BACKGROUND: Psoriatic arthritis is an inflammatory disease associated with joint damage, impaired function, pain, and reduced quality of life. Methotrexate is a disease-modifying anti-rheumatic drug (DMARD) commonly prescribed to alleviate symptoms, attenuate disease activity, and prevent progression of disease.
OBJECTIVES: To assess the benefits and harms of methotrexate for psoriatic arthritis in adults.
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the WHO International Clinical Trials Registry Platform, and www.clinicaltrials.gov for relevant records. We searched all databases from inception to 29 January 2018. We handsearched included articles for additional records and contacted study authors for additional unpublished data. We applied no language restrictions.
SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs that compared methotrexate versus placebo, or versus another DMARD, for adults with psoriatic arthritis. We reported on the following major outcomes: disease response (measured by psoriatic arthritis response criteria (PsARC)), function (measured by the Health Assessment Questionnaire for Rheumatoid Arthritis (HAQ)), health-related quality of life, disease activity (measured by disease activity score (28 joints) with erythrocyte sedimentation rate (DAS28-ESR)), radiographic progression, serious adverse events, and withdrawals due to adverse events.
DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed search results, assessed risk of bias, extracted trial data, and assessed the quality of evidence using the GRADE approach. We undertook meta-analysis only when this was meaningful.
MAIN RESULTS: We included in this review eight RCTs conducted in an outpatient setting, in Italy, the United Kingdom, the United States of America, China, Russia, and Bangladesh. Five studies compared methotrexate versus placebo, and four studies compared methotrexate versus other DMARDs. The average age of participants varied across studies (26 to 52 years), as did the average duration of psoriatic arthritis (one to nine years). Doses of methotrexate varied from 7.5 mg to 25 mg orally per week, but most studies administered approximately 15 mg or less orally per week. Risk of bias was generally unclear or high across most domains for all studies. We considered only one study to have low risk of selection and detection bias. The main study informing results of the primary comparison (methotrexate vs placebo up to six months) was at low risk of bias for all domains except attrition bias and reporting bias.We restricted reporting of results to the comparison of methotrexate versus placebo for up to six months. Low-quality evidence (downgraded due to bias and imprecision) from a single study (221 participants; methotrexate dose 15 mg orally or less per week) informed results for disease response, function, and disease activity. Disease response, measured by the proportion who responded to treatment according to PsARC (response indicates improvement), was 41/109 in the methotrexate group and 24/112 in the placebo group (risk ratio (RR) 1.76, 95% confidence interval (CI) 1.14 to 2.70). This equates to an absolute difference of 16% more responders with methotrexate (4% more to 28% more), and a number needed to treat for an additional beneficial outcome (NNTB) of 6 (95% CI 5 to 25). Mean function, measured by the HAQ (scale 0 to 3; 0 meaning no functional impairment; minimum clinically important difference 0.22), was 1.0 points with placebo and 0.3 points better (95% 0.51 better to 0.09 better) with methotrexate; absolute improvement was 10% (3% better to 17% better), and relative improvement 30% (9% better to 51% better). Mean disease activity as measured by the DAS28-ESR (scale of 0 to 10; lower score means lower disease activity; minimum clinically important difference unknown) was 3.8 points in the methotrexate group and 4.06 points in the placebo group; mean difference was -0.26 points (95% CI -0.65 to 0.13); absolute improvement was 3% (7% better to 1% worse), and relative improvement 6% (16% better to 3% worse).Low-quality evidence (downgraded due to risk of bias and imprecision) from three studies (n = 293) informed our results for serious adverse events and withdrawals due to adverse events. Due to low event rates, we are uncertain if methotrexate results show increased risk of serious adverse events or withdrawals due to adverse events compared to placebo. Results show 1/141 serious adverse events in the methotrexate group and 4/152 in the placebo group: RR 0.26 (95% CI 0.03 to 2.26); absolute difference was 2% fewer events with methotrexate (5% fewer to 1% more). In all, 9/141 withdrawals in the methotrexate group were due to adverse events and 7/152 in the placebo group: RR 1.32 (95% CI 0.51 to 3.42); absolute difference was 1% more withdrawals (4% fewer to 6% more).One study measured health-related quality of life but did not report these results. No study measured radiographic progression.
AUTHORS' CONCLUSIONS: Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for six months; however we are uncertain if it is more harmful. Effects of methotrexate on health-related quality of life, radiographic progression, enthesitis, dactylitis, and fatigue; its benefits beyond six months; and effects of higher-dose methotrexate have not been measured or reported in a randomised placebo-controlled trial.
