OBJECTIVE: To investigate whether methotrexate (MTX) administered orally to rheumatoid arthritis (RA) patients in split doses at 2-3 days' interval, would result in equal or better efficacy, tolerability and compliance, without increasing toxicity compared to single weekly dose given orally or parenterally.
MATERIALS AND METHODS: One hundred and thirty-five patients fulfilling the American College of Rheumatology (ACR) 2010 criteria for RA, on 7.5 mg of MTX weekly orally, with the Simplified Disease Activity Index (SDAI) > 11 were enrolled for a 24-week period. Patients were randomly divided into three groups and were given MTX: Group 1 7.5 mg twice or thrice weekly orally, Group 2 15 mg or 22.5 mg in a single dose weekly orally and Group 3 15 mg or 22.5 mg in a single dose weekly as an intramuscular injection. The primary outcomes were low disease activity (LDA) and mean change in SDAI at week 24, whereas secondary outcomes included remission, adverse events and compliance.
RESULTS: At week 24, adherence to treatment was maximum in Group 1, 69% (P = 0.09). In intention-to-treat analysis at 24 weeks, Group 1, 49%, Group 2, 36% and Group 3, 47% achieved LDA (P = 0.4). There was significant difference in mean change in SDAI at week 24 from baseline (P = 0.008) among the groups. Group 3 patients were more uncomfortable with the mode of administration of MTX (P = 0.003). There was no significant difference in adverse events.
CONCLUSION: Oral split doses of MTX are better than an oral single dose and similar to parenteral MTX in terms of efficacy.
OBJECTIVE: To assess the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in a double-blind phase III trial enrolling patients with active psoriatic arthritis (PsA).
METHODS: Patients naive to biologic therapy with active PsA were randomised to subcutaneous injections of placebo (N=106), adalimumab 40 mg once every 2 weeks (active reference; N=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (N=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (N=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 24.
RESULTS: Significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%) (p≤0.001; non-responder imputation method). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and there was significantly less progression of structural damage at week 24 (p≤0.01). Clearance of plaque psoriasis was greater with ixekizumab than placebo (p≤0.001). Efficacy results with adalimumab, the active reference arm, showed significant improvements versus placebo. Treatment-emergent adverse events were more frequent with ixekizumab (65.7-66.4%) and adalimumab (64.4%) than placebo (47.2%) (p<0.05).
CONCLUSIONS: In biologic-naive patients with active PsA, ixekizumab treatment resulted in improvements in disease activity and physical function, as well as in the inhibition of structural damage progression. Overall, adverse events were more frequent in all active groups compared with placebo.
TRIAL REGISTRATION NUMBER: NCT01695239; EudraCT2011-002326-49; Results.
Both the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) guidelines recommend the use of methotrexate (MTX) for the treatment of rheumatoid arthritis (RA) when there is no contraindication. While MTX is the foundation of RA therapy (Singh et al. in Arthritis Care Res 64:625-639,2012), absorption saturation compromises its oral bioavailability (BA). Differences in the relative BA of oral versus subcutaneous (SC) MTX demonstrate the need for guidance on successful dose-conversion strategies. This study was designed to compare MTX PK profiles as a result of MTX administration via three different treatment administrations: oral, SC MTX administered via an auto-injector (MTXAI) into the abdomen (MTXAIab) and into the thigh (MTXAIth). In this paper, we establish a dose-conversion method based on the BA of MTX from oral and SC administration. SC administration provided higher exposure of MTX than the same dose given orally. Unlike the exposure limitations of oral MTX, dose-proportional exposure was seen with SC MTX.
Treating to target is becoming the standard of care in many medical specialities, including rheumatology. The Tight Control of Psoriatic Arthritis (TICOPA) trial has recently provided evidence of the benefit of treating to target in psoriatic arthritis (PsA), and the revised European League Against Rheumatism (EULAR) recommendations on the management of PsA suggest this approach. However, the question of the optimal measure to use and the practicalities of incorporating this into routine clinical practice remain problematic.
OBJECTIVE: To update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA).
