The purpose of the study is to assess the safety and efficacy of adalimumab in combination with methotrexate in patients with recent onset rheumatoid arthritis (RA), and to assess the long-term safety and maintenance of efficacy after treatment with adalimumab for up to 10 years.
OBJETIVO: Comparar la eficacia y seguridad de adalimumab más metotrexato (MTX) frente a la monoterapia con metotrexato o en monoterapia con adalimumab en pacientes con artritis temprana y agresiva reumatoide (AR) que no habían recibido previamente tratamiento con MTX. MÉTODOS: Se trata de 2 años, multicéntrico, doble ciego, controlado con comparador activo de estudio de 799 pacientes con AR con enfermedad activa de la duración de menos de 3 años que nunca habían sido tratados con MTX. Los tratamientos incluyeron adalimumab 40 mg por vía subcutánea cada dos semanas más metotrexato oral, adalimumab 40 mg por vía subcutánea cada dos semanas, o semanal MTX oral. Co-Variables principales en un año fueron del Colegio Americano de Reumatología mejora de 50% (ACR50) y el cambio medio desde la basal en el índice de Sharp modificado total. RESULTADOS: El tratamiento combinado fue superior tanto al MTX en monoterapia con adalimumab en todos los resultados medidos. En el año 1, más los pacientes que recibieron terapia de combinación mostraron una respuesta ACR50 (62%) que los pacientes que recibieron MTX hizo o monoterapia con adalimumab (46% y 41%, respectivamente, ambos p <0,001). Similar superioridad del tratamiento combinado fue visto en ACR20, ACR70, ACR90 y las tasas de respuesta de 1 y 2 años. No fue la progresión radiográfica significativamente menor (P <0,002) entre los pacientes en el grupo de tratamiento combinado, tanto en los años 1 y 2 (1,3 y 1,9 unidades de agudos, respectivamente) que en los pacientes en el grupo de MTX (5,7 y 10,4 unidades de agudos) o el brazo de adalimumab (3,0 y 5,5 unidades de agudos). Después de 2 años de tratamiento, el 49% de los pacientes que recibieron terapia de combinación mostraron remisión de la enfermedad (Disease Activity Score 28-conjunto de <2,6), y el 49% mostró una respuesta clínica importante (ACR70 de respuesta durante al menos 6 meses continuos), las tasas de aproximadamente el doble de los entre los pacientes que recibieron monoterapia. Los perfiles de eventos adversos fueron comparables en los 3 grupos. CONCLUSIÓN: En esta población de pacientes con temprano y agresivo con AR, la terapia de combinación con adalimumab más metotrexato fue significativamente superior a MTX solo o adalimumab solo en la mejora de los signos y síntomas de la enfermedad, la inhibición de progresión radiográfica, y efectuar la remisión clínica.
OBJECTIVE: To compare the effect of adalimumab plus methotrexate (MTX) versus MTX monotherapy on health-related quality of life (HRQOL) and work activities in patients with early rheumatoid arthritis (RA).
METHODS: Patients in this PREMIER study subanalysis (n = 525) were randomized to adalimumab 40 mg every other week plus MTX or MTX monotherapy. Medical Outcome Study Short-Form 36 Health Survey (SF-36) scores of RA patients were compared with US population norms at Weeks 12, 52, and 104.
RESULTS: Physical Component Summary (PCS) scores at Week 12 for both groups improved from baseline and were significantly lower than US population scores (43.5 combination, 39.4 MTX, 49.4 US norm; p< 0.001). At Week 52, PCS score for adalimumab plus MTX was similar to that of the US population (47.5 vs 48.3; p = 0.25), while the PCS score for MTX was not similar to that of the US population (44.2 vs 48.3; p < 0.001). Criterion- and content-based interpretations for between-treatment differences in PCS scores suggest that those receiving combination therapy had fewer employment difficulties than those receiving MTX.
CONCLUSION: After 2 years, HRQOL for patients with early RA treated with adalimumab plus MTX improved to US norms. Combination therapy had reduced the influence of RA on work activity.
