Stefan Florentinus

Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial

Objective CONCERTO was a randomised, double-blind, parallel-armed study of methotrexate (MTX) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis (RA). Methods Early, biologic and MTX-naive RA patients (N=395) were evenly randomised to open-label adalimumab (40u2005mg every other week) plus weekly blinded 2.5, 5, 10 or 20u2005mg MTX for 26u2005weeks. Clinical, radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance. Results Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint, 28-joint count disease activity score with C reactive protein (DAS28(CRP)) <3.2 (42.9%, 44.0%, 56.6% and 60.2% for 2.5, 5, 10 or 20u2005mg/week MTX, respectively), DAS28(CRP) <2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab. No statistical differences in minimal clinically important differences in physical function were detected. Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by validated clinical indices; differences comparing 10 and 20u2005mg MTX were minimal. Adalimumab serum concentrations increased with ascending dose up to 10u2005mg MTX. More patients experienced infectious adverse events with increasing MTX dose. Conclusions Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile. In early RA patients initiating adalimumab combination therapy, efficacy of 10 and 20u2005mg/week MTX appeared equivalent.

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.

Existing joint erosions increase the risk of joint space narrowing independently of clinical synovitis in patients with early rheumatoid arthritis

IntroductionClinical 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.MethodsThe 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 ADAu2009+u2009MTX. All evaluable joints with JE and JSN measures at 26 and 52xa0weeks 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 52xa0weeks. Analyses were performed based on treatment arm and were also performed within individual joints.ResultsJE 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 ADAu2009+u2009MTX prevents JE/JSN progression independently of its ability to suppress synovitis and limits JE/JSN onset and progression in joints with existing damage.ConclusionsExisting 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 registrationClinicaltrials.gov NCT00195663. Registered 13 September 2005.

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

OBJECTIVEnTo 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.nnnMETHODSnDE020 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.nnnRESULTSnOf 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.nnnCONCLUSIONnADA 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.nnnTRIAL REGISTRATIONnClinicalTrials.gov, http://www.clinicaltrials.gov, NCT00195650.

Analysis of Integrated Radiographic Data From Two Long-Term, Open-Label Extension Studies of Adalimumab for the Treatment of Rheumatoid Arthritis

A longitudinal integration approach evaluated all radiographic scores assessed over 10 years, rather than only completer data, from 2 studies of adalimumab (ADA) for rheumatoid arthritis (RA).

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 <1u2009year. 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+MTXu2009combination therapy but allows a small but significant accrual of radiographic damage.

Low Hemoglobin Predicts Radiographic Damage Progression in Early Rheumatoid Arthritis – Secondary Analysis from a Phase III trial

To study low blood hemoglobin concentrations as a predictor of radiographic damage progression in patients with rheumatoid arthritis (RA).

Achieving comprehensive disease control in patients with early and established rheumatoid arthritis treated with adalimumab plus methotrexate versus methotrexate alone

Objective To evaluate the achievement of comprehensive disease control (CDC) following 1u2009year of treatment with adalimumab+methotrexateu2009versus methotrexate alone and whether early achievement of remission (at week 24 or 26) is associated with CDC at week 52 in patients with either early or established rheumatoid arthritis (RA). Methods Post hoc analyses were conducted in three clinical studies assessing treatment with adalimumab+methotrexate: DE019 (NCT00195702) enrolled patients with established RA who were methotrexate inadequate responders; OPTIMA (NCT00420927) and PREMIER (NCT00195663) enrolled methotrexate-naive patients with early RA. In OPTIMA, patients not achieving stable low disease activity at weeks 22 and 26 in the placebo+methotrexateu2009group could receive open-label adalimumab+methotrexate for 52 weeks (Rescue ADA arm). CDC was defined as the simultaneous achievement of clinical remission (DAS28(CRP)<2.6), normal function (HAQ-DI<0.5) and absence of radiographic progression (ΔmTSS≤0.5). Results Regardless of disease duration, significantly more patients receiving adalimumab+methotrexate achieved CDC compared with methotrexate alone. In the adalimumab+methotrexateu2009group, a numerically greater proportion of patients with early RA (~25%) versus established RA (14%) achieved CDC at 1u2009year; achievement of CDC was notably greater among patients who met criteria for remission at week 24 or 26 (~50% of patients with early RA and 39% with established RA). Conclusion Treatment with adalimumab+methotrexate increases the likelihood of achieving CDC in patients with either early or established RA. Clinical remission at week 24 or 26 is associated with achievement of CDC at week 52. Trial registration number DE019 (NCT00195702), OPTIMA (NCT00420927), PREMIER (NCT00195663); Post-results.

