Use of parenteral methotrexate in rheumatic diseases: A systematic review.

OBJECTIVE: To analyse the efficacy, adherence, patient satisfaction, safety, pharmacodynamics and cost-effectiveness of parenteral methotrexate (MTX) in patients with rheumatic diseases. METHODS: A systematic review of literature was carried out in Medline, Embase and Cochrane Central from the beginning until June 2019. Studies including adult patients with rheumatic diseases being treated with parenteral MTX were identified and data on efficacy, adherence, satisfaction, safety, pharmacokinetics, and cost-effectiveness analysed. As for the designs, systematic reviews, clinical trials, or observational studies were permitted, including cross-sectional and small-sample studies if they were pharmacokinetic studies. RESULTS: Out of 4160 identified articles, 80 articles were finally included. The efficacy profile of parenteral MTX seems useful in general and in those patients with insufficient response to oral MTX. The parenteral route does not seem to increase the rate or severity of adverse events due to the use of MTX. The use of parenteral MTX is an appropriate way to reduce costs in patients with inadequate response to oral MTX. Adherence and satisfaction are favoured by training programmes in the use of the parenteral route. The results in rheumatic diseases other than rheumatoid arthritis (RA) are very scarce and do not enable obtaining conclusive data. CONCLUSIONS: Parenteral MTX can be an alternative to the use of oral MTX, due to its profile of efficacy, safety, adherence and pharmacoeconomic results, especially in those patients with RA.

Revisión sistemática del uso de metotrexato por vía parenteral en enfermedades reumáticas / Use of Parenteral Methotrexate in Rheumatic Diseases: A Systematic Review

Objetivo: Analizar la eficacia, adherencia, satisfacción del paciente, seguridad, farmacodinámica y costo-efectividad del metotrexato (MTX) parenteral en pacientes con enfermedades reumáticas. Métodos: Se llevó a cabo una revisión sistemática basada en una estrategia de búsqueda en Medline, Embase y Cochrane Library (inicio-06/2019). Se identificaron estudios que incluyeran pacientes adultos con enfermedades reumáticas en tratamiento con MTX parenteral y que analizaran datos de eficacia, adherencia, satisfacción, seguridad, farmacocinética o costo-efectividad. En cuanto a los diseños se permitieron revisiones sistemáticas, ensayos clínicos o estudios observacionales, incluyendo transversales y estudios con muestras pequeñas si eran estudios de farmacocinética. Resultados: De 4.160 artículos identificados, se incluyeron finalmente 80. El MTX parenteral parece útil de manera general y en especial en aquellos pacientes con respuesta insuficiente a MTX oral. La vía parenteral no parece aumentar la tasa ni la gravedad de los eventos adversos con respecto a la oral y podría reducir costes en aquellos pacientes con respuesta inadecuada a MTX oral. La adherencia y satisfacción se ven favorecidas por programas de entrenamiento en la vía parenteral. Los resultados en enfermedades reumáticas distintas a la artritis reumatoide (AR) son muy escasos y no permiten obtener datos concluyentes. Conclusiones: El MTX por vía parenteral podría ser una alternativa al uso de MTX oral, por su perfil de eficacia, seguridad, adherencia, satisfacción y resultados fármaco-económicos, especialmente en pacientes con AR.(AU)

Objective: To analyse the efficacy, adherence, patient satisfaction, safety, pharmacodynamics and cost-effectiveness of parenteral methotrexate (MTX) in patients with rheumatic diseases. Methods: A systematic review of literature was carried out in Medline, Embase and Cochrane Central from the beginning until June 2019. Studies including adult patients with rheumatic diseases being treated with parenteral MTX were identified and data on efficacy, adherence, satisfaction, safety, pharmacokinetics, and cost-effectiveness analysed. As for the designs, systematic reviews, clinical trials, or observational studies were permitted, including cross-sectional and small-sample studies if they were pharmacokinetic studies. Results: Out of 4160 identified articles, 80 articles were finally included. The efficacy profile of parenteral MTX seems useful in general and in those patients with insufficient response to oral MTX. The parenteral route does not seem to increase the rate or severity of adverse events due to the use of MTX. The use of parenteral MTX is an appropriate way to reduce costs in patients with inadequate response to oral MTX. Adherence and satisfaction are favoured by training programmes in the use of the parenteral route. The results in rheumatic diseases other than rheumatoid arthritis (RA) are very scarce and do not enable obtaining conclusive data. Conclusions: Parenteral MTX can be an alternative to the use of oral MTX, due to its profile of efficacy, safety, adherence and pharmacoeconomic results, especially in those patients with RA.(AU)