INTRODUCTION: Recent advances in the therapeutics of psoriatic arthritis (PsA) have provided more options to clinicians managing PsA. The purpose of this review is to update the reader on treatment options for PsA using conventional synthetic disease modifying agents (csDMARDs) and novel therapies including tumour necrosis factor alpha inhibitors, interleukin 12/23 inhibitor (ustekinumab), the interleukin 17 antagonists including secukinumab, brodalumab, ixekizumab, and the phosphodiesterase-4 inhibitor, apremilast. Areas covered: We reviewed published articles on the treatment of PsA. Our main sources of data included treatment recommendations, registry studies, systematic literature reviews, major randomised controlled trials for more recently approved drugs, and abstracts from the American College of Rheumatology and EULAR meetings. Expert commentary: An overview of the evidence for the use of various pharmacotherapeutic agents for treatment of this heterogeneous disease was compiled. Treatment options for the various domains of PsA are also discussed.
OBJETIVO: Para actualizar la evidencia sobre la eficacia y seguridad de los agentes farmacológicos en la artritis psoriásica (APs).
MÉTODOS: Revisión sistemática de la literatura de los ensayos controlados aleatorios que compararon las intervenciones farmacológicas en la artritis psoriásica: fármacos anti-inflamatorios no esteroideos, glucocorticoides, enfermedad sintética (fármacos antirreumáticos modificadores de sDMARDs), ya sea convencional o específico, productos biológicos (MBE), placebo o cualquier combinación. Los resultados principales fueron American College of Rheumatology (ACR) 20-50, Psoriasis Area Severity Index 75, la progresión radiográfica, y los retiros debido a eventos adversos (AA). Múltiples estudios de la misma intervención fueron el uso de efectos aleatorios metanálisis.
RESULTADOS: En total, se incluyeron 25 artículos y 12 resúmenes. La eficacia de los inhibidores del factor de necrosis tumoral (incluyendo el recientemente añadido golimumab y certolizumab pegol) fue confirmado y 16 artículos / resúmenes en torno a 3 fármacos con nuevos mecanismos de acción: ustekinumab (UST), secukinumab (SEC) y Apremilast (APR). Todos fueron ensayos en comparación con placebo y se reunió con su punto final primario, ACR20. En 2 estudios con UST ACR20 se encontró con 50% y 44% de los pacientes con UST 90 mg, 42% y 44% con UST 45 mg vs 23% y 20% con el placebo, respectivamente. En dos estudios con SEC ACR20 varió del 54% (SEC 300 mg), 50-51% (SEC 150 mg), 29-51% (SEC 75 mg) y 15-17% (placebo). En cuatro estudios con abril, ACR20 osciló 32-43% (APR 30 mg), 29-38% (APR 20 mg) y 17-20% (placebo). Para las tres drogas, no más retiros debido a eventos adversos que el placebo fueron vistos y, en general, la seguridad parecía satisfactoria. Un ensayo de estrategia, un control estricto de la artritis psoriásica (TICOPA), mostró mejores respuestas ACR con adaptaciones de tratamiento a un estricto control en comparación con la atención estándar.
CONCLUSIONES: UST, SEC y APR son nuevos fármacos con eficacia demostrada para el tratamiento de la artritis psoriásica. No surgen importantes señales de seguridad, pero se necesitan estudios a largo plazo. Esta opinión informada acerca de las recomendaciones de la Liga Europea Contra el Reumatismo para el manejo de la artritis psoriásica.
