Objective: To investigate the effects of a switch from oral methotrexate (MTX) to subcutaneous MTX (scMTX) or adding ciclosporin to oral MTX with a simultaneous reduction of the MTX dose, in case of adverse events (AE) or insuffi cient effect (IE) in rheumatoid arthritis (RA). Methods: The tight control treatment arm of the Computer Assisted Management in Early RA (CAMERA) trial was evaluated. The change in 28-joint Disease Activity Score (DAS28) after taking scMTX (over 1 month) or adding ciclosporin (over 3 months) was compared to the average monthly change in the preceding 3 months. Analyses were performed separately for strategy steps because of AE or IE. Results: Of 151 patients, 57 needed the scMTX strategy step (21 because of AE, 36 because of IE) and 40 the following ciclosporin strategy step (20 and 20, respectively). The decrease in DAS28 after taking the scMTX strategy step was 0.30 points (p<0.05); no significant change in DAS28 was seen after the ciclosporin strategy step. In both strategy steps for AE or IE, quite similar observations were made. Of the patients who took the scMTX strategy step, 63% showed improvement. Conclusion: scMTX seems a useful treatment step after oral MTX in a tight control strategy, whereas the ciclosporin step seems ineffective.
OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) versus oral administration of methotrexate (MTX) in patients with active rheumatoid arthritis (RA).
METHODS: MTX-naive patients with active RA (Disease Activity Score in 28 joints >or= 4) were eligible for the study if they had not previously taken biologic agents and had not taken disease-modifying antirheumatic drugs for 2 weeks prior to randomization. Patients were randomly assigned to receive 15 mg/week of MTX either orally (2 7.5-mg tablets plus a dummy prefilled syringe; n=187 patients) or SC (prefilled syringe containing 10 mg/ml plus 2 dummy tablets; n=188 patients) for 24 weeks. At week 16, patients who did not meet the American College of Rheumatology criteria for 20% improvement (ACR20) were switched from 15 mg of oral MTX to 15 mg of SC MTX and from 15 mg of SC MTX to 20 mg of SC MTX for the remaining 8 weeks, still in a blinded manner. The primary outcome was an ACR20 response at 24 weeks.
RESULTS: At week 24, significantly more patients treated with SC MTX than with oral MTX showed ACR20 (78% versus 70%) and ACR70 (41% versus 33%) responses. Patients with a disease duration >or= 12 months had even higher ACR20 response rates (89% for SC administration and 63% for oral). In 52 of the ACR20 nonresponders (14%), treatment was switched at week 16. Changing from oral to SC MTX and from 15 mg to 20 mg of SC MTX resulted in 30% and 23% ACR20 response rates, respectively, in these patients. MTX was well tolerated. The rate of adverse events was similar in all groups.
CONCLUSION: This 6-month prospective, randomized, controlled trial is the first to examine oral versus SC administration of MTX. We found that SC administration was significantly more effective than oral administration of the same MTX dosage. There was no difference in tolerability.
ANTECEDENTES: Para investigar si el tratamiento intensivo con metotrexato (MTX), de acuerdo a un estricto protocolo y un programa informático de decisión es más beneficiosa en comparación con el tratamiento convencional con metotrexato en la artritis reumatoide temprana.
MÉTODOS: En un ensayo multicéntrico de dos años abierta estrategia de marca, 299 pacientes con artritis reumatoide temprana fueron asignados aleatoriamente al grupo de estrategia intensiva o el grupo de estrategia convencional. Los pacientes de ambos grupos recibieron MTX, el objetivo de la remisión de los tratamientos se apliquen. Los pacientes en el grupo de tratamiento intensivo llegó a la consulta externa una vez al mes, el ajuste de la dosis de MTX se adapta a cada paciente sobre la base de los criterios de respuesta predefinidos, utilizando un programa informático de decisión. Los pacientes del grupo de estrategia convencional llegó a la consulta externa una vez cada tres meses, que fueron tratados de acuerdo con la práctica común. La ciclosporina se añadió si los pacientes tenían una respuesta inadecuada a MTX dosis máxima tolerada.
