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Efficacy of Leflunomide 100mg Weekly Compared to Low Dose Methotrexate in Patients With Active Rheumatoid Arthritis. Double Blind, Randomized Clinical Trial
Eficacia de leflunomida 100mg semanales comparado con dosis bajas de metotrexate en pacientes con artritis reumatoide activa. Estudio clínico doble ciego aleatorizado
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"documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Reumatol Clin. 2012;8:243-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 13314 "formatos" => array:3 [ "EPUB" => 199 "HTML" => 9667 "PDF" => 3448 ] ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original</span>" "titulo" => "Eficacia de leflunomida 100<span class="elsevierStyleHsp" style=""></span>mg semanales comparado con dosis bajas de metotrexate en pacientes con artritis reumatoide activa. Estudio clínico doble ciego aleatorizado" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "243" "paginaFinal" => "249" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Efficacy of leflunomide 100<span class="elsevierStyleHsp" style=""></span>mg weekly compared to low dose methotrexate in patients with active rheumatoid arthritis. Double blind, randomized clinical trial" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figura 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 855 "Ancho" => 1532 "Tamanyo" => 64597 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">En este gráfico se muestran los resultados e respuesta final de ambos grupos a la semana 52 del estudio. Corresponde al grupo de LFN una buena respuesta del 51,5% en comparación del de MTX con un 37,5%. 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Double Blind, Randomized Clinical Trial" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "243" "paginaFinal" => "249" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Jorge Jaimes-Hernández, Claudia Irene Meléndez-Mercado, Angélica Mendoza-Fuentes, Pablo Aranda-Pereira, Gilberto Castañeda-Hernández" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Jorge" "apellidos" => "Jaimes-Hernández" "email" => array:1 [ 0 => "jorjaimes@yahoo.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Claudia Irene" "apellidos" => "Meléndez-Mercado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Angélica" "apellidos" => "Mendoza-Fuentes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Pablo" "apellidos" => "Aranda-Pereira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Gilberto" "apellidos" => "Castañeda-Hernández" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Reumatología, Centro Médico ISSEMYM, Toluca, Mexico" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional de México, México D.F., Mexico" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Eficacia de leflunomida 100<span class="elsevierStyleHsp" style=""></span>mg semanales comparado con dosis bajas de metotrexate en pacientes con artritis reumatoide activa. Estudio clínico doble ciego aleatorizado" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 861 "Ancho" => 1549 "Tamanyo" => 68889 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">This graph shows the results and final response in both groups at week 52 of the study. LFN group presented a good response in 51.5% compared to 37.5% of the MTX patients. Applying EULAR remission criteria (<2.6 points), 7 patients of the LFN group and 6 of the MTX group achieved remission.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Leflunomide (LFN) is a non-biological disease-modifying antirheumatic drug (DMARD), an inhibitor of purine synthesis, which is indicated for the treatment of rheumatoid arthritis (RA). There are several published clinical studies that have demonstrated its benefit and safety, being considered equivalent to treatment with sulfasalazine (SFA) or methotrexate (MTX).<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">One problem that prevails in the treatment of RA is the compliance (respecting prescription doses) and adherence (to maintain the treatment for a long period of time) to DMARD treatment, a difficult situation to achieve due to multiple factors such as are polypharmacy, adverse drug events and the high cost of treatment, especially in those patients who lack social security coverage, all of which makes it difficult to obtain good long-term clinical outcomes in routine clinical practice.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Seeking treatment alternatives that benefit the compliance and adherence of the treatments, as well as maintains the effectiveness of antirheumatic treatment, we developed an open descriptive study using LFN weekly doses of 100<span class="elsevierStyleHsp" style=""></span>mg in active RA patients followed up to 6 months, who achieved clinical improvement according to criteria of the American College of Rheumatology (ACR), with no evidence of serious adverse events.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In the present study, we describe the efficacy and safety results of patients treated in a randomized, comparative, double-blind trial of LFN given at a weekly dose of 100<span class="elsevierStyleHsp" style=""></span>mg, compared with a fixed low dose of MTX 10<span class="elsevierStyleHsp" style=""></span>mg/week with 52 weeks of follow up.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Patients and Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Patient Population</span><p id="par0025" class="elsevierStylePara elsevierViewall">Patients included in the study were adults who met the ACR1987<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> criteria for classification as active RA. Patients were enrolled from June 2004 to December 2007 from the outpatient clinic of RA. Active RA was defined for those patients who had at least 6 or more swollen (SJ) and painful (PJ) joints, morning stiffness greater than 30<span class="elsevierStyleHsp" style=""></span>min and erythrocyte sedimentation rate (ESR) of 20<span class="elsevierStyleHsp" style=""></span>mm/h or greater. Previous treatment with DMARDs should have been suspended at least one month prior to enrollment, and more than 3 months prior for LFN or MTX. Newly diagnosed patients without DMARD treatment were also included.