Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis / Revisión sistemática y metaanálisis de la eficacia y la seguridad de leflunomida y metotrexato en el tratamiento de la artritis reumatoide

Objective: To assess the efficacy and side effects of methotrexate and leflunomide in patients with rheumatoid arthritis (RA) as the first disease-modifying antirheumatic drug (DMARD). Methods: We performed a systematic review and meta-analysis of clinical studies that included patients who took methotrexate, leflunomide, placebo or another DMARD for RA treatment. A systematic review yielded 1971 articles from databases; once completely reviewed, 73 trials that completed inclusion criteria were selected. In structured workshops for discussion and assessment of each article, 6 could be meta-analyzed for the primary and secondary outcomes: achievement of American College of Rheumatology (ACR) 20 and its core set components; and change of serum C-reactive protein (CRP) levels, Health Assessment Questionnaire Disability Index (HAQ-Di), liver enzyme aspartate transaminase/alanine transaminase ratio, new gastrointestinal (GI) side effects and infections. Results: A total of 1984 patients were included: 986 took leflunomide and 998 methotrexate. The probability of achieving ACR 20 had an odds ratio (OR) of 0.88 (95% confidence interval [CI] 0.74, 1.06) with a trend toward favoring methotrexate; reduction of the swollen joint count was greater for methotrexate: mean difference=0.82 (95%CI 0.24, 1.39); tender joint count, physician global assessment, HAQ-Di, and serum CRP levels revealed no significant difference between groups. Increased liver enzymes were more frequent in the leflunomide group, OR=0.38 (95%CI 0.27, 0.53), and new GI complaints were more common with methotrexate (OR=1.44; 95%CI 1.17, 1.79). There was no difference in the incidence of non-severe infections. Conclusion: Leflunomide used as the first DMARD in RA seemed to be as efficacious as methotrexate; only the reduction of swollen joint count was more marked for methotrexate. Leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints

Objetivo: Evaluar la eficacia y los efectos secundarios del metotrexato o la leflunomida en pacientes con AR como primer fármaco modificador de la enfermedad (FAME). Métodos: Se realizó una revisión sistemática y metaanálisis de estudios clínicos que incluyeron a pacientes que tomaron metotrexato, leflunomida, placebo u otro FAME para el tratamiento de la AR. Después de una revisión sistemática, se encontraron 1.971 artículos, una vez revisados completamente, se seleccionaron 73 ensayos que completaron los criterios de inclusión. En talleres estructurados para el debate y la evaluación de cada artículo, 6 pudieron ser metaanalizados para los resultados primarios y secundarios: logro de ACR 20 y sus componentes básicos, así como el cambio de los niveles séricos de PCR, HAQ-DI, enzimas hepáticas AST/ALT, nuevos efectos secundarios gastrointestinales (GI) e infecciones. Resultados: Se incluyó a un total de 1.984 pacientes, 986 tomaron leflunomida y 998 metotrexato. La probabilidad de alcanzar ACR 20 reveló una OR 0,88 (IC del 95%: 0,74; 1,06) con una tendencia a favorecer el metotrexato; la reducción del recuento de articulaciones inflamadas fue mayor para metotrexato: diferencia de medias (MD)=0,82 (IC del 95%: 0,24, 1,39); el recuento de articulaciones sensibles, la evaluación global de médicos, el HAQ-DI, y los niveles séricos de PCR no revelaron diferencias entre los grupos. El aumento de las enzimas hepáticas fue más frecuente en el grupo con leflunomida, OR=0,38 (IC del 95%: 0,27, 0,53) y las nuevas quejas GI fueron más frecuentes en el metotrexato, OR=1,44 (IC del 95% 1,17, 1,79). No hubo diferencias en la incidencia de infecciones no graves. Conclusión: La leflunomida utilizada como el primer FAME en la AR parece ser tan eficaz como el metotrexato; solo la reducción de las articulaciones inflamadas fue mayor para el metotrexato. La leflunomida está relacionada con una mayor elevación de las enzimas hepáticas, pero presenta menos molestias GI

Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis.