Use of Parenteral Methotrexate in Rheumatic Diseases: A Systematic Review. / Revisión sistemática del uso de metotrexato por vía parenteral en enfermedades reumáticas.

OBJECTIVE: To analyse the efficacy, adherence, patient satisfaction, safety, pharmacodynamics and cost-effectiveness of parenteral methotrexate (MTX) in patients with rheumatic diseases. METHODS: A systematic review of literature was carried out in Medline, Embase and Cochrane Central from the beginning until June 2019. Studies including adult patients with rheumatic diseases being treated with parenteral MTX were identified and data on efficacy, adherence, satisfaction, safety, pharmacokinetics, and cost-effectiveness analysed. As for the designs, systematic reviews, clinical trials, or observational studies were permitted, including cross-sectional and small-sample studies if they were pharmacokinetic studies. RESULTS: Out of 4160 identified articles, 80 articles were finally included. The efficacy profile of parenteral MTX seems useful in general and in those patients with insufficient response to oral MTX. The parenteral route does not seem to increase the rate or severity of adverse events due to the use of MTX. The use of parenteral MTX is an appropriate way to reduce costs in patients with inadequate response to oral MTX. Adherence and satisfaction are favoured by training programmes in the use of the parenteral route. The results in rheumatic diseases other than rheumatoid arthritis (RA) are very scarce and do not enable obtaining conclusive data. CONCLUSIONS: Parenteral MTX can be an alternative to the use of oral MTX, due to its profile of efficacy, safety, adherence and pharmacoeconomic results, especially in those patients with RA.

Efficacy and safety of immunomodulatory drugs in patients with anterior uveitis: A systematic literature review.

BACKGROUND: To assess the efficacy and safety of immunomodulatory drugs in patients with noninfectious anterior uveitis (AU). METHODS: Systematic review of studies were retrieved from Medline (1961 to March 2016), Embase (1961 to March 2016), and Cochrane Library (up to March 2016), and a complementary hand search was also performed. The selection criteria were as follows: (population) noninfectious AU patients, adults; (intervention) immunomodulatory drugs (any dose, regimen, route of administration, duration of treatment); (outcome) control of inflammation, steroid-sparing effect, AU flares, adverse events, and so on; (study design) systematic literature reviews, randomized controlled trials, and observational studies. The study quality was assessed using the Jadad scale and according to The Oxford Centre for Evidence-based Medicine (update 2009). RESULTS: We included 13 studies of moderate-poor quality, with a mean duration from 5 months to 20 years, and number of AU patients ranging from 9 to 274. Patient's demographic and clinical characteristics were very heterogeneous. In most cases, uveitis anatomic classification criteria and outcomes definitions were unclear. Some of the studies only included AU patients with a systemic disease associated, mostly spondyloarthritis, others, mixed populations (idiopathic and systemic disease associated patients), and in some articles this data is not described. We found that methotrexate, cyclosporine A, azathioprine, adalimumab, and golimumab might prevent AU flares, improve ocular inflammation and visual acuity, and decrease systemic steroids doses. CONCLUSIONS: Although there is a lack of robust evidence, methotrexate, cyclosporine A, azathioprine, adalimumab, and golimumab might be effective in AU patients.

Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis.