METHODS: GRAPPA rheumatologists, dermatologists, and PsA patients drafted overarching principles for the management of PsA, based on consensus achieved at face-to-face meetings and via online surveys. We conducted literature reviews regarding treatment for the key domains of PsA (arthritis, spondylitis, enthesitis, dactylitis, skin disease, and nail disease) and convened a new group to identify pertinent comorbidities and their effect on treatment. Finally, we drafted treatment recommendations for each of the clinical manifestations and assessed the level of agreement for the overarching principles and treatment recommendations among GRAPPA members, using an online questionnaire.
RESULTS: Six overarching principles had ≥80% agreement among both health care professionals (n = 135) and patient research partners (n = 10). We developed treatment recommendations and a schema incorporating these principles for arthritis, spondylitis, enthesitis, dactylitis, skin disease, nail disease, and comorbidities in the setting of PsA, using the Grading of Recommendations, Assessment, Development and Evaluation process. Agreement of >80% was reached for approval of the individual recommendations and the overall schema.
CONCLUSION: We present overarching principles and updated treatment recommendations for the key manifestations of PsA, including related comorbidities, based on a literature review and consensus of GRAPPA members (rheumatologists, dermatologists, other health care providers, and patient research partners). Further updates are anticipated as the therapeutic landscape in PsA evolves.
BACKGROUND: Plaque psoriasis is a chronic and often debilitating skin disorder and proinflammatory cytokines are known to play a key role in the disease process.
OBJECTIVES: To evaluate the safety and efficacy of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis in a randomized, double-blind, placebo-controlled, dose-ranging phase 2b study.
METHODS: Patients were randomized (n = 271) to receive placebo or oral baricitinib at 2, 4, 8 or 10 mg once daily for 12 weeks (Part A). Dose adjustment for 12 additional weeks was based on percentage improvement in the Psoriasis Area and Severity Index (PASI) score. The primary end point was Psoriasis Area and Severity Index (PASI) 75% (PASI-75) at 12 weeks for North American patients (n = 238); secondary end points were safety and efficacy measures in the entire population.
RESULTS: At week 12, more North American patients in the 8-mg (43%) and 10-mg (54%) baricitinib groups than in placebo group (17%; P < 0·05) achieved PASI-75. All baricitinib-treated groups had greater mean changes from baseline in their PASI scores (P < 0·05) at 12 weeks and (except 2 mg) had higher rates of PASI-50 than the placebo group; statistically significant PASI-90 responses were achieved in the 8-mg and 10-mg groups at 8 and 12 weeks. More than 81% of PASI-75 responders maintained their scores through 24 weeks. During Part A, study discontinuations due to adverse events (AEs) were 0%, 0%, 2·8%, 6·3% and 5·8% and treatment-emergent AE rates were 44%, 50%, 47%, 58% and 64% for placebo and 2-, 4-, 8- and 10-mg baricitinib groups, respectively. No opportunistic infections were observed in any treatment group. Dose-dependent changes in laboratory values were observed.
CONCLUSIONS: Patients with moderate-to-severe psoriasis treated with baricitinib for 12 weeks achieved significant improvements in PASI-75.
OBJECTIVE: To determine the comparative effectiveness of oral versus subcutaneous methotrexate (MTX) as initial therapy for patients with early rheumatoid arthritis (ERA).
METHODS: Patients with ERA (symptoms ≤1 year) initiating MTX therapy were included from a multicentre, prospective cohort study. We compared the effectiveness between starting with oral versus subcutaneous MTX over the first year. Longitudinal multivariable models, adjusted for potential baseline and time-varying confounders, were used to compare treatment changes due to inefficacy or toxicity and treatment efficacy (Disease Activity Score-28 (DAS-28), DAS-28 remission and Health Assessment Questionnaire-Disability Index (HAQ-DI)).
RESULTS: 666 patients were included (417 oral MTX, 249 subcutaneous MTX). Patients prescribed subcutaneous MTX were prescribed a higher dose of MTX (mean dose over first three months 22.3 mg vs 17.2 mg/week). At 1 year, 49% of patients initially treated with subcutaneous MTX had changed treatment compared with 77% treated with oral MTX. After adjusting for potential confounders, subcutaneous MTX was associated with a lower rate of treatment failure ((HR (95% CI) 0.55 (0.39 to 0.79)). Most treatment failures were due to inefficacy with no difference in failure due to toxicity. In multivariable models, subcutaneous MTX was also associated with lower average DAS-28 scores (mean difference (-0.38 (95% CI -0.64 to -0.10)) and a small difference in DAS-28 remission (OR 1.2 (95% CI 1.1 to 1.3)). There was no significant difference in sustained remission or HAQ-DI (p values 0.43 and 0.75).