OBJECTIVE: To evaluate household and work place outcomes for patients with rheumatoid arthritis (RA) who were homemakers or employed workers, respectively, and who were treated with adalimumab plus methotrexate versus methotrexate monotherapy. We also determined baseline predictors of household and work place outcomes. METHODS: Data were from a health economic companion study to PREMIER, a 2-year, randomized controlled trial of methotrexate-naive patients with early RA (<3 years) who received treatment with adalimumab plus methotrexate, adalimumab, or methotrexate. Absenteeism (number of days missed or unfit to work), presenteeism (self-judgment of the effects of RA on job or household performance), and employment status were collected from self-reports at baseline and varying time points during the study. RESULTS: Household and work place outcomes were generally similar for homemakers and employed workers. Over 2 years, patients who received combination therapy missed approximately half as many days as patients who received methotrexate (17.4 versus 36.9 days for employed workers; 7.9 versus 18.6 days for homemakers). Presenteeism was lower (reflecting better productivity) for combination therapy than methotrexate monotherapy. The likelihood of gaining/retaining employment over 2 years was greater for combination therapy than methotrexate monotherapy (odds ratio 1.530, 95% confidence interval 1.038-2.255; P = 0.0318). Baseline radiographic progression was an independent predictor for retaining/gaining employment at 2 years. CONCLUSION: Compared with methotrexate monotherapy, combination therapy was associated with more positive work outcomes: less absenteeism, less presenteeism, and greater likelihood of gaining/retaining employment. Radiographic progression at baseline was predictive of the ability to retain or gain employment.
OBJECTIVE: Rheumatoid arthritis (RA) is associated with significant impairments in health-related quality of life (HRQOL). We evaluated patient-reported outcomes including HRQOL outcomes following adalimumab plus methotrexate (MTX) therapy in patients with early RA.
METHODS: PREMIER was a phase III, multicenter, randomized, double-blind, active-comparator clinical trial in early RA. Patients aged ≥ 18 years were randomly assigned to receive adalimumab 40 mg every other week (eow) plus weekly MTX, weekly MTX, or adalimumab 40 mg eow for 104 weeks. American College of Rheumatology (ACR) criteria were used to evaluate clinical efficacy and response. Outcomes were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI), Short-Form 36 Health Survey (SF-36), Short-Form 6 Dimension (SF-6D), visual analog scale (VAS) assessments of global disease activity (patient's global assessment; PtGA) and pain, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Health Utility Index Mark 3 (HUI-3).
RESULTS: Of 799 patients enrolled, 268 received adalimumab plus MTX, 257 received MTX monotherapy, and 274 received adalimumab monotherapy. Patients treated with adalimumab plus MTX demonstrated significant baseline to Week 104 improvements in HAQ-DI (p < 0.0001), SF-36 Physical Component Summary (p < 0.0001), 4 SF-36 domains [physical function (p < 0.0001), bodily pain (p <0.0001), vitality (p = 0.0139), role limitations-physical (p = 0.0005)], SF-6D (p = 0.0152), VAS-PtGA (p < 0.0001), VAS-pain (p < 0.0001), FACIT-F (p < 0.0001), and HUI-3 (p = 0.0034) scores versus patients treated with MTX monotherapy. Both SF-6D and HUI-3 were found to be sensitive preference-based measures for assessing the effects of treatment on multidimensional function. No clinically meaningful differences between adalimumab and MTX monotherapy groups were observed for most measures. For each measure, there was significant association between HRQOL improvement and ACR clinical response.
CONCLUSION: Adalimumab plus MTX significantly improved physical functioning and HRQOL in patients with early RA over 2 years of treatment. (ClinicalTrials.gov identifier NCT00195663).
BACKGROUND/PURPOSE: The systemic inflammation of rheumatoid arthritis (RA) can have detrimental effects on the hematopoietic and cardiovascular systems. Additionally, effective DMARD treatments for RA can be hemato- or hepatotoxic. The effects of adalimumab (ADA) in combination with methotrexate (MTX) therapy on these systems in patients with early or long-standing RA have not been previously summarized. This analysis evaluates the effects of ADA+MTX therapy compared to MTX monotherapy on laboratory and vital sign parameters relevant to hematopoietic, cardiovascular, and hepatic organ systems. METHODS: Clinical trials DE013 and OPTIMA (MTX-naïve patients, early RA, mean duration=0.8 yrs in DE013, 0.35 yrs in OPTIMA) and DE019 (MTX-incomplete responders, long-standing RA, mean duration=11 yrs) were double-blind studies that compared ADA+MTX therapy to MTX monotherapy for ≥6 months. This post hocanalysis determined the percentage of patients who developed neutropenia, lymphocytopenia, thrombocytopenia, anemia, reduction in Hgb from baseline, increases in creatinine, increases in AST or ALT, and prevalence of stage 2 hypertension at any time during the first 6 months of ADA treatment. Mean laboratory values and vital signs (all studies) and fasting lipids (OPTIMA only) were determined at baseline and 6 months and compared using a contrast within a one-way analysis of variance. RESULTS: Incidence rates for laboratory abnormalities are listed in the table. After 6 months, mean increase in Hgb levels was higher in ADA+MTX arms than in the MTX-only arms in early RA and in long-standing RA. Mean HDL cholesterol changes were not different in the ADA+MTX treatment group compared to MTX alone. Mean total and LDL cholesterol increased numerically with ADA+MTX therapy vs. MTX alone. No differences were observed in the incidences or mean changes in serum creatinine, ALT, or AST between ADA+MTX therapy and MTX alone. CONCLUSION: Over an observation period of 6 months, RA patients treated with ADA+MTX exhibited laboratory abnormalities and hypertension at levels and frequencies similar to those seen in patients treated with MTX alone. In fact, ADA+MTX therapy was associated with a statistically significantly reduced incidence of anemia and lymphocytopenia. Similar results were observed whether evaluating ADA treatment in MTX-naïve patients or in those with long-standing RA
OBJECTIVES: Tumour necrosis factor inhibition plus methotrexate is believed to inhibit radiographic progression independent of inflammation. This analysis assessed whether these protective effects are exerted on bone (joint erosion; JE) and/or cartilage (joint space narrowing; JSN), and what the independent effects of JE/JSN progression are on longer-term patient-reported outcomes.