UNLABELLED: Allopurinol is the most widely used urate-lowering drug (ULD). Together with efficacy and cost, safety is an aspect that helps taking clinical decisions. This systematic review analyzes allopurinol safety. The literature search was performed in MEDLINE, EMBASE, and the Cochrane Library (January 2014). SELECTION CRITERIA: (a) patients >18, (b) gout by the ACR criteria or evidence of urate crystal in synovial fluid, (c) comparator (placebo or other ULD), and (d) RCTs, cohorts, or meta-analysis. PRIMARY OUTCOMES: rate of adverse events and death. The quality was assessed with the Jadad's scale. A meta-analysis with fixed effects was performed. From 544 studies, seven met the eligibility criteria and were included. All RCT presented a low power for safety. All RCTs included a mixed population of patients with gout and hyperuricemia. Allopurinol (300 mg) was compared to febuxostat (40-240 mg) in five RCTs, to benzbromarone and probenecid in two RCTs, and to placebo in one. In the RCTs comparing allopurinol with benzbromarone and probenecid, the highest discontinuation rate was with probenecid (26 %), followed by allopurinol (11 %) and benzbromarone (4 %). The incidence of adverse events was similar between allopurinol (range 38.6-85) and febuxostat (range 41.8-80). Six patients on febuxostat and three on allopurinol died during the studies; no deaths were judged related to drug. The combined risk of adverse events was RR = 1.04 (95 % CI 0.98, 1.11). Allopurinol is a safe option, slightly better than other ULDs. The grade of evidence is high, but further research is needed to evaluate higher doses and long-term safety.

Índices compuestos para evaluar la actividad de la enfermedad y el daño estructural en pacientes con lupus eritematoso: revisión sistemática de la literatura / Clinical composite measures of disease activity and damage used to evaluate patients with systemic lupus erythematosus: a systematic literature review

Objetivos. Determinar que índices compuestos serían los más apropiados para la evaluación de la actividad o el daño estructural en pacientes con lupus eritematoso sistémico (LES). Métodos. Se realizó una revisión sistemática para identificar estudios de validación de índices de actividad y daño en pacientes con LES. De cada instrumento se recogió información sobre cada aspecto de la validación, como la viabilidad, la fiabilidad, la validez y la sensibilidad al cambio utilizando un formulario ad hoc. Resultados. Se incluyeron 38 estudios de validación de 6 índices compuestos para la evaluación de actividad (BILAG, ECLAM, SLAM, SLEDAI, LAI y SLAQ) y 3 índices para la evaluación de daño (SLICC/ACR-DI, LDIQ y BILD). De estos instrumentos, solo el SLAQ, el LDIQ y el BILD son autoadministrados. En relación con los parámetros de fiabilidad, solo se evaluó la consistencia interna de 3 índices (BILAG, SLAQ y SDI); con resultados para el α de Cronbach de 0,35 a 0,87. La fiabilidad intraobservador fue examinada mediante el coeficiente de correlación intraclase para el BILAG, con un resultado de 0,48 (IC del 95%, 0,23-0,81) y mediante análisis de variancia para el SLAM-R (0,78), SLEDAI (0,33) y el LAI (0,81). La fiabilidad interobservador fue evaluada mediante coeficientes de correlación para el ECLAM (0,90-0,93), el SLAM (0,86) y el MEX-SLEDAI (0,87-0,89). Respecto a las dimensiones de validez, la validez de constructo se evaluó mediante medidas de convergencia con otros instrumentos, en concreto con la valoración global del medico, mostrando resultados similares entre todos los índices (0,48-0,75). Por último, la sensibilidad al cambio se evaluó en todos los índices, excepto el LAI, SDI y LDIQ, obteniendo resultados de respuesta media estandarizada de 0,12 a 0,75. Conclusiones. A pesar de los múltiples índices validados para la evaluación de pacientes con LES, no se ha encontrado suficiente evidencia para determinar cuál es el más apropiado. Los índices BILAG y SLEDAI, con moderada fiabilidad y poca sensibilidad al cambio, son los 2 índices con una validación más completa y los más empleados (AU)