OBJECTIVE: To assess the efficacy and side effects of methotrexate and leflunomide in patients with rheumatoid arthritis (RA) as the first disease-modifying antirheumatic drug (DMARD). METHODS: We performed a systematic review and meta-analysis of clinical studies that included patients who took methotrexate, leflunomide, placebo or another DMARD for RA treatment. A systematic review yielded 1971 articles from databases; once completely reviewed, 73 trials that completed inclusion criteria were selected. In structured workshops for discussion and assessment of each article, 6 could be meta-analyzed for the primary and secondary outcomes: achievement of American College of Rheumatology (ACR) 20 and its core set components; and change of serum C-reactive protein (CRP) levels, Health Assessment Questionnaire Disability Index (HAQ-Di), liver enzyme aspartate transaminase/alanine transaminase ratio, new gastrointestinal (GI) side effects and infections. RESULTS: A total of 1984 patients were included: 986 took leflunomide and 998 methotrexate. The probability of achieving ACR 20 had an odds ratio (OR) of 0.88 (95% confidence interval [CI] 0.74, 1.06) with a trend toward favoring methotrexate; reduction of the swollen joint count was greater for methotrexate: mean difference=0.82 (95%CI 0.24, 1.39); tender joint count, physician global assessment, HAQ-Di, and serum CRP levels revealed no significant difference between groups. Increased liver enzymes were more frequent in the leflunomide group, OR=0.38 (95%CI 0.27, 0.53), and new GI complaints were more common with methotrexate (OR=1.44; 95%CI 1.17, 1.79). There was no difference in the incidence of non-severe infections. CONCLUSION: Leflunomide used as the first DMARD in RA seemed to be as efficacious as methotrexate; only the reduction of swollen joint count was more marked for methotrexate. Leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints.

Primary prophylaxis with ciprofloxacin in cirrhotic patients with ascites: a randomized, double blind study.

UNLABELLED: INTRODUCTION AND AIM. There is scarce information about primary prophylaxis in cirrhotic patients. The aim was to assess the efficacy of ciprofloxacin for primary prophylaxis for bacterial infections in patients with cirrhosis of the liver and ascites. MATERIAL AND METHODS. A randomized, double-blind placebo-controlled clinical trial was conducted. Patients were randomized to receive oral ciprofloxacin 500 mg/day or placebo for one month. A basal evaluation and repeated assessments at 4, 6, 12, 18, and 24 weeks afterwards, or whenever a primary endpoint occurred were done. STATISTICAL ANALYSIS: probability curves were constructed with the Kaplan-Meier method and compared by the log-rank test. RESULTS. 95 patients were randomized to ciprofloxacin group (n = 49; 51.6%) and placebo group (n = 46; 48.4%). Six-teen (32.6%) patients in the ciprofloxacin group developed bacterial infections and thirteen (28.2%) patients developed bacterial infections in the placebo group (p = NS). The probability to remain free of bacterial infections did not reach statistical significance (p = 0.38). Probability of survival at 24 weeks was 91% in placebo group and 98% in the ciprofloxacin group (p = 0.28). The absolute risk reduction was 5%, the relative risk reduction was 6% and the NNT was 20 patients. CONCLUSION. Primary prophylaxis with ciprofloxacin for one month in cirrhotic patients with ascites who do not have a currently accepted indication, did not show a preventive effect on the development of bacterial infections at one month follow-up. Moreover in women could increases the odds for UTI. The administration of ciprofloxacin seemed to decrease the risk of mortality.

Vascular invasion in pancreatic cancer: predictive values for endoscopic ultrasound and computed tomography imaging.

OBJECTIVES: To evaluate the accuracy of endoscopic ultrasound (EUS) to determine vascular invasion in patients with pancreatic cancer. METHODS: Data were obtained prospectively from patients with a pancreatic lesion who underwent EUS, computed tomographic (CT) imaging, and surgery from March 2005 to March 2010. RESULTS: Fifty patients were included with a mean ± SD age 61 ± 11.5 years; 27 (54%) were women. The sensitivity, specificity, positive predictive value, and negative predictive value for EUS were the following: 61.1 (95% CI, 38.6-79.7), 90.3 (95% CI, 75.1-96.7), 78.6 (95% CI, 52.4-92.4), and 80 (95% CI, 64.1-90), respectively. The area under the curve for EUS and that for CT were 0.80 (95% CI, 0.68-0.92) and 0.74 (95% CI, 0.61-0.86), respectively. The positive predictive value for arterial invasion was 100% (95% CI, 61-100) for EUS and 60% (95% CI, 31.3-83.2) for CT. There were no complications associated with the EUS or the CT. CONCLUSION: Endoscopic US is a very good option to detect vascular invasion in patients with pancreatic cancer and is especially sensitive for arterial invasion. When it is available, we recommend that it be performed in addition to CT staging.

Prophylactic activated recombinant factor VII in liver resection and liver transplantation: systematic review and meta-analysis.

