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">26</span></a>.</p><p id="par0180" class="elsevierStylePara elsevierViewall">Without a randomised clinical trial to support it, the evidence on rituximab efficiency in primary APS is based on descriptions of cases and case series described in the medical literature. In the previous published review, Erre et al.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">20</span></a> analysed 12 patients with APS treated with rituximab, of whom 6 had primary APS (all of them are included in our review). In these patients, an improvement or resolution of all cases of thrombocytopenia was confirmed (5 patients), along with an improvement in cerebral vasculopathy in one patient, recovery of haemolytic anaemia in 2 cases and only one thrombotic recurrence as DVT at 36 months of follow-up (8 patients).</p><p id="par0185" class="elsevierStylePara elsevierViewall">The effect of rituximab on the APLAs and the clinical response is controversial. Several authors have described how, in patients with APS treated with rituximab, there is a close correlation between the decrease in the APLAs titres and the correction of thrombocytopenia<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">11,18</span></a>, or the prevention of new onsets of thrombosis<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a>. In this sense, the lack of clinical response and the maintenance of elevated APLAs titres<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> have also been related, which could be considered a therapeutic failure of rituximab. On the other hand, there are also descriptions of patients in whose cases, despite a good clinical response, APLAs titration was not modified<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a>. In the recent clinical trial conducted by Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> on the safety and efficacy of rituximab in the treatment of manifestations not included in APS qualifying criteria, it is stated that this drug can be effective in the control of some manifestations without identifying substantial changes in APLAs titres. The scarce number of patients with APLAs determination after the treatment in this review prevents us from drawing definite conclusions on the matter, but it mainly seems to be a correlation between the clinical response and a decrease in the titration of all or part of the APLAs.</p><p id="par0190" class="elsevierStylePara elsevierViewall">In the 2 cases where the CD19+ lymphocyte count is described, the results in relation to the clinical response are suspicious. In one case there was a correlation between lymphocyte depletion and complete clinical response<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a>, while in the other case the absence of clinical response coincided with oscillating CD19+ lymphocyte count.</p><p id="par0195" class="elsevierStylePara elsevierViewall">Based on the results obtained from this review, a potential benefit of rituximab could be proposed in the treatment of refractory cases of primary APS or, at least, in the treatment of some of its clinical manifestations. Of these, thrombocytopenia has been the most frequent indication in the use of rituximab, with a variable response interval of: 30% complete response, 40% partial response and 30% with no significant improvement. This finding is compatible with, or even improves, the response rates of rituximab in patients with idiopathic thrombopenic purpura<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">27</span></a>. Skin involvement, which is the second most frequent indication, also seems to have a very good response (62.5% complete response and 37.5% partial response). Despite the scarce number of patients (2 cases), a very good response has also been observed in the cases of thrombosis (100% complete response) and in the long-term follow-up of cardiac valvular involvement (66.7% resolutions). However, with the current evidence, rituximab has demonstrated little efficacy in cases of APS and cognitive deterioration<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a>.</p><p id="par0200" class="elsevierStylePara elsevierViewall">The present study has some limitations, such as its retrospective character and the great heterogeneity of rituximab prescription causes and the different administration guidelines, follow-up periods and response assessment both in clinical and serological terms. The following should also be noted: the reduced number of patients identified and the impossibility of obtaining all the data in each case, the potential screening bias based on which the trend is to publish only those cases with satisfactory results, and the coexistence of other immunosuppressant drugs in the treatment, which makes it difficult to establish the real role of rituximab in these patients. Moreover, all the reviewed articles, except for one, are isolated cases or case series.</p><p id="par0205" class="elsevierStylePara elsevierViewall">The multifactorial aetiology of thrombosis in patients with APLA and the partial knowledge of the mechanisms by which these induce thrombosis and other clinical manifestations are the main barriers for the development of new drugs to treat APS. However, it is possible for the antithrombotic therapeutic approach to be replaced in the future by an immunomodulation approach more centred on the pathogenic mechanisms and not on the APLAs effect<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">28</span></a>.</p><p id="par0210" class="elsevierStylePara elsevierViewall">Despite all the above-mentioned limitations, the data obtained in this study proves a potential benefit of rituximab in the treatment of some of the clinical manifestations of primary APS, such as thrombocytopenia and skin involvement. The association between clinical changes and the variations in APLAs titres is yet to be analysed. In this sense, randomised clinical trials should be developed to establish the real role of rituximab in the treatment of primary APS. Given the difficulties entailed in the performance of such a study, clinicians must be encouraged to share their experience in this field.