Objectives: To determine the most appropriate indices to evaluate the disease activity and damage in patients with sytemic lupus erythematosus (SLE). Methods: A systematic literature search was performed to identify validation studies of indices used to evaluate disease activity and damage. We collected information for each instrument on every aspect of validation including feasibility, reliability, validity and sensitivity to change using ad hoc forms. Results: A total of 38 articles were included addressing the validation of 6 composite indices to evaluate disease activity (BILAG, ECLAM, SLAM, SLEDAI, LAI and SLAQ); and 3 indices to evaluate damage (SLICC/ACE-DI, LDIQ and BILD). Only the SLAQ, LIDIQ and the BILD were self-administered. Feasibility and internal consistency was only studied in 3 indices (BILAG, SLAQ and SDI) with a Cronbach’s alpha ranging from .35 to 0.87. The intra-observer reliability was examined by the intraclass correlation coefficient for BILAG with a result of 0.48 (95%CI: 0,23-0,81) and using analysis of variance for SLAM-R (0,78), SLEDAI (0,33) and the LAI (0,81). The inter-observer feasibility was evaluated using the correlation coefficient for ECLAM (0,90-0,93), the SLAM (0,86) and MEX-SLEDAI (0,97-0,89). The construct validity was examined by means of convergence with other instruments, specifically with global assessment by the physician, with similar results between indices (0,48-0,75). Lastly, responsiveness was tested in all indices except LAI, SDI and LDIQ, with a standardized response mean ranging from 0.12 to 0.75. Conclusions: Although multiple instruments have been validated for use in SLE it was not possible to find direct evidence of which is the most appropriate. BILAG and SLEDAI, with moderate feasibility and low responsiveness, are the 2 indices with a most complete validation and more extensively used (AU)

Clinical composite measures of disease activity and damage used to evaluate patients with systemic lupus erythematosus: A systematic literature review.

OBJECTIVES: To determine the most appropriate indices to evaluate the disease activity and damage in patients with sytemic lupus erythematosus (SLE). METHODS: A systematic literature search was performed to identify validation studies of indices used to evaluate disease activity and damage. We collected information for each instrument on every aspect of validation including feasibility, reliability, validity and sensitivity to change using ad hoc forms. RESULTS: A total of 38 articles were included addressing the validation of 6 composite indices to evaluate disease activity (BILAG, ECLAM, SLAM, SLEDAI, LAI and SLAQ); and 3 indices to evaluate damage (SLICC/ACE-DI, LDIQ and BILD). Only the SLAQ, LIDIQ and the BILD were self-administered. Feasibility and internal consistency was only studied in 3 indices (BILAG, SLAQ and SDI) with a Cronbach's α ranging from 0.35 to 0.87. The intra-observer reliability was examined by the intraclass correlation coefficient for BILAG with a result of 0.48 (95%CI: 0,23-0,81) and using analysis of variance for SLAM-R (0,78), SLEDAI (0,33) and the LAI (0,81). The inter-observer feasibility was evaluated using the correlation coefficient for ECLAM (0,90-0,93), the SLAM (0,86) and MEX-SLEDAI (0,97-0,89). The construct validity was examined by means of convergence with other instruments, specifically with global assessment by the physician, with similar results between indices (0,48-0,75). Lastly, responsiveness was tested in all indices except LAI, SDI and LDIQ, with a standardized response mean ranging from 0.12 to 0.75. CONCLUSIONS: Although multiple instruments have been validated for use in SLE it was not possible to find direct evidence of which is the most appropriate. BILAG and SLEDAI, with moderate feasibility and low responsiveness, are the 2 indices with a most complete validation and more extensively used.

Systematic review of the value of ultrasound and magnetic resonance musculoskeletal imaging in the evaluation of response to treatment of gout.