Background: Psoriatic arthritis is an inflammatory arthritis the primary manifestations of which are locomotor and skin disease. Although a number of guidelines have been published citing strategies for reducing disease progression, the evidence base for disease-modifying agents is unclear. This forms the focus of this systematic review. Methods: The systematic review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 checklist. We selected randomized controlled trials (RCTs) that looked at the impact of interventions with disease-modifying agents, either synthetic drugs or biologics on musculoskeletal outcomes, notably American College of Rheumatology 20 percent responders. Results were analyzed using Review Manager 5.1.6 (Cochrane Collaboration, Oxford, UK). Whilst our primary focus was on published trials, we also looked at new trials presented in abstract form in 2013-2014 that were not yet published to avoid omitting important and up-to-date information on developing treatments. Results: Our in-depth analysis included 28 trials overall enrolling 5,177 patients published between the 1980s and now as well as limited analysis of some studies in abstract form as described earlier. The most frequently available locomotor outcome measure was the American College of Rheumatology 20 percent responders. The risk ratio for achieving an American College of Rheumatology 20 percent responders response was positive in favor of treatment (risk ratio 2.30; 95% confidence interval 1.78-2.96); however, there was evidence of considerable heterogeneity between trials. Overall randomized controlled trials of established synthetic disease-modifying agents were largely negative (methotrexate, ciclosporin and sulfasalazine) though leflunomide showed a small positive effect. A new synthetic agent, apremilast, did show a positive benefit. For biologics, TNF inhibitors already licensed for use were effective and similar benefits were seen with newer agents including ustekinumab, secukinumab, brodalumab, and abatacept, although the latter did not impact on skin problems. Important limitations of the systematic review included, first, the fact that for many agents there were little data and, second, much of the recent data for newer biologics were only available in abstract form. Conclusion: Conventional disease-modifying agents, with the possible exception of lefluno-mide, do not show clear evidence of disease-modifying effects in psoriatic arthritis, though a newer synthetic disease-modifying agents, apremilast, appears more effective. Biologic agents appear more beneficial, although more evidence is required for newer agents. This review suggests that it may be necessary to review existing national and international management guidelines for psoriatic arthritis.
OBJETIVO: El metotrexato es un tratamiento eficaz para una variedad de enfermedades inflamatorias. Falta evidencia sobre el riesgo de lesión hepática grave. El objetivo de este estudio fue evaluar el riesgo relativo y la gravedad de la enfermedad hepática entre los pacientes tratados con metotrexato. MÉTODOS: Se realizaron búsquedas en PubMed y en el Registro Cochrane Central de Ensayos Controlados del 1 de enero de 1990 al 24 de abril de 2014 para ensayos controlados aleatorios doble ciego de metotrexato frente a agentes comparadores en adultos con artritis reumatoide, psoriasis, artritis psoriásica o enfermedad inflamatoria intestinal. Se excluyeron los estudios con menos de 100 sujetos o con menos de 24 semanas de duración. Dos investigadores investigaron independientemente ambas bases de datos. Todos los autores revisaron los estudios seleccionados. Se compararon las diferencias de riesgo relativo (RR) utilizando el método de efectos aleatorios de Mantel-Haenszel para evaluar eventos adversos hepáticos totales, anomalías menores en las enzimas hepáticas (≤ 3 ULN), anomalías importantes en las enzimas hepáticas (> 3 ULN o retirada del tratamiento) Insuficiencia hepática, fibrosis, cirrosis o muerte. RESULTADOS: Un total de 32 estudios con 13177 participantes cumplieron con los criterios de inclusión. El metotrexato se asoció con un mayor riesgo de eventos hepáticos adversos totales, RR = 2,19 (IC del 95%: 1,73-2,77, I (2) = 68%), así como anomalías menores y mayores de la enzima hepática, RR = 2,16 (95% IC: 1,67-2,79, I (2) = 68%) y RR = 2,63 (IC del 95%: 1,90-3,64, I (2) = 10%), respectivamente. Los pacientes tratados con metotrexato no presentaron riesgo aumentado de insuficiencia hepática, cirrosis o muerte, RR = 0,12 (IC del 95%: 0,01-1,09, I (2) = 0%). Conclusión: Nuestro estudio encontró un aumento del riesgo de elevadas transaminasas pero no insuficiencia hepática, cirrosis o muerte con metotrexato en comparación con otros agentes. No pudimos evaluar la toxicidad hepática a largo plazo debido a la corta duración de los ensayos clínicos incluidos.
INTRODUCCIÓN: El tratamiento farmacológico actual de espondiloartritis (SpA) incluye varios medicamentos: medicamentos antiinflamatorios no esteroideos, corticoides, fármacos antirreumáticos modificadores de la enfermedad tradicionales y fármacos biológicos.
Zonas cubiertas: se completó una búsqueda sistemática de la literatura utilizando las bases de datos electrónicas más grandes (Medline, Embase y Cochrane), a partir de 1995, con el objetivo de revisar los datos de los agentes tradicionales y biológicos comercializados para el tratamiento SpA. Se consideraron los ensayos controlados aleatorios y los grandes estudios observacionales. Además, los estudios realizados en pacientes tratados con otros SpA, aún no aprobado, drogas (rituximab, agentes anti-IL6, Apremilast, inhibidores de IL17 y anakinra) también fueron tomadas en cuenta.