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflict of interest</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare that there are no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres568392" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec585746" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres568391" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamento y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec585745" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Patients and method" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "Data collection" ] ] ] 6 => array:3 [ "identificador" => "sec0020" "titulo" => "Results" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Clinical case" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Patients" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "General characteristics and previous manifestations" ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Indications and doses of rituximab and concomitant drugs" ] 4 => array:2 [ "identificador" => "sec0045" "titulo" => "Clinical response to rituximab and follow-up" ] 5 => array:2 [ "identificador" => "sec0050" "titulo" => "Behaviour of antiphospholipid antibodies with rituximab" ] 6 => array:2 [ "identificador" => "sec0055" "titulo" => "CD19+ lymphocyte count before and after treatment with rituximab" ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Adverse effects of rituximab treatment" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-10-13" "fechaAceptado" => "2014-01-23" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec585746" "palabras" => array:5 [ 0 => "Rituximab" 1 => "Antiphospholipid syndrome" 2 => "Primary antiphospholipid syndrome" 3 => "Thrombocytopenia" 4 => "Heart valve disease" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec585745" "palabras" => array:5 [ 0 => "Rituximab" 1 => "Síndrome antifosfolipídico" 2 => "Síndrome antifosfolipídico primario" 3 => "Trombocitopenia" 4 => "Valvulopatía" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Antiphospholipid syndrome (APS) is characterised by the presence of antiphospholipid antibodies (aPL) and thrombotic and/or obstetric manifestations. Patients without another associated autoimmune disease are considered to have primary APS. Some patients develop thrombosis recurrence despite anticoagulant treatment and some clinical features do not respond to standard therapy. Rituximab may be an alternative in these cases. We review the published scientific evidence on the use of rituximab in the treatment of primary APS.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Description of a case and review of the literature with descriptive analysis of the demographic, clinical, and immunologic features, treatment and outcome of patients.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We identified 24 patients (15 women [62.5%]), with a mean age of 37.0<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>13.4 years. The reasons for the use of rituximab were thrombocytopenia (41.7%), skin involvement (33.3%), neurologic and heart valve involvement (12.5%), hemolytic anaemia (8.3%) and pulmonary and renal involvement (4.2%). Lupus anticoagulant was present in 72.7% of the cases, the IgG and IgM isotypes of anticardiolipin antibodies in 75 and 50%, respectively, and the anti-β2GPI (IgG and IgM) antibodies in 80% of the patients. Thirteen (54.1%) patients received two doses of 1000<span class="elsevierStyleHsp" style=""></span>mg of rituximab fortnightly, 10 (41.7%) four doses of 375<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> weekly and 1 (4.2%) eight doses of 375<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> weekly. Eleven (45.8%) patients presented a complete clinical response, seven (29.2%) a partial response and six (25%) did not respond to rituximab. Four patients with clinical improvement presented with aPL titer decrease and in one patient, aPL levels did not change. In one patient without clinical response, aPL remained positive. A clinical-immunologic dissociation existed in two additional cases.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The results obtained suggest a possible potential benefit of rituximab in the treatment of some clinical manifestations of primary APS such as thrombocytopenia, skin and heart valve involvement.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Fundamento y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El síndrome antifosfolipídico (SAF) se caracteriza por la presencia de anticuerpos antifosfolipídicos (AAF) y complicaciones trombóticas y/o obstétricas. Cuando no se asocia a ninguna otra enfermedad autoinmunitaria recibe el nombre de SAF primario. En algunas ocasiones, el tratamiento antitrombótico no es suficiente para evitar la recurrencia trombótica, y algunas manifestaciones clínicas no responden al tratamiento estándar. Rituximab puede ser una alternativa en estos casos. Nuestro objetivo fue revisar la evidencia científica publicada del uso de rituximab en el tratamiento del SAF primario.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Descripción de un caso propio y revisión de la literatura médica con análisis descriptivo de las características demográficas, clínicas, analíticas, terapéuticas y evolutivas de los pacientes incluidos.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se han identificado 24 pacientes (15 mujeres [62,5%]), con una edad media (DE) de 37,0 (13,4) años. Las indicaciones de uso de rituximab fueron trombocitopenia (41,7%), afectación cutánea (33,3%), afectación neurológica y valvular cardíaca (12,5%), anaemia hemolítica (8,3%) y afectación pulmonar y renal (4,2%). El anticoagulante lúpico fue positivo en el 72,7% de los casos, los isotipos IgG e IgM de los anticuerpos anticardiolipina en el 75 y 50%, respectivamente, y los anticuerpos anti-β2GPI (IgG e IgM) en el 80%. Trece (54,1%) pacientes recibieron 2 dosis quincenales de 1.000<span class="elsevierStyleHsp" style=""></span>mg de rituximab, 10 (41,7%) 4 dosis semanales de 375<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span>, y uno (4,2%) 8 dosis semanales de 375<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span>. Once (45,8%) pacientes presentaron una respuesta clínica completa, 7 (29,2%) una respuesta parcial y 6 (25%) no experimentaron ningún cambio sustancial. Cuatro pacientes con mejoría clínica presentaron una reducción en el título de los AAF, y en uno, los valores no cambiaron. Un paciente sin respuesta clínica los mantuvo positivos. Existió una disociación clínico-analítica en un par de casos.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los datos obtenidos evidencian un posible beneficio potencial de rituximab en el tratamiento de alguna de las manifestaciones clínicas del SAF primario, como la trombocitopenia, la afectación cutánea y la afectación valvular cardíaca.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamento y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Please cite this article as: Pons I, Espinosa G, Cervera R. Eficacia y seguridad de rituximab en el tratamiento del síndrome antifosfolipídico primario: análisis de 24 casos a partir de la revisión de la bibliografía. Med Clin (Barc). 