BACKGROUND AND AIM: Intraoperative blood loss is a frequent complication of hepatic resection and orthotopic liver transplantation. Recombinant activated coagulation factor VII (rFVIIa) is a coagulation protein that induces hemostasis by directly activating factor X. There is no clear information about the prophylactic value of rFVIIa in hepatobiliary surgery, specifically in liver resection and orthotopic liver transplantation. The aim of this study was to assess the effect of rFVIIa prophylaxis to prevent mortality and bleeding resulting from hepatobiliary surgery. METHODS: Relevant randomized trials were identified by searching The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index. Randomized clinical trials comparing different rFVIIa prophylactic schemas against placebo or no intervention to prevent bleeding in hepatobiliary surgery were included. Adults undergoing liver resection, partial hepatectomy, or orthotopic liver transplantation were included. Dichotomous data were analyzed calculating odds ratios (ORs) and 95% confidence intervals (CIs). Continuous data were analyzed calculating mean differences (MD) and 95% CIs. RESULTS: Four randomized controlled trials were included. There were no significant differences between rFVIIa and placebo for mortality (OR 0.96; 95% CI 0.35-2.62), red blood cell units (MD 0.32; 95% CI -0.08-0.72) or adverse events (OR 1.55; 95% CI 0.97-2.49). CONCLUSIONS: The available information is limited, precluding the ability to draw conclusions regarding bleeding prophylaxis in hepatobiliary surgery using rFVIIa. Although an apparent lack of effect was observed in all outcomes studied, further research is needed.

Vigorous, but differential mononuclear cell response of cirrhotic patients to bacterial ligands.

AIM: To study the role of gram-positive and gram-negative bacteria in the pathogenesis of liver injury, specifically the activation of inflammatory mediators. METHODS: Peripheral blood mononuclear cells of 20 out-patients were studied, 10 of them with cirrhosis. Peripheral blood mononuclear cells were isolated and exposed to lipopolysaccharide or lipoteichoic acid. CD14, Toll-like receptor 2 and 4 expression was determined by flow cytometry, and tumor necrosis factor (TNF) α, interleukin (IL)-1ß, IL-6, IL-12 and IL-10 secretion in supernatants was determined by ELISA. RESULTS: Higher CD14, Toll-like receptor 2 and 4 expression was observed in peripheral blood mononuclear cells from cirrhotic patients, (P < 0.01, P < 0.006, P < 0.111) respectively. Lipopolysaccharide and lipoteichoic acid induced a further increase in CD14 expression (P < 0.111 lipopolysaccharide, P < 0.013 lipoteichoic acid), and a decrease in Toll-like receptor 2 (P < 0.008 lipopolysaccharide, P < 0.008 lipoteichoic acid) and Toll-like receptor 4 (P < 0.008 lipopolysaccharide, P < 0.028 lipoteichoic acid) expression. With the exception of TNFα, absolute cytokine secretion of peripheral blood mononuclear cells was lower in cirrhotic patients under non-exposure conditions (P < 0.070 IL-6, P < 0.009 IL-1ß, P < 0.022 IL-12). Once exposed to lipopolysaccharide or lipoteichoic acid, absolute cytokine secretion of peripheral blood mononuclear cells was similar in cirrhotic and non-cirrhotic patients, determining a more vigorous response in the former (P < 0.005 TNFα, IL-1ß, IL-6, IL-2 and IL-10 lipopolysaccharide; P < 0.037 TNFα; P < 0.006 IL-1ß; P < 0.005 IL-6; P < 0.007 IL-12; P < 0.014 IL-10 lipoteichoic acid). Response of peripheral blood mononuclear cells was more intense after lipopolysaccharide than after lipoteichoic acid exposure. CONCLUSION: Peripheral blood mononuclear cells of cirrhotic patients are able to respond to a sudden bacterial ligand exposure, particularly lipopolysaccharide, suggesting that immune regulation mechanisms are still present.

Utility of a simplified predictive model to predict rebleeding in patients with high-risk stigmata ulcers.

AIM: To evaluate a simplified Predictive Model (sPM) to predict rebleeding in patients with high-risk stigmata ulcers. PATIENTS AND METHODS: Retrospectively, patients seen from March 2002 to September 2007 with peptic ulcers Forrest Ia, Ib, IIa and/or IIb were included. A sPM based on modified Blatchford Score Risk System (mBRS) was used. RESULTS: One hundred and seven patients were included. The positive and negative predictive values for rebleeding with mBRS ≤1 were 15% [95% confidence interval (CI): 4-42] and 72% (95% CI: 61-80), respectively; for sPM ≤1 these values were 16% (95% CI: 8-29) and 65.3% (95% CI: 52-76), respectively. The odds ratio for rebleeding in patients with sPM ≤1 was 0.77 (95% CI: 0.6-0.97, P=0.03) and odds ratio for mBRS ≤1 was 0.84 (95% CI: 0.64-1.1, P=0.3). CONCLUSIONS: In patients with high-risk stigmata ulcers with sPM and mBRS ≤1 the risk of rebleeding is low and their early discharge could be considered.