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The use of prednisone or its equivalent was allowed with a regular dose not exceeding 10<span class="elsevierStyleHsp" style=""></span>mg daily for the shortest possible time. Patients were excluded if a history of high alcohol consumption was present and pregnancy or a possibility thereof. Baseline laboratory studies requested for inclusion were: normal count of white blood cells, hemoglobin concentration greater than 12<span class="elsevierStyleHsp" style=""></span>g/dl, albumin levels ≥3.5<span class="elsevierStyleHsp" style=""></span>g/d, normal liver function tests and if female, negative pregnancy test.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Study Protocol</span><p id="par0035" class="elsevierStylePara elsevierViewall">A randomized controlled trial with a 52-week follow up started in 2004 after approval by the local Committee for Research and Ethics with the registration number 11331-1200-209B-UEeI 322-2003 at the State and Municipalities Social Security Institute of Mexico (ISSEMyM), conducted under the guidelines of the International Declaration of Helsinki. The process of informed consent was required for all patients and in addition, females and patients of reproductive age were required to show confirmation of not being pregnant and the use of effective birth control during the development of protocol or until the doctor indicated.</p><p id="par0040" class="elsevierStylePara elsevierViewall">All patients underwent complete medical history, physical examination, laboratory tests and radiographs of hands and feet, the latter for purposes of diagnostic classification. Clinimetric determinations were recorded, which included: 28 joint count (tender and swollen), patient (PGA) and physician (MDGA) global assessment on a visual analog scale (VAS 0–100<span class="elsevierStyleHsp" style=""></span>mm), patient pain score (VAS 0–100<span class="elsevierStyleHsp" style=""></span>mm), a validated functional physical limitation questionnaire for Spanish-speaking patients (HAQ-Di in Spanish)<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>; baseline laboratory studies required were erythrocyte sedimentation rate (ESR, Westergren), C-reactive protein, blood count and liver function tests. Clinical and laboratory tests were performed at the start of patient enrollment and monthly for 3 months, followed by visits every 2 months to complete the 52-week follow up. The X-ray studies of hands and feet were made only at the beginning of the protocol. All laboratory tests and imaging were performed at Toluca's ISSEMyM Medical Center, under standardized techniques validated according to international protocols of good clinical laboratory practice.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The primary study objective was to evaluate the clinical improvement of the disease according to ACR improvement criteria, with 20% improvement in swollen and tender joints and at least one of the following to determine ACR improvement: pain, global assessment of disease by the patient and the physician, HAQ-DI and acute phase reactants. Also included were additional ACR 50 and 70<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> results, DAS 28, the criteria for disease activity and improvement of the European League Against Rheumatism (EULAR) at each visit and at the end of the study, EULAR<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> referral criteria and recording of treatment discontinuation due to adverse events.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The criteria for discontinuation of patients in the study were applied to all those who did not achieve ACR 20 improvement at week 16, or if the patient had serious adverse events (SAE), which would require unblinding the drug safety status. For patients who had elevation of transaminases in a recurring manner, we discontinued them from the study with the following criteria: values greater than 2.5 times normal transaminase levels (AST and ALT) for 2 consecutive months.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Assigning Treatment Groups</span><p id="par0055" class="elsevierStylePara elsevierViewall">Patients were randomized into 2 blocks using a table of random numbers, without the intervention of the research group (1:1): the target for the LFN group and a control group of MTX. For the target LFN group, a loading dose of 100<span class="elsevierStyleHsp" style=""></span>mg/day for 3 consecutive days was given, based on the average half-life of the drug, and administered at a weekly dose of 100<span class="elsevierStyleHsp" style=""></span>mg. For the MTX group, a fixed low dose of 10<span class="elsevierStyleHsp" style=""></span>mg weekly was administered; for both groups, placebos were administered in numerical form in an equivalent manner to achieve the blinding of patients and medical researchers.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical Analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">The primary objective of the study was to compare the efficacy and safety of a weekly dose of 100<span class="elsevierStyleHsp" style=""></span>LFN mg compared to the effect achieved with low dose of MTX 10<span class="elsevierStyleHsp" style=""></span>mg weekly. The efficacy was measured by ACR 20 improvement criteria as a study endpoint at 52 weeks of treatment. Variables also included were ACR 50 and 70 improvement, EULAR improvement criteria, and an independent evaluation of the ESR and HAQ-Di variables.