2015;144:97–104.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1152 "Ancho" => 1492 "Tamanyo" => 98631 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of the studies included in the review. APS: antiphospholipid syndrome.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">ACA: anticardiolipin antibodies; anti-β2GPI: antibodies anti-β2-glucoprotein I; SD: standard deviation; F: female; APS: antiphospholipid syndrome; <span class="elsevierStyleSmallCaps">M</span>: male.</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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">Number (%) \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"><span class="elsevierStyleItalic">Gender (M/F)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9/15 (35.5/62.5) \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"><span class="elsevierStyleItalic">Age (mean ± SD)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">37.0<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>13.4 \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"><span class="elsevierStyleItalic">Previous diagnosis of primary APS</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 (83.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Previous clinical manifestations</span></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Thrombosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 (70.8) \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">Obstetric morbidity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (29.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Indications for the use of rituximab</span></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (41.7) \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">Skin involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (33.3) \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">Neurological involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (12.5) \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">Cardiac valvular involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (12.5) \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">Thrombosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (8.3) \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">Serious haemolytic anaemia<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (8.3) \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">Pulmonary involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (4.2) \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">Renal involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (4.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Laboratory data</span></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lupus anticoagulant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8/11 (72.7) \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">ACA IgG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9/12 (75.0) \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">ACA IgM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5/10 (50.0) \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">Anti-β2GPI IgG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4/5 (80.0) \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">Anti-β2GPI IgM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4/5 (80.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab925022.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Defined as <100 × 10<span class="elsevierStyleSup">9</span>/l platelets.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Defined as <7.0 g/l haemoglobin.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Demographic, clinical and analytical characteristics of the patients.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">NR: no response; CR: complete response; PR: partial response.</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">Author and reference \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">Indication \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">Progress \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 (weeks) \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia, cognitive alteration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cognitive alteration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skin ulcers (livedoid vasculitis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skin ulcers (pyoderma gangrenosum) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia, valvulopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Valvulopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">120 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skin ulcers (pyoderma gangrenosum) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skin ulcers (pyoderma gangrenosum) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cognitive alteration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Valvulopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82 \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">Camacho-Lovillo et al.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skin necrosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">96 \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">Scheiman Elazary et al.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alveolar haemorrhage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">96 \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">Sciascia et al.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">11</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">42 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Tsagalis et al.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nephrotic syndrome, livedo reticularis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">108 \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">Adamson et al.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Transient ischaemic attack \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32 \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">Rückert et al.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia, haemolytic anaemia, skin involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">120 \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">Chalam et al.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">15</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombosis (cerebral venous sinuses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36 \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">Ames et al.