BACKGROUND: Imaging may be useful for monitoring response to therapy. Within the OMERACT proposal for the core set domains for outcome measures in chronic gout, serum urate levels, recurrence of gouty flares, tophus regression, and joint damage imaging have been included, among other proposed issues. OBJECTIVES: To perform a systematic literature review of the usefulness of magnetic resonance imaging (MRI) and ultrasound (US) on assessment of treatment response in patients with gout. METHODS: MEDLINE, EMBASE, Cochrane Library (up to February 2012), and abstracts presented at the 2010 and 2011 meetings of the American College of Rheumatology and European League Against Rheumatism, were searched for treatment studies of any duration and therapeutic options, examining the ability of MRI/US to assess treatment response in gouty patients. Meta-analyses, systematic reviews, randomized clinical trials, cohort and case-control studies and validation studies were included. Quality was appraised using validated scales. RESULTS: There were only 3 US published studies in the literature that analysed US utility on assessment of response to treatment in patients with gout. All of them were prospective case studies with a small number of patients and they were reviewed in detailed. A total of 36 patients with gout were examined with US. All of them had a baseline serum urate >6mg/dL. US features of gout (double contour sign, hyperechoic spots in synovial fluid, hyperechoic cloudy areas, tophus diameter and volume) achieved significant reduction in patients who reached the objective of uricemia ≤6mg/dL in all the studies; however, patients in whom levels did not drop below 6mg/dL had no change of US features of gout. Other parameters evaluated in one study included ESR, CRP, number of tender joints (TRN), number of swollen joints, and pain score (SP). All of them decreased with uricemia reduction, but only TRN and SP were statistically significant. No data was found on the value of MRI on treatment response assessment in patients with gout. CONCLUSIONS: The improvement in ultrasound features shows concurrent validity with uric acid reduction. According to the published evidence, US can be a useful tool for monitoring treatment of gouty patients, although more research is needed. The value of MRI on treatment response assessment in patients with gout remains to be determined.

Denosumab for the treatment of osteoporosis: a systematic literature review.

PURPOSE: To determine the efficacy and safety of denosumab in osteoporosis. METHODS: A systematic search was performed in MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (1950 to July 2010), meeting abstracts (2009-2010), trial registries, and reference lists. The selection criteria were as follows: (population) osteoporosis patients of any age; (intervention) treatment with denosumab; (outcome) efficacy and safety; (study design) randomized clinical trials (RCTs); no language restrictions. Two reviewers independently screened titles and abstracts and subsequently extracted data from the selected studies including quality items, and on outcomes of interest. A meta-analysis was performed for safety issues. RESULTS: A total of 25 studies were included. Denosumab reduces the risk of new radiographic vertebral fracture in a 68% compared with placebo (p<0.001) and increases bone mineral density (BMD) at lumbar spine, total hip, and one-third radius more than alendronate and placebo. A single subcutaneous dose of denosumab resulted in a dose-dependent, rapid, profound, and sustained decrease bone turnover markers (BTMs). Denosumab was in general well tolerated. A meta-analysis has shown an increase in the incidence of urinary infections (p=0.012) and eczema (p<0.001) in the patients treated with denosumab. Meta-analysis of efficacy was complicated due to the study features. CONCLUSIONS: Denosumab given subcutaneously twice yearly is associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. Denosumab is associated with greater and sustained increases in BMD and reductions in BTMs compared with placebo and/or alendronate and with a risk of urinary infections and eczema.

Calcium supplementation and kidney stone risk in osteoporosis: a systematic literature review.

OBJECTIVES: This paper aims to examine the risk of nephrolithiasis in patients with osteoporosis and calcium supplementation. METHODS: This work is based on the systematic review of studies retrieved by a sensitive search strategy in Medline and Embase (1991-2010), and the Cochrane Central register of Controlled Trials (CENTRAL) up to 2010. The abstracts of the annual scientific meetings of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) (2008-2010) were also examined. The selection criteria were the following: patients with osteoporosis, on calcium supplementation alone or associated with other treatments for osteoporosis. We measured the likelihood of developing kidney stones, renal colic, changes in urinary sediment and serum parameters. We selected systematic literature reviews, randomised clinical trials (RCT) and cohort studies. RESULTS: We included 10 studies, 8 RCT and 2 cohort studies of moderate quality. All patients had osteoporosis (>8.000 patients), they were mostly women with a mean age of 50-70 years. Daily calcium doses varied from 120 mg up to 1.500 mg, and treatment duration from 3 days to 3 years. Changes in urinary sediment were found, but in general they were not clinically relevant. No cases of nephrolitiasis were found in more than a half of the included studies. In total there were 3 cases of kidney stone, 2 urinary tract calcifications, 16 cases of nephrolithiasis or urolithiasis, 4 of haematuria and 5 patients reporting kidney pain. CONCLUSIONS: According to our results, calcium supplements in the treatment of osteoporosis alone or in combination with another type of treatment does not significantly increase the risk of nephrolithiasis or renal colic.