CONCLUSIONS: Initial treatment with subcutaneous MTX was associated with lower rates of treatment changes, no difference in toxicity and some improvements in disease control versus oral MTX over the first year in patients with ERA.
OBJECTIVE: To evaluate ustekinumab efficacy and safety in psoriatic arthritis (PsA) patients with peripheral arthritis and physician-reported spondylitis (termed the 'spondylitis subset').
METHODS: Adults with active PsA (PSUMMIT-1/PSUMMIT-2, n=615/312) were randomised to ustekinumab 45 mg, 90 mg or placebo at week 0/week 4/q12 week. At week 16, patients with <5% improvement in tender and swollen joints entered blinded early escape. A subset of patients with physician-identified spondylitis was evaluated with spondylitis-specific assessments, including Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score employing C reactive protein (ASDAS-CRP), through week 24.
RESULTS: 256/927 (27.6%) PSUMMIT-1/PSUMMIT-2 patients (placebo/ustekinumab, n=92/164) comprised the evaluable spondylitis subset. At week 24, in this analysis subset, significantly more patients achieved BASDAI20/50/70 responses (54.8%/29.3%/15.3% vs 32.9%/11.4%/0%; p≤0.002), improvement in BASDAI question 2 concerning axial pain (1.85 vs 0.24; p<0.001) and mean per cent ASDAS-CRP improvements (27.8% vs 3.9%; p<0.001) for ustekinumab versus placebo recipients, respectively. Comparable to the overall study population, significant improvements were also achieved in psoriasis, peripheral arthritis, enthesitis, dactylitis, physical function and peripheral joint radiographs in the spondylitis subset.
CONCLUSIONS: In this post-hoc analysis of PsA patients with baseline peripheral arthritis and physician-reported spondylitis, ustekinumab-treated patients demonstrated significant improvements in axial signs and symptoms through week 24.
TRIAL REGISTRATION NUMBER: PSUMMIT-1 (NCT01009086, EudraCT 2009-012264-14) and PSUMMIT-2 (NCT01077362, EudraCT 2009-012265-60); post-study results.
ANTECEDENTES: Desde la publicación de las recomendaciones de la Liga Europea Contra el Reumatismo para el tratamiento farmacológico de la artritis psoriásica (APs) en 2012, han surgido nuevas pruebas y nuevos agentes terapéuticos. El objetivo fue actualizar estas recomendaciones.
MÉTODOS: Una revisión sistemática de la literatura se llevó a cabo en relación con el tratamiento farmacológico de la artritis psoriásica. Posteriormente, se formularon recomendaciones basadas en la evidencia y la opinión de los expertos de los 34 miembros del grupo de trabajo. Se asignaron los niveles de evidencia y fortalezas de recomendaciones.
RESULTADOS: Las recomendaciones actualizadas comprenden 5 principios generales y 10 recomendaciones, que cubre las terapias farmacológicas para la APs de las drogas no esteroides antiinflamatorios (AINE), a sintética convencional (csDMARD) y (MBE) fármacos antirreumáticos modificadores biológicos de la enfermedad, cualquiera que sea su modo de de acción, teniendo manifestaciones articulares y extraarticulares de la artritis psoriásica en cuenta, pero centrándose en la participación musculoesquelético. Los principios generales abordan la necesidad de objetivos de decisión y de tratamiento compartido. Las recomendaciones se refieren a csDMARDs como terapia inicial después del fracaso de los AINE y la terapia local para la enfermedad activa, seguido, si es necesario, por un MBE o un DMARD sintético dirigida (tsDMARD). La primera MBE normalmente sería un inhibidor del factor de necrosis tumoral (TNF). MBE dirigidas a la interleuquina (IL) 12/23 (ustekinumab) o IL-17 vías (secukinumab) se pueden usar en pacientes en los que los inhibidores del TNF son inapropiadas y un tsDMARD tales como fosfodiesterasa-4 inhibidor (Apremilast) si MBE son inapropiados. Si la primera estrategia de MBE falla, cualquier otra MBE o tsDMARD pueden ser utilizados.