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 \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">Rubenstein et al.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">48 \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">Rubenstein et al.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">164 \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">Trappe et al.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia, skin involvement \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \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">Erdozain et al.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">19</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Haemolytic anaemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \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">Case described \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Thrombocytopenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">356 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab925023.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Treatment indication, clinical progress and follow-up period.</p>" ] ] 3 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">ASA: acetylsalicylic acid; ACE: acenocumarol; AZA: azathioprine; CPM: cyclophosphamide; C: corticosteroids; CsA: cyclosporine; HCQ: hydroxychloroquine; LMWH: low molecular weight heparin; IVIG: intravenous immunoglobulin; TAC: tacrolimus; TPO: agonists of the thrombopoietin receptor; VIN: vincristine; WAR: warfarin.</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">Author and reference \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">Rituximab guidelines \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">Previous treatments \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">Concomitant treatment \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, IVIG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HCQ, ASA \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">WAR \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ASA score, WAR \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HCQ, WAR \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, IVIG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">WAR \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, TPO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HCQ, WAR \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">WAR \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HCQ, WAR \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ASA \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HCQ, ASA \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">Erkan et al.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ASA \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">Camacho-Lovillo et al.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, CPM, LMWH<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, LMWH, IVIG \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">Scheiman Elazary et al.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, AZA, IVIG, CPM, PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">WAR \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">Sciascia et al.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">11</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4)<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, IVIG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">WAR \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">Tsagalis et al.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4)<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">c</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ASA, LMWH \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">Adamson et al.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly (×2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AZA<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ASA, WAR \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">Rückert et al.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, IVIG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Chalam et al.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">15</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Ames et al.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, AZA, IVIG, CsA, VIN, CPM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LMWH \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">Rubenstein et al.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, PR, IVIG, CPM, VIN, AZA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">WAR \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">Rubenstein et al.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, VIN, IVIG, CPM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Trappe et al.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, IVIG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LMWH \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">Erdozain et al.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">19</span></a> \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/m<span class="elsevierStyleSup">2</span> weekly (×4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, TAC, WAR \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">Described case \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/m<span class="elsevierStyleSup">2</span> weekly (×4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">C, AZA, IVIG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACE \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab925024.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Cases in which rituximab constituted the first line of treatment</p>" ] 1 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">New administration after 375<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> monthly<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>2.</p>" ] 2 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "c" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">New administration of 1,000<span class="elsevierStyleHsp" style=""></span>mg fortnightly<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>2 at 15 months.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Rituximab guidelines, previous drugs and concomitant treatment.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">ACA: anticardiolipin antibodies; anti-β2GPI: antibodies anti-β2-glucoprotein I; APLA: antiphospholipid antibodies; CR: complete response;</p><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">LA: lupus anticoagulant; NA: not available; NR: no response; PR: partial response; ↓: titres decrease;↑: titres increase.