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Efficacy was established by independent-samples ANOVA between groups at 8, 24 and 52 weeks. Data were considered statistically significant if <span class="elsevierStyleItalic">P</span>≤.05. Safety was analyzed according to the percentage of adverse events reported in each group.</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0070" class="elsevierStylePara elsevierViewall">Of the 90 patients evaluated for study entry, 5 were excluded, and the 85 remaining were randomized into 2 groups as follows: a group of 43 patients were assigned to LFN and 42 to MTX (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Both groups of patients were assessed at least once during follow up from the baseline visit. The demographics and disease characteristics were similar for both groups (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Three patients were treated with DMARDs prior to enrollment, 2 for the LFN group. One of them who received LFN 20<span class="elsevierStyleHsp" style=""></span>mg/day and hydroxychloroquine for 2 months discontinued treatment for 7 months before being randomized to the LFN group. A second patient, with an irregular treatment, took MTX for a month, 3 months after being randomized to the LFN group. Finally, in a patient receiving conventional LFN, diffuse alopecia developed after 2½ months and treatment was suspended; the patient was sent to our hospital and included in pre-randomization, after no treatment was given for 3 months, to the MTX group. Sixty-three patients completed 52 weeks of treatment, 31 in the LFN (72%) and 32 in the MTX group (74.4%). Early discontinuation of patients at week 16 occurred more often in the LFN than in the MTX group (19.4 vs 5%), respectively. At the end of the study, the total of patients who left were 21, either by loss to follow up or adverse events. Twelve cases occurred (27.9%) in the LFN and 10 patients (23.8%) in the MTX group. Discontinuation due to lack of efficacy was found in 2 patients in the LFN group (5.2%) and in 4 cases with MTX (12.1%) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The ACR improvement criteria were assessed at weeks 8, 24, and 52. In patients assigned to LFN, 28 (80%) achieved ACR 20 at week 24 and in 29 cases (93.5%) at week 52. For the MTX group the results showed that 30 patients (83%) achieved ACR 20 at week 24 and 25 (78.1%) at week 52; comparing the two groups, there was no statistically significant difference (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). Evaluating the results of the study end point for ACR 50 and ACR 70 we found no significant differences by comparing the groups for these variables (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The independent variables were evaluated and the results of the HAQ-Di at baseline scored 0.96 for the LFN group and 0.83 for MTX (<span class="elsevierStyleItalic">P</span>=.27). The final evaluation of study data showed a score of 0.23 for LFN and 0.39 for MTX, with a reduction of 0.7 and 0.43, respectively for each study group, with a marginal difference when evaluating this data (<span class="elsevierStyleItalic">P</span>=.05) in the LFN group.</p><p id="par0085" class="elsevierStylePara elsevierViewall">EULAR criteria for improvement and remission were evaluated at week 52 of the study. Initial DAS 28 results of the LFN group were 5.83 and 3.45 at 52 weeks (2.38 reduction points). For the MTX group a baseline score of 5.60 was seen, 3.67 at study end, with a net reduction of 1.93 points. There were also no statistically significant differences when comparing results between the two groups (<span class="elsevierStyleItalic">P</span>=.43). The standard cutoffs to define improvement in EULAR DAS 28 were as follows: <3.2 points=good response, from 3.2 to 5.1 moderate response >5.1 points no response (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Applying the EULAR remission criteria (<2.6 points), 11 patients of both groups met this criterion.</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Safety</span><p id="par0090" class="elsevierStylePara elsevierViewall">Serious adverse events were considered by investigators in 9 cases, 2 dermatological reactions occurred in patients in the LFN group, one of them developing severe rash, another erythema multiforme on the trunk. Six patients had elevated liver enzymes 2.5 times above the normal range, four of them received LFN and 2 belonged to the MTX group and they were all withdrawn from the study (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><p id="par0095" class="elsevierStylePara elsevierViewall">Less important events recorded for both groups included vasculitis, pruritus, alopecia, and headache. Presence of infections was observed in both groups, with a slightly higher percentage in patients with MTX treatment (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Gastrointestinal adverse events (GI) are described in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>, where episodes of diarrhea were more often present in the LNF group. The data recorded regarding alterations in liver function tests were as follows: 7 and 17 cases had elevated liver enzymes in the LFN and MTX groups. Four (9.3%) in the LFN group remained >2.5 times the normal range, so patients were withdrawn from the study. In 3 other patients, despite the high values referred to above, these returned to normal levels during the study. For the MTX group, 2 patients had elevations for which they were eliminated, another 7 returned to normal baseline levels without recurrence at study end; there were no statistically significant differences when comparing both groups (<span class="elsevierStyleItalic">P</span>=.02) (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>). Three cases of hypertension were detected, 2 in the LFN and one in the MTX group for both groups and classified as a minor event. Finally hematologic abnormalities documented in the LFN group consisted of leukopenia in 4 patients, 2 with anemia and one with thrombocytopenia; in the case of MTX there were 2 cases of leukopenia, 2 with anemia and one with mild thrombocytopenia.