CONCLUSIONES: Estas recomendaciones proporcionan las partes interesadas con un consenso actualizada sobre el tratamiento farmacológico de la artritis psoriásica y estrategias para alcanzar resultados óptimos en la artritis psoriásica, basado en una combinación de pruebas y la opinión de expertos.
OBJETIVO: Desarrollar una nueva pauta de tratamiento farmacológico basado en la evidencia para la artritis reumatoide (AR).
MÉTODOS: Se realizó una revisión sistemática para sintetizar la evidencia de los beneficios y los daños de diferentes opciones de tratamiento. Se utilizó la clasificación de las recomendaciones de la evaluación, la metodología de Evaluación (GRADE) Desarrollo y en evaluar la calidad de las pruebas. Empleamos un proceso de consenso del grupo para clasificar la fuerza de las recomendaciones (ya sean fuertes o condicionales). Una recomendación sólida indica que los médicos están seguros de que los beneficios de una intervención son muy superiores a los daños (o viceversa). Una recomendación condicional denota incertidumbre sobre el equilibrio entre los beneficios y los daños y / o una mayor variabilidad significativa en los valores y las preferencias del paciente.
RESULTADOS: La guía cubre el uso de los fármacos tradicionales modificadores de la enfermedad (DMARD) antirreumáticos, agentes biológicos, tofacitinib, y los glucocorticoides en los primeros 6 meses (<) y estableció (6 meses o más) RA. Además, proporciona recomendaciones sobre el uso de un enfoque de tratar al objetivo, se estrecha y descontinuar medicamentos y el uso de agentes biológicos y FAME en pacientes con hepatitis, insuficiencia cardíaca congestiva, enfermedad maligna, y las infecciones graves. La directriz se refiere a la utilización de las vacunas en pacientes que inician / recepción de FARME o agentes biológicos, la detección de la tuberculosis en pacientes que inician / recepción de agentes biológicos o tofacitinib, y la vigilancia de laboratorio para los DMARD tradicionales. La guía incluye 74 recomendaciones: 23% son fuertes y el 77% son condicionales.
CONCLUSIÓN: Esta directriz RA debe servir como una herramienta para los médicos y pacientes (nuestros dos audiencias objetivo) para las decisiones de tratamiento farmacológico en situaciones clínicas más frecuentes. Estas recomendaciones no son prescriptivos, y las decisiones de tratamiento deben ser tomadas por los médicos y los pacientes a través de un proceso de toma de decisiones compartida, teniendo en cuenta los valores de los pacientes, las preferencias y las comorbilidades. Estas recomendaciones no deben ser utilizados para limitar o no permitir el acceso a las terapias.
To investigate whether methotrexate (MTX) administered orally to rheumatoid arthritis (RA) patients in split doses at 2-3 days' interval, would result in equal or better efficacy, tolerability and compliance, without increasing toxicity compared to single weekly dose given orally or parenterally.
MATERIALS AND METHODS:
One hundred and thirty-five patients fulfilling the American College of Rheumatology (ACR) 2010 criteria for RA, on 7.5 mg of MTX weekly orally, with the Simplified Disease Activity Index (SDAI) > 11 were enrolled for a 24-week period. Patients were randomly divided into three groups and were given
MTX:
Group 1 7.5 mg twice or thrice weekly orally, Group 2 15 mg or 22.5 mg in a single dose weekly orally and Group 3 15 mg or 22.5 mg in a single dose weekly as an intramuscular injection. The primary outcomes were low disease activity (LDA) and mean change in SDAI at week 24, whereas secondary outcomes included remission, adverse events and compliance.
RESULTS:
At week 24, adherence to treatment was maximum in Group 1, 69% (P = 0.09). In intention-to-treat analysis at 24 weeks, Group 1, 49%, Group 2, 36% and Group 3, 47% achieved LDA (P = 0.4). There was significant difference in mean change in SDAI at week 24 from baseline (P = 0.008) among the groups. Group 3 patients were more uncomfortable with the mode of administration of MTX (P = 0.003). There was no significant difference in adverse events.
CONCLUSION:
Oral split doses of MTX are better than an oral single dose and similar to parenteral MTX in terms of efficacy.