DICTAMEN DE EXPERTOS: Los agentes biológicos, especialmente los fármacos anti-TNF, se han traducido en avances significativos en la mejora de los síntomas y signos clínicos, reduciendo características inflamatorias en las pruebas de laboratorio y los hallazgos de imagen, y la recuperación de todos los índices funcionales. Los fármacos anti-TNF han cambiado radicalmente la evolución de la progresión radiográfica en articulaciones periféricas; los primeros datos decepcionantes en cuanto a su eficacia en la formación de hueso nuevo de SpA axial ha sido cuestionado recientemente por estudios que incluían a pacientes que han sido diagnosticados y tratados antes. La oportunidad de ampliar el intervalo de administración o reducir las dosis de los agentes anti-TNF puede influir favorablemente en los costos. Ustekinumab, el primer medicamento biológico no anti-TNF comercializada para la artritis psoriásica, ofrece nuevas posibilidades a los pacientes que no responden a anti-TNF.
OBJETIVO: Evaluar el riesgo relativo de enfermedad pulmonar en pacientes con psoriasis, artritis psoriásica y enfermedad inflamatoria intestinal tratados con metotrexato. SELECCIÓN DEL ESTUDIO: Ensayos controlados aleatorios doble ciego de metotrexato versus placebo o agentes comparadores activos en adultos con artritis psoriásica, psoriasis o enfermedad inflamatoria del intestino. Se excluyeron los estudios con menos de 50 participantes o con menos de 12 semanas de duración. SÍNTESIS DE DATOS: Dos investigadores investigaron independientemente ambas bases de datos. Todos los autores revisaron los estudios seleccionados. Se compararon las diferencias de riesgo relativo utilizando el método de efectos aleatorios de Mantel-Haenszel para evaluar eventos respiratorios adversos totales, eventos adversos respiratorios infecciosos, eventos adversos respiratorios no infecciosos, enfermedad pulmonar intersticial y muerte. Resultados: Siete estudios cumplieron con los criterios de inclusión, seis con placebo como comparador. La heterogeneidad entre los estudios no fue significativa (I (2) = 0%), permitiendo la combinación de los resultados del ensayo. Se documentaron 504 eventos adversos respiratorios en 1630 participantes. El metotrexato no se asoció con un mayor riesgo de eventos respiratorios adversos (riesgo relativo 1,03, intervalo de confianza del 95% 0,90 a 1,17), infecciones respiratorias (1,02, 0,88 a 1,19) o eventos respiratorios no infecciosos (1,07, 0,58 a 1,96). No se produjeron muertes pulmonares. Conclusiones: Los hallazgos sugieren que no hubo un mayor riesgo de enfermedad pulmonar en pacientes tratados con metotrexato con enfermedades inflamatorias no malignas. Dadas las limitaciones del estudio, sin embargo, no podemos excluir un riesgo pequeño pero clínicamente importante.
In 2009, GRAPPA published their first evidence-based recommendations for the treatment of psoriasis and psoriatic arthritis (PsA). Since then, new information has been published and drugs developed. We summarize evidence for the efficacy of available treatments for peripheral joint involvement in PsA. We performed a systematic review of current literature on the efficacy of different therapies, management, and therapeutic strategies for peripheral arthritis involvement in PsA, in order to provide information for the development of the new GRAPPA treatment recommendations.
Existen numerosas directrices y recomendaciones para el tratamiento de la psoriasis en diversas poblaciones. Una población importante son los pacientes con artritis psoriásica (PsA) que tienen síntomas de la enfermedad de la articulación y la piel. En pacientes con ambas facetas de la enfermedad psoriásica, la piel y las articulaciones deben tratarse por separado, pero también simultáneamente. Como varias terapias sistémicas son aprobadas para uno o ambos, el concepto de tratar ambas facetas con el mismo fármaco es factible. Esta revisión resume la evidencia de los estudios en pacientes con PsA sobre la eficacia de estos fármacos sobre la enfermedad psoriásica de la piel en estos pacientes.
Nail involvement in psoriatic diseases causes significant physical and functional disabilities. Evaluating, measuring, and treating nail involvement is important in improving the health outcomes and quality of life among patients with psoriasis and psoriatic arthritis (PsA). We performed a systematic analysis of the literature on nail psoriasis to help inform an update of treatment recommendations by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).
Psoriatic arthritis is an inflammatory disease associated with joint damage, impaired function, pain, and reduced quality of life. Methotrexate is a disease-modifying anti-rheumatic drug (DMARD) commonly prescribed to alleviate symptoms, attenuate disease activity, and prevent progression of disease.
OBJECTIVES:
To assess the benefits and harms of methotrexate for psoriatic arthritis in adults.