</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">Author and reference \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">Initial titration of APLA \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">Clinical progress \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Final titration of APLA \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">Camacho-Lovillo et al.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA, anti-βGPI (−) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA, anti-βGPI (−) \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">Scheiman Elazary et al.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA, anti-βGPI (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACA ↑, anti-βGPI ↓ \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">Sciascia et al.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">11</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA IgG, anti-βGPI IgG (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA IgG, anti-βGPI IgG ↓, ACA IgM, anti-βGPI IgM (−) \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">Tsagalis et al.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACA IgG IgM (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACA IgG, IgM ↓ \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">Adamson et al.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACA IgG (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACA IgG (+) \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">Rückert et al.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA (−), anti-βGPI (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anti-βGPI IgG, IgM ↓ \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">Chalam et al.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">15</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA IgG (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \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">Ames et al.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA IgG IgM (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACA IgG, IgM (+) \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">Rubenstein et al.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA IgG (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \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">Rubenstein et al.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA IgG (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \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">Trappe et al.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA, anti-βGPI (+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ACA IgM (−), ACA IgG, anti-βGPI IgG, IgM (+) \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">Erdozain et al.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">19</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA, ACA IgM (+), ACA IgM (−) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NA \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">Described case \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA (+), ACA IgG IgM (−) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LA (−), ACA (−) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab925021.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Initial titration of antiphospholipid antibodies and progress of the analytical profile based on the clinical response.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:28 [ 0 => array:3 [ "identificador" => "bib0145" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Miyakis" 1 => "M.D. Lockshin" 2 => "T. Atsumi" 3 => "D.W. Branch" 4 => "R.L. Brey" 5 => "R. Cervera" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1538-7836.2006.01753.x" "Revista" => array:6 [ "tituloSerie" => "J Thromb Haemost" "fecha" => "2006" "volumen" => "4" "paginaInicial" => "295" "paginaFinal" => "306" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16420554" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0150" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Morbidity and mortality in the antiphospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G. Espinosa" 1 => "R. Cervera" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/MCP.0b013e32832d0463" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Pulm Med" "fecha" => "2008" "volumen" => "15" "paginaInicial" => "413" "paginaFinal" => "417" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19436204" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0155" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of refractory anti-phospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "T. Scoble" 1 => "S. Wijetilleka" 2 => "M.A. Khamashta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.autrev.2011.04.030" "Revista" => array:6 [ "tituloSerie" => "Autoimmun Rev" "fecha" => "2011" "volumen" => "10" "paginaInicial" => "669" "paginaFinal" => "673" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21558021" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0160" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antiphospholipid Syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G. Ruiz-Irastorza" 1 => "M. Crowther" 2 => "W. Branch" 3 => "M.A. Khamashta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(10)60709-X" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2010" "volumen" => "376" "paginaInicial" => "1498" "paginaFinal" => "1509" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20822807" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0165" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biologic therapy for autoimmune diseases: an update" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Z. Rosman" 1 => "Y. Shoenfeld" 2 => "G. Zandman-Goddard" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1741-7015-11-88" "Revista" => array:5 [ "tituloSerie" => "BMC Med" "fecha" => "2013" "volumen" => "11" "paginaInicial" => "88" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23557513" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0170" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus. The randomized, double-blind, phase <span class="elsevierStyleSmallCaps">II</span>/<span class="elsevierStyleSmallCaps">III</span> systemic lupus erythematosus evaluation of rituximab trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.T. Merrill" 1 => "C.M. Neuwelt" 2 => "D.J. Wallace" 3 => "J.C. Shanahan" 4 => "K.M. Latinis" 5 => "J.C. Oates" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.27233" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2010" "volumen" => "62" "paginaInicial" => "222" "paginaFinal" => "233" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20039413" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0175" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of rituximab in patients with active proliferative lupus nephritis. The lupus nephritis assessment with rituximab study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B.H. Rovin" 1 => "R. Furie" 2 => "K. Latinis" 3 => "R.J. Looney" 4 => "F.C. Fervenza" 5 => "J. Sanchez-Guerrero" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.34359" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2012" "volumen" => "64" "paginaInicial" => "1215" "paginaFinal" => "1226" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22231479" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0180" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rituximab in systemic lupus erythematosus: a systematic review of off-label use in 188 cases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Ramos-Casals" 1 => "M.J. Soto" 2 => "M.J. Cuadrado" 3 => "M.A. Khamashta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/0961203309106174" "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2009" "volumen" => "18" "paginaInicial" => "767" "paginaFinal" => "776" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19578100" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0185" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recurrence of cutaneous necrosis in an infant with probable catastrophic antiphospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Camacho-Lovillo" 1 => "J. Bernabeu-Wittel" 2 => "E. Iglesias-Jimenez" 3 => "D. Falcón-Neyra" 4 => "O. Neth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1525-1470.2012.01832.x" "Revista" => array:6 [ "tituloSerie" => "Pediatr Dermatol" "fecha" => "2013" "volumen" => "30" "paginaInicial" => "e63" "paginaFinal" => "e64" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22957833" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0190" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rituximab induces resolution of recurrent diffuse alveolar hemorrhage in a patient with primary antiphospholipid antibody syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Scheiman Elazary" 1 => "P.P. Klahr" 2 => "A.Y. Hershko" 3 => "Z. Dranitzki" 4 => "A. Rubinow" 5 => "Y. Naparstek" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/0961203311422713" "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2012" "volumen" => "21" "paginaInicial" => "438" "paginaFinal" => "440" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21993385" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0195" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment-induced downregulation of antiphospholipid antibodies: effect of rituximab alone on clinical and laboratory features of antiphospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Sciascia" 1 => "C. Naretto" 2 => "D. Rossi" 3 => "M. Bazzan" 4 => "D. Roccatello" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/0961203311400115" "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2011" "volumen" => "20" "paginaInicial" => "1106" "paginaFinal" => "1108" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21652607" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0200" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effective treatment of antiphospholipid syndrome with plasmapheresis and rituximab" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G. Tsagalis" 1 => "E. Psimenou" 2 => "L. Nakopoulou" 3 => "A. Laggouranis" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Hippokratia" "fecha" => "2010" "volumen" => "14" "paginaInicial" => "215" "paginaFinal" => "216" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20981174" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0205" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical improvement in antiphospholipid syndrome after rituximab therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Adamson" 1 => "S. Sangle" 2 => "A. Kaul" 3 => "G.R. Hughes" 4 => "D.P. D’Cruz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/RHU.0b013e31818f38d4" "Revista" => array:6 [ "tituloSerie" => "J Clin Rheumatol" "fecha" => "2008" "volumen" => "14" "paginaInicial" => "359" "paginaFinal" => "360" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19033874" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0210" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Successful treatment of life-threatening Evans syndrome due to antiphospholipid antibody syndrome by rituximab-based regimen: a case with long-term follow-up" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Rückert" 1 => "H. Glimm" 2 => "M. Lübbert" 3 => "C. Grüllich" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/0961203307087876" "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2008" "volumen" => "17" "paginaInicial" => "757" "paginaFinal" => "760" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18625656" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0215" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rituximab effectively reverses papilledema associated with cerebral venous sinus thrombosis in antiphospholipid antibody syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "K.V. Chalam" 1 => "S.K. Gupta" 2 => "S. Agarwal" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur J Ophthalmol" "fecha" => "2007" "volumen" => "17" "paginaInicial" => "867" "paginaFinal" => "870" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17932872" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0220" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Limited effect of rituximab on thrombocytopaenia and anticardiolipin antibodies in a patient with primary antiphospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "P.R. Ames" 1 => "C. Tommasino" 2 => "G. Fossati" 3 => "G. Scenna" 4 => "V. Brancaccio" 5 => "F. Ferrara" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00277-006-0226-x" "Revista" => array:6 [ "tituloSerie" => "Ann Hematol" "fecha" => "2007" "volumen" => "86" "paginaInicial" => "227" "paginaFinal" => "228" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17119963" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0225" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rituximab treatment for resistant antiphospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "E. Rubenstein" 1 => "D.G. Arkfeld" 2 => "S. Metyas" 3 => "S. Shinada" 