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">There were no adverse events that would jeopardize the lives of patients in any of the 2 groups.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">In daily practice, rheumatologists have a need for RA treatment regimens that are effective and safe, in addition to being flexible in their administration, in order to maintain adherence and compliance to treatment and thus achieve the goals and objectives of clinical improvement or remission of disease.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">LFN is a non-biological DMARDs belonging to the isoxazole class; after administration it is rapidly converted to its active metabolite A77 1726; this metabolite induces its therapeutic effect by inhibiting the enzyme dihydrorotate dehydrogenase. This is an important key enzyme in pyrimidine de novo production in T lymphocytes. This molecule has a long plasma life of about 2 weeks (14–18 days).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Published studies indicate that the ACR 20 improvement criteria in patients with RA treated with MTX monotherapy ranges from 40% to 60% at 6 and 12 months of follow up.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> On the other hand, it is well known that treatment of RA patients at doses of 20 LFN mg/day has shown benefit in clinical response similar to MTX and other DMARDs as SSZ.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11–13</span></a> Jakez-Ocampo et al. published a pilot study using LFN as an open treatment at 100<span class="elsevierStyleHsp" style=""></span>mg weekly in patients with refractory RA.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> This study included 16 patients, 8 of them in treatment with LFN 100<span class="elsevierStyleHsp" style=""></span>mg/week and another 8 with the regular dose of 20<span class="elsevierStyleHsp" style=""></span>mg daily followed by a period of one year. The base treatment of patients was not changed, including at least the combination of 2 or 3 DMARDs in association with different doses of steroids. The results showed benefits in the initial treatment group of LFN 20<span class="elsevierStyleHsp" style=""></span>mg/day; however, at the end of the study, no statistically significant differences between the 2 groups, including the development of ACR 20 improvement, was seen. Minor events were reported more frequently in the LFN 20<span class="elsevierStyleHsp" style=""></span>mg/day group. A second study was conducted by the same authors,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> this time in 3 groups with a diagnosis of early RA (less than one year since onset). Thirty patients were divided into 3 groups: the first group of 10 patients treated with LFN 100<span class="elsevierStyleHsp" style=""></span>mg/week, the second group of 10 patients treated with LFN 20<span class="elsevierStyleHsp" style=""></span>mg/day and a third group treated with MTX at a dose of 7.5–15<span class="elsevierStyleHsp" style=""></span>mg/week, with a one year of follow up. By the eighth week of the study, response was observed in all 3 groups, noting again the fastest response in the LFN<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>mg/day group compared to LFN 100/week and MTX/week with a <span class="elsevierStyleItalic">P</span>=.001 and <span class="elsevierStyleItalic">P</span>=.03, respectively. The variables assessed at the end of the study showed no significant differences in any of the 3 groups. In relation, the presence of adverse events was more frequent in the LFN 20<span class="elsevierStyleHsp" style=""></span>mg/day and MTX/week groups compared to LFN 100<span class="elsevierStyleHsp" style=""></span>mg/week.</p><p id="par0120" class="elsevierStylePara elsevierViewall">In addition, our group previously performed an open 6 month clinical trial at LFN weekly dose of 100<span class="elsevierStyleHsp" style=""></span>mg in patients with active RA.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Fifty patients were enrolled in the study, starting treatment with a loading dose of 100<span class="elsevierStyleHsp" style=""></span>mg/day for 3 days followed by a weekly dose of 100<span class="elsevierStyleHsp" style=""></span>LFN mg for a period of 6 months. After 12 weeks, 75% of patients had achieved ACR 20 improvement response and 58% achieved an ACR 50. At study end, 74% achieved ACR 20, 64% of patients achieved ACR 50 and ACR 70 28% improvements.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Adverse events reported in the study ranged from 2% to 16%, which included headache, rash, hair loss, elevated liver enzymes and diarrhea. It was concluded that clinical benefit in response to a weekly regimen of 100<span class="elsevierStyleHsp" style=""></span>mg of LFN is associated with minor adverse events already reported previously.</p><p id="par0130" class="elsevierStylePara elsevierViewall">The results obtained in this study show that both drugs, at doses lower than those recommended, help compliance and adherence to treatment in a very acceptable percentage, emphasizing that the low dose of MTX of 10<span class="elsevierStyleHsp" style=""></span>mg/week is only presently recommended at baseline, increasing it if tolerated quickly and in a stepwise fashion.