RESULTADOS: Setenta y seis (50%) pacientes del grupo de estrategia intensiva logrado por lo menos un período de remisión durante el juicio de dos años, en comparación con 55 pacientes (37%) en el grupo de estrategia convencional (p = 0,03). Las áreas bajo la curva para casi todas las variables clínicas fueron significativamente menores, es decir, no había un mejor efecto clínico para el grupo de tratamiento intensivo en comparación con el grupo de tratamiento convencional.
CONCLUSIÓN: Los resultados de este estudio muestran que es posible mejorar sustancialmente la eficacia clínica temprano en el curso de la enfermedad mediante la intensificación del tratamiento con MTX, con el objetivo de la remisión, a la medida para cada paciente. Por otra parte, los reumatólogos participantes indicaron que el programa informático de decisión podría ser una herramienta útil en su práctica clínica diaria.
OBJETIVO: Hay varias estrategias de tratamiento han demostrado valor en la mejora de la artritis reumatoide (AR), pero la estrategia óptima para la prevención a largo plazo daños en las articulaciones y el deterioro funcional no está clara. Se realizó este estudio para comparar los resultados clínicos y radiográficos de 4 diferentes estrategias de tratamiento, con un seguimiento intenso en todos los pacientes. MÉTODOS: En un ensayo clínico multicéntrico, aleatorizado, 508 pacientes fueron asignados a 1 de 4 estrategias de tratamiento: secuencial modificadores de la enfermedad en monoterapia fármaco antirreumático (grupo 1), paso a la terapia combinada (grupo 2), la terapia de combinación inicial con una reducción paulatina de alta La combinación de dosis de prednisona (grupo 3), y la terapia inicial con el infliximab antagonista del factor de necrosis tumoral (grupo 4). Ajustes del tratamiento se realizan cada 3 meses en un esfuerzo por obtener la actividad de la enfermedad baja (Disease Activity Score en 44 articulaciones de <o = 2,4). RESULTADOS: La terapia de combinación inicial incluye ya sea con infliximab prednisona (grupo 3) o (grupo 4) dio lugar a principios de la mejoría funcional que hizo la monoterapia secuencial (grupo 1) y step-up terapia combinada (grupo 2), con una puntuación media a los 3 meses en el versión holandesa del Cuestionario de Evaluación de la Salud (D-HAQ), de 1,0 en los grupos 1 y 2 y 0,6 en los grupos 3 y 4 (P <0,001). Después de 1 año, con una media de D-HAQ resultados fueron de 0,7 en los grupos 1 y 2 y 0,5 en los grupos 3 y 4 (p = 0,009). Los incrementos medios en total de Sharp / Van puntaje der Heijde conjunta radiográficas fueron de 2,0, 2,5, 1,0, y 0,5 en grupos de 1-4, respectivamente (P <0,001). No hubo diferencias significativas en el número de eventos adversos y los retiros entre los grupos. CONCLUSIÓN: En pacientes con AR temprana, la terapia de combinación inicial, incluida cualquiera de prednisona o infliximab resultó en una mejoría a principios funcionales y menos daño radiológico después de 1 año que hizo la monoterapia secuencial o paso-a la terapia de combinación.
OBJECTIVE: To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA).
METHODS: A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (> or = 25 mg weekly). Separated by 2 weeks, a pharmacokinetic analysis was performed in each patient after oral and subcutaneous administration of the same dose of MTX. MTX serum concentrations were measured by a fluorescence polarization immunoassay. Pharmacokinetic analysis was performed with an iterative 2-stage Bayesian population procedure, obtaining population and individual pharmacokinetic parameters.
RESULTS: The median MTX dose was 30 mg weekly (range 25-40 mg). A 2-compartment model best described the serum MTX concentration versus time curves. The mean bioavailability after oral MTX was 0.64 (range 0.21-0.96) compared to subcutaneous administration. There was a statistically significant difference in the bioavailability of the 2 administration regimens.