FRI0180 Higher likelihood of response in rheumatoid arthritis patients treated in a real-life setting with adalimumab in combination with methotrexate, but not with other dmards, versus adalimumab monotherapy

Background Clinical trial data support the superiority of combining adalimumab (ADA) with DMARD(s) vs ADA alone. The use and effectiveness of ADA + DMARD(s) over monotherapy require confirmation in real-life settings. Objectives To compare the use and response of ADA taken with or without DMARD(s) in a real-life setting. Methods Biologic-naïve rheumatoid arthritis (RA) patients (pts) registered through the BSRBR (Sep ‘02-Mar ‘10) who received their 1st ADA dose were followed for 6 months. At enrollment, pts required a DAS28 >5.1 and ≥2 DMARD failures. Pts were categorized by baseline DMARD use: combination therapy without MTX (non-MTX DMARD), with MTX (MTX DMARD), and ADA monotherapy. Clinical and functional responses were assessed as the proportions achieving 1) clinically meaningful reductions from baseline (Δ) in DAS28 (>1.2) and HAQ (>0.22), respectively, or 2) the more stringent targets, DAS28 <3.2 and HAQ <0.5, respectively. Logistic regression modeled the odds of response for the non-MTX DMARD and MTX DMARD groups relative to ADA monotherapy, following adjustment for baseline differences. Results Of 4470 pts initiating ADA, 3123 (70%) received ≥1 DMARD (727 non-MTX DMARD, 2396 MTX DMARD) and 1347 (30%) received ADA monotherapy. At month 6, mean DAS28 and HAQ improved in all 3 groups (Table), with the greatest improvements observed for pts receiving MTX. There was a significantly higher likelihood of achieving ΔDAS28 >1.2, DAS28 <3.2, and ΔHAQ >0.22 in the MTX DMARD group compared with ADA monotherapy, with a trend for the non-MTX DMARD group. A trend for a higher likelihood of achieving HAQ <0.5 was observed in both DMARD groups. Conclusions In this cohort with severe RA, ADA improved overall disease activity and function at 6 months, both as monotherapy and in combination with DMARD(s). Combining ADA with MTX, but not with other DMARDs, appeared to increase the likelihood of response vs monotherapy in this real-life setting. Acknowledgements AbbVie Inc. is a co-sponsor of the BSRBR. AbbVie Inc. participated in the analysis and interpretation of the data, and in the writing, reviewing, and approval of the final version of the abstract. Medical writing support was provided by Benjamin Wolfe, PhD, of AbbVie Inc. Disclosure of Interest P. Kiely Consultant for: AbbVie Inc., BMS, MSD, UCB, Pfizer, Roche, Savient, S. Florentinus Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., S. Keidel Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., A. Lacerda Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., M. Karunaratne Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., R. McCaskill Shareholder of: AbbVie Inc., Employee of: AbbVie Inc.

Long-term use of adalimumab as monotherapy after attainment of low disease activity with adalimumab plus methotrexate in patients with rheumatoid arthritis

Objective To evaluate long-term clinical, functional and radiographic outcomes in an open-label extension (OLE) study in patients with rheumatoid arthritis (RA) receiving adalimumab monotherapy or adalimumab+methotrexate following attainment of low disease activity (LDA) with adalimumab+methotrexate. Methods Methotrexate-naive patients with early RA were randomised to adalimumab, methotrexate or adalimumab +methotrexate in a double-blind, 2-year study. Patients who completed the study and achieved LDA (28-joint Disease Activity Score using C reactive protein (DAS28(CRP)<3.2) could receive adalimumab monotherapy for up to 8 additional years in the OLE; open-label methotrexate could be added per investigator’s discretion. This post hoc analysis included data up to OLE year 3 (study year 5) from patients receiving adalimumab+methotrexateu2009who achieved LDA at year 2 followed by adalimumab monotherapy or methotrexate reinitiation. Normal physical function was defined as Disability Index of the Health Assessment Questionnaire <0.5u2009and radiographic non-progression as change in modified total Sharp score ≤0.5. Results Of 140 patients initiating adalimumab monotherapy, 84 (60%) received adalimumab only (methotrexate non-use) and 56 (40%) reinitiated methotrexate (methotrexate use) during OLE treatment. Median (IQR) time to first methotrexate use was 5.1 (0.1–31.4) weeks. Among methotrexate users, 61% retained LDA, 48% achieved DAS28(CRP) <2.6, 45% had normal physical function and 46% had no radiographic progression at year 5; for non-users, 63%, 50%, 58% and 50%, respectively, achieved these milestones. Adverse event rates were similar between methotrexate non-use and use patients. Conclusions Adalimumab monotherapy effectively maintained good clinical, functional and radiographic outcomes for up to 3 additional years in ≥50% of patients who attained LDA after 2 years of adalimumab+methotrexateu2009therapy. Trial registration number NCT00195663; Post-results.