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> We observed that at week 52, retention of patients was 31 patients (72%) and 32 cases (76%) for the LFN and MTX groups, respectively, with an overall retention of 74%, a situation that differs from reports by other authors, which present more than a 50% loss in studies to LFN at a standard<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> dose; a similar number is reported in patients with long-term treatment with MTX.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The results of ACR improvement, HAQ-DI and ESR did not differ between groups, stressing that the dose of MTX used is currently considered suboptimal and not comparable for assessment of the efficacy of MTX in this study, as the current recommendations of EULAR point out, where a rapid increase up to 20 or 25<span class="elsevierStyleHsp" style=""></span>mg/week is indicated in order to reduce clinical activity. Of patients who completed the study in the LFN group, 28 achieved an ACR 20 response (90.3%) at week 52 (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>); however, applying the calculation of patients intended to treat (ITT), the ACR 20 response was 67.4%. Two patients were eliminated from the LFN group for not achieving ACR 20 improvement, compared to MTX where 4 cases did not achieve it.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Regarding adverse events, those seen in the LFN group were similar to those reported in the literature, affecting the skin with erythematous urticaria, alopecia and diarrhea. Liver toxicity was apparently lower in the LFN group, and only one patient remained with persistent enzyme elevation; in this case we ruled out viral hepatitis, and only found fatty liver by conventional ultrasound. The few non-serious adverse events identified were probably related to the low dose of LFN employed.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">We conclude that the weekly dose of 100<span class="elsevierStyleHsp" style=""></span>mg of LFN provides an adequate and sustained response in patients who respond to this drug, allowing for greater adhesion and compliance than reported in the literature for conventional treatment, besides apparently showing fewer reported adverse events compared with the recommended standard dose. It currently constitutes the loading dose in common practice and is not commonly used as described here; therefore, unfortunately some countries have recalled tablets with LFN 100<span class="elsevierStyleHsp" style=""></span>mg. This scheme also opens the possibility of its use as monotherapy or in combination with other DMARDs, including MTX as an attractive option avoiding polypharmacy.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Moreover, the weekly dose of 100<span class="elsevierStyleHsp" style=""></span>LFN mg/week represents a savings for patients, using a lower dose of the drug while maintaining its effectiveness and this situation applies only in countries where there is no health system that allows full coverage of the population.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Finally, we emphasize that the lack of efficacy observed in patients in the MTX group could be a reflection of the low dose used for the purposes of this study, but by no means constitute a recommendation by the authors for use in daily clinical practice.</p><p id="par0155" class="elsevierStylePara elsevierViewall">Studies with larger populations and longer durations will ratify the results we obtained in this study.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Financing</span><p id="par0160" class="elsevierStylePara elsevierViewall">This study or the researchers had no financial relationship with the pharmaceutical industry. The drugs employed were obtained through the institute (ISSEMyM) where research was carried out.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of Interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres125927" "titulo" => array:5 [ 0 => "Abstract" 1 => "Objective" 2 => "Patients and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec113223" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres125928" "titulo" => array:5 [ 0 => "Resumen" 1 => "Objetivos" 2 => "Pacientes y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec113222" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Patients and Methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patient Population" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Study Protocol" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Assigning Treatment Groups" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Statistical Analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Safety" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Financing" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of Interest" ] 11 => array:2 [ "identificador" => "xack38128" "titulo" => "Acknowledgements" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-12-31" "fechaAceptado" => "2012-03-30" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec113223" "palabras" => array:4 [ 0 => "Leflunomide" 1 => "Treatment of rheumatoid artritis" 2 => "Monotherapy" 3 => "Adverse events in leflunomide" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec113222" "palabras" => array:4 [ 0 => "Leflunomida" 1 => "Tratamiento de artritis reumatoide" 2 => "Monoterapia" 3 => "Eventos adversos de leflunomida" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To determine the clinical efficacy and safety of Leflunomide (LFN) 100<span class="elsevierStyleHsp" style=""></span>mg/week compared to low dose Methotrexate (MTX) 10<span class="elsevierStyleHsp" style=""></span>mg/week in a double-blind, randomized, controlled trial with 52 weeks of follow up in Rheumatoid Arthritis (RA) patients.