METHODS: PREMIER was a 2-year, randomised, controlled trial of adalimumab plus methotrexate (ADA+MTX) versus the monotherapies. The impact of treatment on the relationships between time-averaged disease activity (TA-DAS28(CRP)) and changes in JE/JSN and associations of JE/JSN with the disability index of the health assessment questionnaire (HAQ-DI) at baseline and weeks 52 and 104 were assessed through non-parametric approaches of analysis of variance and quantile regression. JE/JSN association with employment status was evaluated at baseline and weeks 52 and 104 through logistic regression.
RESULTS: Increasing tertiles of TA-DAS28(CRP) were associated with JE and JSN progression in the monotherapy groups, a phenomenon largely absent in ADA+MTX-treated patients. Although JSN was not associated with HAQ-DI at baseline, it was at 52 and 104 weeks. In contrast, JE was not associated with HAQ-DI at any time point examined. Odds of being employed at baseline, 52 weeks and 104 weeks were significantly associated with lower JSN, but not JE, scores.
CONCLUSIONS: ADA+MTX inhibited both JE and JSN progression independently of disease activity. JSN played a more prominent role in patient-reported outcomes than JE. Preventing the onset or worsening of JSN probably represents a critical aspect of effective disease management of early rheumatoid arthritis patients.
OBJECTIVE: To evaluate the longterm safety of adalimumab administered with or without methotrexate (MTX) and compare the efficacy of combination therapy initialization to adalimumab or MTX monotherapy initialization during the open-label extension (OLE) of the PREMIER trial (ClinicalTrials.gov Identifier:NCT00195663).
METHODS: Patients with early rheumatoid arthritis (RA) were randomized to receive blinded adalimumab + MTX, adalimumab alone, or MTX alone for 2 years. Following the double-blinded period, patients enrolling in the OLE were given adalimumab for up to 8 additional years, beginning as monotherapy; investigators could add MTX at their discretion. Results for clinical, functional, and radiographic progression were collected for up to 10 years of treatment.
RESULTS: During the PREMIER OLE, 250/497 patients (50.3%) completed the trial without new safety signals arising. Similar proportions of patients discontinued the trial early, although lack of efficacy was reported less often for patients initially randomized to the adalimumab + MTX arm (9.3%; 21.2%, and 23.7% for adalimumab and MTX monotherapies, respectively). Clinical and functional disease control was maintained throughout the trial. Patients initially randomized to adalimumab + MTX displayed better outcomes, particularly in prevention of radiographic progression (modified total Sharp score change = 4.0, 8.8, 11.0 at Year 10 for the initial adalimumab + MTX, adalimumab, and MTX arms, respectively).
CONCLUSION: Intensive therapy with adalimumab + MTX combination in patients with early RA has longterm benefits compared to patients initiating with 2-year adalimumab or MTX monotherapy that persists up to 10 years following adalimumab OLE. No new safety findings were observed following longterm adalimumab treatment.
