Testing treat-to-target outcomes with initial methotrexate monotherapy compared with initial tumour necrosis factor inhibitor (adalimumab) plus methotrexate in early rheumatoid arthritis.

OBJECTIVES: To compare responses in patients with early rheumatoid arthritis (RA) initially treated with the tumour necrosis factor inhibitor (TNFi) adalimumab+methotrexate (MTX) versus MTX monotherapy who may have continued receiving MTX or switched to adalimumab rescue therapy after inadequate response to MTX. METHODS: OPTIMA enrolled MTX-naive patients with active RA for <1 year. This post hoc analysis determined the proportion of patients, stratified by initial treatment, who achieved 28-joint modified Disease Activity Score based on C reactive protein <3.2, normal function and/or no radiographic progression at weeks 26, 52 and 78. RESULTS: Significantly greater proportions of patients initially treated with adalimumab+MTX (n=466) compared with MTX monotherapy (n=460) achieved good clinical (53% vs 30%), functional (45% vs 33%) and radiographic (87% vs 72%) outcomes at week 26. From weeks 26 to 78, adalimumab rescue patients achieved similar clinical and functional outcomes versus patients initially treated with adalimumab+MTX. However, significantly more patients initially treated with adalimumab+MTX had no radiographic progression at weeks 52 and 78 versus patients initially treated with MTX (both timepoints: 86% vs 72%). CONCLUSIONS: In early RA, starting with MTX monotherapy and adding TNFi after 26 weeks yields similar longer term clinical results as starting with TNFi+MTX combination therapy but allows a small but significant accrual of radiographic damage.

Final 10-year effectiveness and safety results from study DE020: adalimumab treatment in patients with rheumatoid arthritis and an inadequate response to standard therapy.

OBJECTIVE: To evaluate the long-term effectiveness and safety of 10 years of adalimumab (ADA) treatment in DMARD-refractory RA patients and to analyse efficacy based on RF status and baseline disease duration. METHODS: DE020 was a multicentre, phase 3, open-label continuation study. Adult RA patients who received s.c. ADA (40 mg every other week or monthly) in one of four early assessment studies could receive ADA for ≤10 years in DE020. Assessments included the 28-joint DAS with CRP (DAS28-CRP), Simplified Disease Activity Index (SDAI), HAQ Disability Index (HAQ-DI) and safety as events per 100 patient-years. RESULTS: Of 846 enrolled patients, mean age at baseline was 55.6 years, 78.1% were women, mean disease duration was 11.7 years and 27.0% were RF(-). Among 286 (33.8%) patients who completed 10 years of ADA, 168/236 (71.2%) achieved DAS28-CRP ≤3.2, 101/238 (42.4%) achieved HAQ-DI <0.5 and 90/241 (37.3%) achieved DAS28-CRP ≤3.2 plus HAQ-DI <0.5. DAS28-CRP- or SDAI-based remission was observed in 135/236 (57.2%) and 70/236 (29.7%) patients, respectively. Effectiveness outcomes were similar regardless of RF status. Higher proportions of patients with shorter vs longer baseline disease duration (≤2 vs >2 years) achieved HAQ-DI <0.5 (60.6% vs 39.5%; P = 0.023) and DAS28-CRP ≤3.2 plus HAQ-DI <0.5 (58.1% vs 32.5%; P = 0.006). Adverse events (317.2 events per 100 patient-years) during ADA exposure were consistent with the expected safety profile for TNF inhibitors. CONCLUSION: ADA led to sustained clinical and functional responses in the 33.8% of treatment-refractory RA patients who completed 10 years of treatment. Patients with shorter disease duration achieved better outcomes, highlighting the need for early treatment. No unexpected safety findings were observed. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT00195650.

Longterm effect of delaying combination therapy with tumor necrosis factor inhibitor in patients with aggressive early rheumatoid arthritis: 10-year efficacy and safety of adalimumab from the randomized controlled PREMIER trial with open-label extension.

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.

Is new drug prescribing in primary care specialist induced?

BACKGROUND: Medical specialists are often seen as the first prescribers of new drugs. However, the extent to which specialists influence new drug prescribing in primary care is largely unknown. METHODS: This study estimates the influence of medical specialists on new drug prescribing in primary care shortly after market introduction. The influence of medical specialists on prescribing of five new drugs was measured in a cohort of 103 GPs, working in 59 practices, over the period 1999 until 2003. The influence of medical specialists on new drug prescribing in primary care was assessed using three outcome measures. Firstly, the proportion of patients receiving their first prescription for a new or reference drug from a specialist. Secondly, the proportion of GPs prescribing new drugs before any specialist prescribes to their patients. Thirdly, we compared the time until the GP's first own prescribing between GPs who waited for prescriptions from specialists and those who did not. RESULTS: The influence of specialists showed considerable differences among the new drugs studied. The proportion of patients receiving their first prescription from a specialist was greatest for the combination salmeterol/fluticasone (60.2%), and lowest for rofecoxib (23.0%). The proportion of GPs prescribing new drugs before waiting for prescriptions from medical specialists ranged from 21.1% in the case of esomeprazole to 32.9% for rofecoxib. Prescribing new drugs by specialists did not shorten the GP's own time to prescribing. CONCLUSION: This study shows that the influence of medical specialists is clearly visible for all new drugs and often greater than for the existing older drugs, but the rapid uptake of new drugs in primary care does not seem specialist induced in all cases. GPs are responsible for a substantial amount of all early prescriptions for new drugs and for a subpopulation specialist endorsement is not a requisite to initiate in new drug prescribing. This contradicts with the idea that the diffusion of newly marketed drugs always follows a two-step model, with medical specialists as the innovators and GPs as the followers.