</p> <span class="elsevierStyleSectionTitle">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Patients who met ARC1987 criteria for RA were included. All patients had medical records, including laboratory tests and hand X-rays. Clinical evaluations for improvement and ACR and EULAR response criteria were performed. Statistical analysis for independent's samples between both groups defined a <span class="elsevierStyleItalic">P</span> value of ≤.05. Safety was evaluated by comparing the proportion of adverse events (AE) registered.</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Of the 90 patients screened, five were withdrawn and the remaining 85 patients were randomized: 43 LFN and 42 MTX. Sixty-three patients completed the study, 72% in the LFN group and 74.4% in the MTX group. ACR20 improvement criteria were achieved by LFN group in 90.3%, and in MTX 78.1% (<span class="elsevierStyleItalic">P</span>=.14) at week 52. EULAR improvement criteria applied at the end point showed a DAS28 score for the LFN group of 3.45, and for the MTX group was 3.67 (<span class="elsevierStyleItalic">P</span>=.43). Total withdrawals including loss during follow up, AE and lack of efficacy for each group was 12 patients in the LFN group, and 10 patients in the MTX group. Regarding safety, no serious AE of a life threatening nature were reported.</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">These outcomes confirm that LFN 100<span class="elsevierStyleHsp" style=""></span>mg/week offers an adequate and sustained improvement effect on the clinical manifestations of RA, similar to low dose treatment with MTX 10<span class="elsevierStyleHsp" style=""></span>mg/every week after 52 weeks of follow up; it may be a good therapeutic option alone or in combination with other anti-rheumatic drugs.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estudio clínico aleatorizado para determinar la eficacia y seguridad de leflunomida (LFN) 100<span class="elsevierStyleHsp" style=""></span>mg/semana en artritis reumatoide (AR), comparado con dosis bajas de metotrexate (MTX) 10<span class="elsevierStyleHsp" style=""></span>mg/semana a 52 semanas.</p> <span class="elsevierStyleSectionTitle">Pacientes y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron pacientes con criterios de AR activa (ACR1987). Fueron realizados estudios de laboratorio, radiografías de manos y determinaciones clinimétricas para establecer criterios de respuesta clínica de ACR y EULAR. El análisis estadístico se obtuvo a través de mejoría ACR20. La eficacia se estableció por análisis de ANOVA de muestras independientes entre ambos grupos (p<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>0,05). La seguridad fue analizada con porcentaje de eventos adversos.</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">De 90 pacientes evaluados, 5 fueron eliminados; 85 aleatorizados e incluidos en 2 grupos: 43 (LFN) y 42 (MTX). Completaron el estudio con LFN el 72% y con MTX el 74,4%. El criterio de mejoría de ACR20 al final del estudio fue alcanzado para LFN en 90,3% y para MTX 78,1%, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,14. El valor DAS28 al final para LFN fue de 3,45, y para MTX de 3,67, no existiendo diferencias significativas (p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,43). Los pacientes excluidos para LFN fueron 11, y 10 para MTX. La falla terapéutica se definió en 5,2% para LFN, y 12,1 en el caso de MTX. No se reportaron eventos adversos graves que pusieran en riesgo la vida de los pacientes.</p> <span class="elsevierStyleSectionTitle">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los resultados confirman que LFN usada en dosis semanales de 100<span class="elsevierStyleHsp" style=""></span>mg, ofrece una adecuada y sostenida mejoría de las manifestaciones clínicas de AR, al compararlo con una dosis baja de MTX. Pudiendo ser una opción terapéutica en algunos pacientes como monoterapia o en combinación con otros antirreumáticos.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Jaimes-Hernández J, et al. Eficacia de leflunomida 100<span class="elsevierStyleHsp" style=""></span>mg semanales comparado con dosis bajas de metotrexate en pacientes con artritis reumatoide activa. Estudio clínico doble ciego aleatorizado. Reumatol Clin. 2012;8:243–9.</p>" ] ] "multimedia" => array:8 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2069 "Ancho" => 2340 "Tamanyo" => 174368 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">This Flowchart shows the progression of the patients evaluated and included in the study. Patients were excluded if they did not meet inclusion criteria, two were lost to follow-up and one withdrew informed consent before randomization. Twelve patients withdrew from the LFN group and 10 from the MTX. The reason for exclusion is explained in detail in the text. End of the study was achieved in 74% for both groups, 31 patients in the LFN and 32 in the MTX.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1035 "Ancho" => 1500 "Tamanyo" => 71547 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Percentage of patients reaching the ACR 20 response criteria at 24 and 52 weeks. There were no statistically significant differences between groups.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 986 "Ancho" => 1514 "Tamanyo" => 76893 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Percentage of patients who achieved ACR improvement. No statistically significant difference was seen when comparing the two groups.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 861 "Ancho" => 1549 "Tamanyo" => 68889 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">This graph shows the results and final response in both groups at week 52 of the study. LFN group presented a good response in 51.5% compared to 37.5% of the MTX patients. Applying EULAR remission criteria (<2.6 points), 7 patients of the LFN group and 6 of the MTX group achieved remission.