CONCLUSION: Bioavailability of a higher oral dose of MTX in adult patients with RA is highly variable, and on average two-thirds that of the subcutaneous administration. To improve efficacy of MTX at dosages of 25 mg weekly or more, a change to parenteral administration should be considered.
OBJECTIVE: To compare the clinical efficacy of methotrexate and tolerance to the drug in patients with rheumatoid arthritis who were switched from intramuscular to oral administration because of a shortage of the intramuscular preparation.
METHODS: 143 patients were switched from intramuscular to oral methotrexate. Of these, 47 were switched back to the intramuscular form. A multiple choice questionnaire was sent by mail to evaluate clinical and biological criteria of efficacy and tolerance.
RESULTS: When methotrexate was first switched from intramuscular to oral administration, increased disease activity, exacerbation of morning pain and hand stiffness, duration of morning stiffness, increased joint pain, and increased joint swelling were observed. There was a greater frequency of gastrointestinal symptoms, but without a significant increase in liver abnormalities. When intramuscular methotrexate became available again, 47 of the 143 patients were switched back and were followed for at least three months. On average, disease manifestations were improved and side effects reduced by the switch.
CONCLUSIONS: Methotrexate given intramuscularly had improved clinical efficacy with fewer side effects than given orally. Intramuscular methotrexate administration should be considered when rheumatoid arthritis remains active in spite of high dose oral methotrexate.
OBJECTIVE: Delay of disease-modifying anti-rheumatic drug (DMARD) therapy is a major contributing factor for poor outcome in rheumatoid arthritis (RA). Although early therapy has been shown to be particularly effective, there is still uncertainty about the optimal time point of DMARD introduction. We wanted to test if a therapeutic window of opportunity may exist within the first few months of the disease.
METHODS: In this case-control parallel-group study, 20 very early RA (VERA) patients with median disease duration of 3 months were age and gender matched to a group of 20 late early RA (LERA) patients with median disease duration of 12 months until first DMARD initiation. Follow-up time was 36 months. Primary outcome measures were the disease activity score (DAS28) and radiological joint destruction using the Larsen method.
RESULTS: Already after 3 months of DMARD therapy we found a significant difference of improvement in favour of the VERA patients in the DAS28. This trend continued over the study period. At study end the DAS28 showed an improvement of 2.8+/-1.5 in the VERA vs 1.7+/-1.2 in the LERA group (P(c)<0.05). The Larsen scores showed a statistically significant retardation of progression in the VERA compared with the LERA.
CONCLUSION: Our results indicate that there is a window of opportunity for highly successful treatment of RA in the first year, and especially within the first 3 months of therapy. Thus, early diagnosis and therapy may be the crucial step in achieving optimal control of disease progression and prognosis in RA.
ANTECEDENTES: Las estrategias actuales de tratamiento para la artritis reumatoide incluyen el uso de modificadores de la enfermedad los fármacos antirreumáticos, pero una minoría de los pacientes logran una buena respuesta. El objetivo fue probar la hipótesis de que un mejor resultado se puede lograr mediante el empleo de una estrategia de tratamiento ambulatorio intensivo de los pacientes con artritis reumatoide - para el control sostenido, el ala de la actividad de la enfermedad - en comparación con la atención ambulatoria de rutina. MÉTODOS: Se diseñó un estudio doble ciego, ensayo controlado aleatorio en dos hospitales de enseñanza. Se seleccionaron 183 pacientes para su inclusión. 111 fueron asignados aleatoriamente manejo intensivo o cuidados de rutina. Medidas de resultado primarias fueron la caída media en la puntuación de actividad de la enfermedad y la proporción de pacientes con una buena respuesta (definida como una puntuación de actividad de la enfermedad <2,4 y una caída en la partitura desde el inicio de> 1,2). El análisis fue por intención de tratar. RESULTADOS: Un paciente se retiró después de la aleatorización y siete abandonaron durante el estudio. La media de caer en la puntuación de actividad de la enfermedad fue mayor en el grupo intensivo que en el grupo de rutina (-3,5 vs -1,9, la diferencia de 1,6 [IC 95% 1,1-2,1], p <0,0001). En comparación con la atención habitual, los pacientes tratados intensivamente eran más propensos a tener una buena respuesta (definición, 45/55 [82%] frente a 24/55 [44%], odds ratio 5,8 [IC 95%: 2,4-13,9], p <0,0001 ) o en remisión (puntuación de actividad de la enfermedad <1,6; 36/55 [65%] frente a 9/55 [16%], 9,7 [3,9-23,9], p <0,0001). Tres de los pacientes asignados atención de rutina y un manejo de la asignación intensiva murieron durante el estudio, pero ninguno fue juzgado atribuible al tratamiento. INTERPRETACIÓN: una estrategia de manejo ambulatorio intensivo de la artritis reumatoide mejora sustancialmente la actividad de la enfermedad, la progresión de la enfermedad radiográfica, la función física y calidad de vida sin costo adicional.