SEARCH METHODS:
We searched CENTRAL, MEDLINE, Embase, the WHO International Clinical Trials Registry Platform, and www.clinicaltrials.gov for relevant records. We searched all databases from inception to 29 January 2018. We handsearched included articles for additional records and contacted study authors for additional unpublished data. We applied no language restrictions.
SELECTION CRITERIA:
We included all randomised controlled trials (RCTs) and quasi-RCTs that compared methotrexate versus placebo, or versus another DMARD, for adults with psoriatic arthritis. We reported on the following major outcomes: disease response (measured by psoriatic arthritis response criteria (PsARC)), function (measured by the Health Assessment Questionnaire for Rheumatoid Arthritis (HAQ)), health-related quality of life, disease activity (measured by disease activity score (28 joints) with erythrocyte sedimentation rate (DAS28-ESR)), radiographic progression, serious adverse events, and withdrawals due to adverse events.
DATA COLLECTION AND ANALYSIS:
Two review authors independently reviewed search results, assessed risk of bias, extracted trial data, and assessed the quality of evidence using the GRADE approach. We undertook meta-analysis only when this was meaningful.
MAIN RESULTS:
We included in this review eight RCTs conducted in an outpatient setting, in Italy, the United Kingdom, the United States of America, China, Russia, and Bangladesh. Five studies compared methotrexate versus placebo, and four studies compared methotrexate versus other DMARDs. The average age of participants varied across studies (26 to 52 years), as did the average duration of psoriatic arthritis (one to nine years). Doses of methotrexate varied from 7.5 mg to 25 mg orally per week, but most studies administered approximately 15 mg or less orally per week. Risk of bias was generally unclear or high across most domains for all studies. We considered only one study to have low risk of selection and detection bias. The main study informing results of the primary comparison (methotrexate vs placebo up to six months) was at low risk of bias for all domains except attrition bias and reporting bias.We restricted reporting of results to the comparison of methotrexate versus placebo for up to six months. Low-quality evidence (downgraded due to bias and imprecision) from a single study (221 participants; methotrexate dose 15 mg orally or less per week) informed results for disease response, function, and disease activity. Disease response, measured by the proportion who responded to treatment according to PsARC (response indicates improvement), was 41/109 in the methotrexate group and 24/112 in the placebo group (risk ratio (RR) 1.76, 95% confidence interval (CI) 1.14 to 2.70). This equates to an absolute difference of 16% more responders with methotrexate (4% more to 28% more), and a number needed to treat for an additional beneficial outcome (NNTB) of 6 (95% CI 5 to 25). Mean function, measured by the HAQ (scale 0 to 3; 0 meaning no functional impairment; minimum clinically important difference 0.22), was 1.0 points with placebo and 0.3 points better (95% 0.51 better to 0.09 better) with methotrexate; absolute improvement was 10% (3% better to 17% better), and relative improvement 30% (9% better to 51% better). Mean disease activity as measured by the DAS28-ESR (scale of 0 to 10; lower score means lower disease activity; minimum clinically important difference unknown) was 3.8 points in the methotrexate group and 4.06 points in the placebo group; mean difference was -0.26 points (95% CI -0.65 to 0.13); absolute improvement was 3% (7% better to 1% worse), and relative improvement 6% (16% better to 3% worse).Low-quality evidence (downgraded due to risk of bias and imprecision) from three studies (n = 293) informed our results for serious adverse events and withdrawals due to adverse events. Due to low event rates, we are uncertain if methotrexate results show increased risk of serious adverse events or withdrawals due to adverse events compared to placebo. Results show 1/141 serious adverse events in the methotrexate group and 4/152 in the placebo group: RR 0.26 (95% CI 0.03 to 2.26); absolute difference was 2% fewer events with methotrexate (5% fewer to 1% more). In all, 9/141 withdrawals in the methotrexate group were due to adverse events and 7/152 in the placebo group: RR 1.32 (95% CI 0.51 to 3.42); absolute difference was 1% more withdrawals (4% fewer to 6% more).One study measured health-related quality of life but did not report these results. No study measured radiographic progression.
AUTHORS' CONCLUSIONS:
Low-quality evidence suggests that low-dose (15 mg or less) oral methotrexate might be slightly more effective than placebo when taken for six months; however we are uncertain if it is more harmful. Effects of methotrexate on health-related quality of life, radiographic progression, enthesitis, dactylitis, and fatigue; its benefits beyond six months; and effects of higher-dose methotrexate have not been measured or reported in a randomised placebo-controlled trial.