</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 972 "Ancho" => 1597 "Tamanyo" => 112164 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">The behavior of the average serum levels of liver enzymes for each group, indicating that over time the LFN group had a tendency to maintain optimal levels.</p>" ] ] 5 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">SD: standard deviation; VAS: visual analog scale; DMARD: disease modifying antirheumatic drugs.</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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Leflunomide Group±SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Methotrexate Group±SD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of patients (No.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age, years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42.8 (±11.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42.1 (±10.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.76<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Female, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">88.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.56<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Duration of the disease, months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25.2 (±6.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20.9 (±3.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.57<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tender joint count, 0–28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.1 (±5.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11.5 (±6.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.74<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Swollen joint count, 0–28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.9 (±4.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.5 (±4.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.17<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Global disease score by the patient (activity), 0–100<span class="elsevierStyleHsp" style=""></span>mm, VAS<span class="elsevierStyleSup">&</span>. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43.1 (±15.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44.5 (±15.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.67<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Global disease score by the physician (activity), 0–100<span class="elsevierStyleHsp" style=""></span>mm, VAS<span class="elsevierStyleSup">&</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52.2 (±12.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52.1 (±15.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.95<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pain score, 0–100<span class="elsevierStyleHsp" style=""></span>mm, WAS<span class="elsevierStyleSup">&</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70.7 (±26.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70.6 (±20.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.98<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HAQ-Di \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.96 (±0.09) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.83 (±0.07) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.27<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DAS 28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.8 (±0.96) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.6 (±0.88) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.24<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Theumatoid factor presence, % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 (±95.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 (±90.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.53<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Erythrosedimentation rate, mm/h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35.4 (±13.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30.2 (±15.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">.10<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prior DMARD treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (4.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (2.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212436.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara"><span class="elsevierStyleItalic">P</span>: no statistically significant differences were seen between groups; <span class="elsevierStyleItalic">P</span>≤.05.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Disease Characteristics and Demographic Data.</p>" ] ] 6 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">A greater number of upper respiratory tract infections were seen in the MTX than in the LFN group.</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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">LFN=43</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">MTX=42</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">No. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">(%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">No. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">(%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Upper respiratory tract infections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28.5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urinary infection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastroenteritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Herpes zoster \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vulvovaginitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212437.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Infectious Diseases Registered.</p>" ] ] 7 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Gastrointestinal events such as gastritis and diarrhea were more frequently reported in the LFN than in the MTX group, as seen in the literature; however, abdominal distension was more common in the MTX group.