4 => "S. Ehresmann" 5 => "H.A. Liebman" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Rheumatol" "fecha" => "2006" "volumen" => "33" "paginaInicial" => "355" "paginaFinal" => "357" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16465669" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0230" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Successful treatment of thrombocytopenia in primary antiphospholipid antibody syndrome with the anti-CD20 antibody rituximab – monitoring of antiphospholipid and anti-GP antibodies: a case report" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "R. Trappe" 1 => "A. Loew" 2 => "P. Thuss-Patience" 3 => "B. Dörken" 4 => "H. Riess" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00277-005-0028-6" "Revista" => array:6 [ "tituloSerie" => "Ann Hematol" "fecha" => "2006" "volumen" => "85" "paginaInicial" => "134" "paginaFinal" => "135" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16292550" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0235" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sustained response to rituximab of autoimmune hemolytic anemia associated with antiphospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J.G. Erdozain" 1 => "G. Ruiz-Irastorza" 2 => "M.V. Egurbide" 3 => "C. Aguirre" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Haematologica" "fecha" => "2004" "volumen" => "89" "paginaInicial" => "ECR34" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15377486" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0240" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of rituximab on clinical and laboratory features of antiphospholipid syndrome: a case report and a review of literature" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G.L. Erre" 1 => "S. Pardini" 2 => "R. Faedda" 3 => "G. Passiu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/0961203307085251" "Revista" => array:6 [ "tituloSerie" => "Lupus" "fecha" => "2008" "volumen" => "17" "paginaInicial" => "50" "paginaFinal" => "55" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18089684" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0245" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A pilot open label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D. Erkan" 1 => "J. Vega" 2 => "G. Ramon" 3 => "E. Kozora" 4 => "M.D. Lockshin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.37759" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2013" "volumen" => "65" "paginaInicial" => "464" "paginaFinal" => "471" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23124321" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0250" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thrombogenic properties of murine anti-cardiolipin antibodies induced by beta 2 glycoprotein 1 and human immunoglobulin G antiphospholipid antibodies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S.S. Pierangeli" 1 => "S.W. Liu" 2 => "G. Anderson" 3 => "J.H. Barker" 4 => "E.N. Harris" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Circulation" "fecha" => "1996" "volumen" => "94" "paginaInicial" => "1746" "paginaFinal" => "1751" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8840870" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0255" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Some patients with primary antiphospholipid syndrome have increased circulating CD5+ B cells that correlate with levels of IgM antiphospholipid antibodies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M.C. Velasquillo" 1 => "J. Alcocer-Varela" 2 => "D. Alarcón-Segovia" 3 => "J. Cabiedes" 4 => "J. Sánchez-Guerrero" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Exp Rheumatol" "fecha" => "1991" "volumen" => "9" "paginaInicial" => "501" "paginaFinal" => "505" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1720070" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0260" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immunization of naive BALB/c mice with human beta2-glycoprotein I breaks tolerance to the murine molecule" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Tincani" 1 => "B. Gilburd" 2 => "M. Abu-Shakra" 3 => "M. Blank" 4 => "F. Allegri" 5 => "R. Ottaviani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.10304" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2002" "volumen" => "46" "paginaInicial" => "1399" "paginaFinal" => "1404" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12115248" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0265" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anticardiolipin antibodies in NZW<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>BXSB F1 mice. A model of antiphospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Hashimoto" 1 => "M. Kawamura" 2 => "K. Ichikawa" 3 => "T. Suzuki" 4 => "T. Sumida" 5 => "S. Yoshida" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "1992" "volumen" => "149" "paginaInicial" => "1063" "paginaFinal" => "1068" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1634762" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0270" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CTLA4Ig prevents initiation but not evolution of anti-phospholipid syndrome in NZW/BXSB mice" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Akkerman" 1 => "W. Huang" 2 => "X. Wang" 3 => "M. Ramanujam" 4 => "L. Schiffer" 5 => "M. Madaio" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/08916930400008524" "Revista" => array:6 [ "tituloSerie" => "Autoimmunity" "fecha" => "2004" "volumen" => "37" "paginaInicial" => "445" "paginaFinal" => "451" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15621570" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0275" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Braendstrup" 1 => "O.W. Bjerrum" 2 => "O.J. Nielsen" 3 => "B.A. Jensen" 4 => "N.T. Clausen" 5 => "P.B. Hansen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/ajh.20276" "Revista" => array:6 [ "tituloSerie" => "Am J Hematol" "fecha" => "2005" "volumen" => "78" "paginaInicial" => "275" "paginaFinal" => "280" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15795920" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0280" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New approaches for managing antiphospholipid syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2017 October | 9 | 0 | 9 |
| 2017 September | 18 | 5 | 23 |
| 2017 August | 12 | 7 | 19 |
| 2017 July | 8 | 1 | 9 |
| 2017 June | 17 | 7 | 24 |
| 2017 May | 4 | 3 | 7 |
| 2017 April | 13 | 2 | 15 |
| 2017 March | 7 | 3 | 10 |
| 2017 February | 7 | 1 | 8 |
| 2017 January | 6 | 1 | 7 |