Clinical synovitis is often associated with damage to bone and cartilage. Previous data have suggested that joint erosions (JE) are more prevalent than joint space narrowing (JSN) and that the two processes are partly independent of each other. The objective of this study was to evaluate whether the presence of JE in an individual joint can lead to development of JSN and if existing JSN leads to new onset of JE, in the absence of synovitis. Methods: The Prospective Multi-Centre Randomised, Double-Blind, Active Comparator-Controlled, Parallel-Groups Study Comparing the Fully Human Monoclonal Anti-TNFα Antibody Adalimumab Given Every Second Week With Methotrexate Given Weekly and the Combination of Adalimumab and Methotrexate Administered Over 2 Years in Patients With Early Rheumatoid Arthritis (PREMIER) enrolled early rheumatoid arthritis (RA) patients who were randomized to one of three treatments: methotrexate (MTX), adalimumab (ADA), or ADA + MTX. All evaluable joints with JE and JSN measures at 26 and 52weeks and synovitis assessments from week 26 to 52 were included. Synovitis was assessed every 2-8 weeks by swollen joint counts between weeks 26 and 52. Radiographs were taken at week 26 and 52. Two readers, blinded to time and sequence, scored 14 bilateral joints individually for JE and JSN. Multivariate logistic modeling was used to characterize the dependence of JE/JSN onset at 52weeks. Analyses were performed based on treatment arm and were also performed within individual joints. Results: JE and swelling were independently and comparably associated with onset of JSN at week 52. Assessment by individual joints indicated that existing JE, independent of swelling, was significantly associated with JSN onset in higher proportions of metatarsophalangeal (MTP; 7/10) than proximal interphalangeal (PIP; 1/8) or metacarpophalangeal (MCP; 1/10) joints. Treatment with ADA + MTX prevents JE/JSN progression independently of its ability to suppress synovitis and limits JE/JSN onset and progression in joints with existing damage. Conclusions: Existing JE predisposes individual joints to development of JSN independently of synovitis in the same joint. Weight-bearing MTP joints with JE may be at increased risk for JSN when compared with MCPs and PIPs. Trial registration: Clinicaltrials.gov NCT00195663. Registered 13 September 2005.
OBJECTIVE: To estimate the cost-effectiveness of adalimumab plus methotrexate (MTX) versus MTX monotherapy in early, aggressive rheumatoid arthritis (RA) when explicitly modelling short-term (reversible) and long-term (irreversible, ie, joint damage) disease activity and physical function.
METHODS: A microsimulation model was developed to unify, in a single cost-effectiveness model, measures of reversible and irreversible disease activity and physical function based on data from the PREMIER trial. Short term, reversible disease activity was modelled using DAS28 variables, including swollen joint counts, tender joint counts, C reactive protein concentration and pain. The DAS28 variables were then used in a logistic regression to predict short-term American College of Rheumatology (ACR) responses, which informed treatment continuation and switches. Long term, irreversible, radiographically documented joint damage was modelled using modified Total Sharp Score (mTSS). The model then linked both short-term disease activity and mTSS to the Health Assessment Questionnaire score, which was used to calculate direct and indirect costs, and quality adjusted life-years (QALYs).
RESULTS: When both reversible and irreversible effects of therapy were included, combination therapy was estimated to produce 6-month 50% ACR responses in 75% of patients versus 54% in MTX monotherapy. Compared to MTX monotherapy, combination therapy resulted in 2.68 and 3.04 discounted life years and QALYs gained, respectively. Combination therapy also resulted in a net increase in direct costs of £106,207 for a resulting incremental cost/QALY gain of £32,425. When indirect costs were included in the analysis, the ICER (incremental cost-effectiveness ratio) decreased to £27,238. Disregarding irreversible effects increased the incremental cost-effectiveness ratio to £78,809 (when only direct costs were included).
CONCLUSIONS: Starting with adalimumab plus MTX combination therapy in early, aggressive RA is cost-effective when irreversible damage is adequately considered.
OBJECTIVE: To study low blood hemoglobin concentrations as a predictor of radiographic damage progression in patients with rheumatoid arthritis (RA).
METHODS: Post hoc analyses were performed in patients from the PREMIER trial with early RA undergoing 2 years of adalimumab (ADA), methotrexate (MTX), or ADA + MTX combination therapy. Low disease activity was defined as a score <3.2 on the 28-joint Disease Activity Score using the C-reactive protein level (DAS28-CRP), and clinical response by the American College of Rheumatology criteria for 20% improvement at week 24. Baseline or mean hemoglobin concentrations over time, or anemia as defined using sex-specific World Health Organization criteria, were analyzed in mixed-effects models for longitudinal data in men and women as predictors of progressive joint damage, as measured by the modified total Sharp/van der Heijde score (ΔSHS). Data were adjusted for treatment and other patient characteristics, including the DAS28-CRP.
RESULTS: Baseline hemoglobin was inversely associated with ΔSHS in adjusted analyses (P < 0.05 for both sexes). Baseline anemia predicted greater ΔSHS in MTX-treated patients over 104 weeks, and in ADA- and combination-treated patients over 26 weeks. Lower hemoglobin concentrations over time, as well as time with anemia, were associated with greater damage progression (P < 0.001). The effect of low hemoglobin concentrations on joint damage progression remained significant, even in patients achieving low disease activity.
CONCLUSION: Low hemoglobin is a DAS28-CRP-independent predictor of radiographic joint damage progression in MTX-treated patients with early RA. This effect decreases over time in ADA- and combination-treated patients, and in clinical responders irrespective of treatment modality.
The purpose of the study is to assess the safety and efficacy of adalimumab in combination with methotrexate in patients with recent onset rheumatoid arthritis (RA), and to assess the long-term safety and maintenance of efficacy after treatment with adalimumab for up to 10 years.