</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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">LFN=43</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">MTX=42</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">No. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">(%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">No. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">(%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gastritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diarrhea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abdominal Distension \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nausea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.3 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212435.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Non-liver Gastrointestinal Effects.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:19 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.L. Scott" 1 => "J.S. Smolen" 2 => "J.R. Kalden" 3 => "L.B.A. Van de Putte" 4 => "A. Larsen" 5 => "T.K. Kvien" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2001" "volumen" => "60" "paginaInicial" => "913" "paginaFinal" => "923" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11557646" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Cohen" 1 => "G.W. Cannon" 2 => "M. Schiff" 3 => "A. Weaver" 4 => "R. Fox" 5 => "N. Olsen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1529-0131(200109)44:9<1984::AID-ART346>3.0.CO;2-B" "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2001" "volumen" => "44" "paginaInicial" => "1984" "paginaFinal" => "1992" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11592358" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improved functional ability in patients with rheumatoid arthritis—longterm treatment with leflunomide versus sulfasalazine" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.R. Kalden" 1 => "D.L. Scott" 2 => "J.S. Smolen" 3 => "M. Schattenkirchner" 4 => "B. Rozman" 5 => "B.D. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 17 | 14 | 31 |
| 2024 October | 69 | 42 | 111 |
| 2024 September | 96 | 22 | 118 |
| 2024 August | 111 | 38 | 149 |
| 2024 July | 88 | 38 | 126 |
| 2024 June | 128 | 41 | 169 |
| 2024 May | 88 | 34 | 122 |
| 2024 April | 98 | 22 | 120 |
| 2024 March | 75 | 38 | 113 |
| 2024 February | 80 | 47 | 127 |
| 2024 January | 73 | 27 | 100 |
| 2023 December | 75 | 34 | 109 |
| 2023 November | 70 | 30 | 100 |
| 2023 October | 104 | 48 | 152 |
| 2023 September | 137 | 44 | 181 |
| 2023 August | 64 | 19 | 83 |
| 2023 July | 76 | 32 | 108 |
| 2023 June | 63 | 27 | 90 |
| 2023 May | 66 | 18 | 84 |
| 2023 April | 85 | 27 | 112 |
| 2023 March | 93 | 42 | 135 |
| 2023 February | 104 | 32 | 136 |
| 2023 January | 46 | 25 | 71 |
| 2022 December | 78 | 47 | 125 |
| 2022 November | 96 | 36 | 132 |
| 2022 October | 77 | 36 | 113 |
| 2022 September | 53 | 45 | 98 |
| 2022 August | 87 | 36 | 123 |
| 2022 July | 79 | 50 | 129 |
| 2022 June | 76 | 40 | 116 |
| 2022 May | 68 | 40 | 108 |
| 2022 April | 78 | 56 | 134 |
| 2022 March | 60 | 60 | 120 |
| 2022 February | 90 | 44 | 134 |
| 2022 January | 84 | 43 | 127 |
| 2021 December | 53 | 35 | 88 |
| 2021 November | 71 | 54 | 125 |
| 2021 October | 71 | 57 | 128 |
| 2021 September | 64 | 44 | 108 |
| 2021 August | 92 | 47 | 139 |
| 2021 July | 64 | 43 | 107 |
| 2021 June | 57 | 47 | 104 |
| 2021 May | 68 | 48 | 116 |
| 2021 April | 153 | 109 | 262 |
| 2021 March | 84 | 36 | 120 |
| 2021 February | 52 | 29 | 81 |
| 2021 January | 61 | 20 | 81 |
| 2020 December | 58 | 21 | 79 |
| 2020 November | 46 | 42 | 88 |
| 2020 October | 13 | 15 | 28 |
| 2020 September | 43 | 33 | 76 |
| 2020 August | 30 | 16 | 46 |
| 2020 July | 44 | 29 | 73 |
| 2020 June | 55 | 16 | 71 |
| 2020 May | 59 | 23 | 82 |
| 2020 April | 59 | 17 | 76 |
| 2020 March | 9 | 11 | 20 |
| 2019 January | 1 | 0 | 1 |
| 2018 May | 4 | 1 | 5 |
| 2018 April | 57 | 7 | 64 |
| 2018 March | 57 | 7 | 64 |
| 2018 February | 36 | 6 | 42 |
| 2018 January | 40 | 7 | 47 |
| 2017 December | 46 | 12 | 58 |
| 2017 November | 41 | 6 | 47 |
| 2017 October | 33 | 5 | 38 |
| 2017 September | 70 | 5 | 75 |
| 2017 August | 73 | 8 | 81 |
| 2017 July | 69 | 7 | 76 |
| 2017 June | 91 | 16 | 107 |
| 2017 May | 100 | 11 | 111 |
| 2017 April | 91 | 6 | 97 |
| 2017 March | 86 | 14 | 100 |
| 2017 February | 48 | 9 | 57 |
| 2017 January | 63 | 3 | 66 |
| 2016 December | 80 | 19 | 99 |
| 2016 November | 114 | 5 | 119 |
| 2016 October | 114 | 10 | 124 |
| 2016 September | 173 | 5 | 178 |
| 2016 August | 116 | 2 | 118 |
| 2016 July | 41 | 7 | 48 |
| 2016 January | 3 | 0 | 3 |
| 2015 December | 2 | 0 | 2 |
| 2015 October | 2 | 0 | 2 |
| 2015 September | 1 | 0 | 1 |
| 2015 August | 2 | 14 | 16 |
| 2015 July | 17 | 6 | 23 |
| 2015 June | 54 | 8 | 62 |
| 2015 May | 60 | 14 | 74 |
| 2015 April | 51 | 6 | 57 |
| 2015 March | 52 | 5 | 57 |
| 2015 February | 46 | 6 | 52 |
| 2015 January | 59 | 10 | 69 |
| 2014 December | 49 | 11 | 60 |
| 2014 November | 44 | 10 | 54 |
| 2014 October | 40 | 9 | 49 |
| 2014 September | 31 | 13 | 44 |
| 2014 August | 45 | 11 | 56 |
| 2014 July | 35 | 19 | 54 |
| 2014 June | 48 | 6 | 54 |
| 2014 May | 46 | 10 | 56 |
| 2014 April | 56 | 11 | 67 |
| 2014 March | 54 | 14 | 68 |
| 2014 February | 38 | 11 | 49 |
| 2014 January | 49 | 13 | 62 |
| 2013 December | 39 | 9 | 48 |
| 2013 November | 30 | 11 | 41 |
| 2013 October | 39 | 14 | 53 |
| 2013 September | 38 | 12 | 50 |
| 2013 August | 104 | 11 | 115 |
| 2013 July | 61 | 12 | 73 |
| 2013 June | 44 | 7 | 51 |
| 2013 May | 40 | 17 | 57 |
| 2013 April | 43 | 9 | 52 |
| 2013 March | 45 | 13 | 58 |
| 2013 February | 33 | 7 | 40 |
| 2013 January | 31 | 16 | 47 |
| 2012 December | 33 | 16 | 49 |
| 2012 November | 44 | 32 | 76 |
| 2012 October | 29 | 21 | 50 |
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