OBJECTIVE: To describe the outcome of patients with juvenile idiopathic arthritis (JIA) treated with subcutaneous (Sc) methotrexate (MTX) after failing oral MTX (either because of inefficacy or toxicity) in a clinic population.
METHODS: The study cohort was identified from our clinical database, and consisted of 61 children with JIA treated with MTX between 1988-2001. All patients fulfilled International League Against Rheumatism (ILAR) criteria for JIA and had disease duration of >/= 6 months and 3 or more active joints before institution of MTX. All patients had a core set of outcome variables assessed at baseline and at 3 months after achieving both maximum oral and SC MTX. Outcome variables included physician global assessment of disease activity, number of active joints, number of joints with limited range of motion, duration of early morning stiffness, and erythrocyte sedimentation rate (ESR). Improvement was defined as at least 30% improvement from baseline in 3 of 5 variables in the core set, with no more than one of the remaining variables worsening by more than 30%.
RESULTS: A total of 61 patients, 43 females and 18 males with JIA were studied. The disease subtypes were systemic 8, polyarticular 25 (12 rheumatoid factor positive), oligoarticular 14, enthesitis related arthritis 5, and unclassified 4. Thirty-one patients were switched to SC MTX, 13 of whom had not improved, and 18 who had improved, but had nausea (11) or insufficient clinical improvement (7). After 3 months of SC MTX treatment, 76% of patients were classified as improved and 23% as not improved. Toxicity on SC MTX was less than on oral MTX.
CONCLUSION: Our results suggest that for patients failing oral MTX either because of inefficacy or toxicity, the use of SC MTX has a high likelihood of success with more than 70% of patients achieving clinically significant improvement, without clinically significant toxicity.
Objective: To investigate the effects of a switch from oral methotrexate (MTX) to subcutaneous MTX (scMTX) or adding ciclosporin to oral MTX with a simultaneous reduction of the MTX dose, in case of adverse events (AE) or insuffi cient effect (IE) in rheumatoid arthritis (RA). Methods: The tight control treatment arm of the Computer Assisted Management in Early RA (CAMERA) trial was evaluated. The change in 28-joint Disease Activity Score (DAS28) after taking scMTX (over 1 month) or adding ciclosporin (over 3 months) was compared to the average monthly change in the preceding 3 months. Analyses were performed separately for strategy steps because of AE or IE. Results: Of 151 patients, 57 needed the scMTX strategy step (21 because of AE, 36 because of IE) and 40 the following ciclosporin strategy step (20 and 20, respectively). The decrease in DAS28 after taking the scMTX strategy step was 0.30 points (p<0.05); no significant change in DAS28 was seen after the ciclosporin strategy step. In both strategy steps for AE or IE, quite similar observations were made. Of the patients who took the scMTX strategy step, 63% showed improvement. Conclusion: scMTX seems a useful treatment step after oral MTX in a tight control strategy, whereas the ciclosporin step seems ineffective.
