Benoît Guérette

Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial

BACKGROUND Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy. METHODS This trial was done at 161 sites worldwide. Patients with early (<1 year duration) rheumatoid arthritis naive to methotrexate were randomly allocated (by interactive voice response system, in a 1:1 ratio, block size four) to adalimumab (40 mg every other week) plus methotrexate (initiated at 7·5 mg/week, increased by 2·5 mg every 1-2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks (period 1). Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target (28-joint disease activity score with C-reactive protein [DAS28]<3·2 at weeks 22 and 26) were randomised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks (period 2). Patients achieving the target with initial methotrexate continued methotrexate-monotherapy. Inadequate responders were offered adalimumab plus methotrexate. All patients and investigators were masked to treatment allocation in period 1. During period 2, treatment reallocation of patients who achieved the target was masked to patients and investigators; patients who did not achieve the target remained masked to original randomisation, but were aware of the subsequent assignment. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexate-monotherapy. Adverse events were monitored throughout period 2. This trial is registered with ClinicalTrials.gov, number NCT00420927. FINDINGS The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2-28%], p=0·0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups. INTERPRETATION Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate. FUNDING AbbVie.

Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study

Objective To assess the efficacy and safety of adalimumab plus methotrexate (ADA+MTX) compared with methotrexate monotherapy in achieving stable low disease activity (LDA; disease activity score (DAS28(CRP)) <3.2 at weeks 22 and 26) and clinical, radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis (RA). Methods 1032 patients with active RA were randomly assigned 1:1 to ADA+MTX or placebo plus methotrexate (PBO+MTX) for 26 weeks. Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP) <3.2 at weeks 22 and 26. Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission. Results Among patients completing 6 months, 44% (207/466) ADA+MTX versus 24% (112/460) PBO+MTX patients achieved stable LDA at weeks 22 and 26 (p<0.001). Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses, more clinical remissions, greater mean reductions in DAS28(CRP), no radiographic progression, and normal functional status at week 26 (p<0.001 for all). The only factor predicting stable LDA was disease activity at week 12. Patients achieving ACR/EULAR remission, particularly in the PBO+MTX group, had some advantage in radiographic outcomes compared with patients who only achieved LDA (but not remission). The overall frequency of adverse events was comparable between groups. There were more serious infections and deaths in the ADA+MTX group, with a possible age effect. Conclusions Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical, radiographic and functional outcomes in patients with early active RA. Before initiating treatment with adalimumab, individual patient evaluation of the benefit/risk ratio should be carefully considered.

Responses to Adalimumab in Patients With Active Psoriatic Arthritis Who Have Not Adequately Responded to Prior Therapy: Effectiveness and Safety Results From an Open-label Study

Objective. To evaluate the effectiveness and safety of adalimumab in patients with active psoriatic arthritis (PsA) and an inadequate response to prior therapy. Methods. Patients were treated with subcutaneous injections of adalimumab 40 mg every other week in addition to their standard antirheumatic therapies in a 12-week, open-label study. Effectiveness evaluations at Week 12 included American College of Rheumatology (ACR) and Psoriasis Area and Severity Index (PASI) response rates, Psoriatic Arthritis Response Criteria (PsARC), active dactylitis, enthesitis, and target lesion assessment. Physical function was evaluated using the Health Assessment Questionnaire Disability Index (HAQ-DI). Results. A total of 127 patients were enrolled. At Week 12, patients achieved ACR20, ACR50, and ACR70 response rates of 78.0%, 55.9%, and 21.3%, respectively. PASI50 and PASI75 response rates were 64.7% and 47.1%. A PsARC response was experienced by 70.1% of patients. Between baseline and Week 12, clinically and statistically significant reductions occurred in the mean total plaque score of the target lesion as well as in the percentages of patients with active dactylitis and enthesitis. A mean improvement in HAQ-DI was also observed (−0.44; p < 0.001). Three serious adverse events were reported, but none was considered related to adalimumab therapy. Conclusion. Adalimumab-treated patients achieved significant improvements in both skin and joint manifestations of PsA, as well as in physical function. Adalimumab was well tolerated and had a safety profile similar to that observed in other clinical trials of adalimumab for the treatment of PsA. ClinicalTrials.gov identifier: NCT00427362.

Association of joint space narrowing with impairment of physical function and work ability in patients with early rheumatoid arthritis: protection beyond disease control by adalimumab plus methotrexate

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.

Clinical, Functional, and Radiographic Benefits of Longterm Adalimumab Plus Methotrexate: Final 10-year Data in Longstanding Rheumatoid Arthritis

Objective. To examine the longterm effectiveness and safety of adalimumab in patients with longstanding rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX), and to assess the effect of a 1-year delay in initiation of combination therapy. Methods. DE019 was a 1-year randomized controlled trial (RCT) in which patients received adalimumab 20 mg weekly, adalimumab 40 mg every other week (eow), or placebo; all received concomitant MTX. Patients completing the RCT could receive open-label adalimumab 40 mg eow + MTX for an additional 9 years. Clinical, functional, and radiographic outcomes were assessed using composite measures of disease activity (e.g., American College of Rheumatology responses, 28-joint Disease Activity Score with C-reactive protein, Simplified Disease Activity Index), Health Assessment Questionnaire-Disability Index, and the modified total Sharp score (mTSS), respectively. Results. Of the 619 patients randomized, 457 entered the open-label extension; 202 completed 10 years. At Year 10, patients demonstrated effective disease control and inhibition of radiographic progression. Differences in clinical and functional responses between adalimumab + MTX and placebo + MTX observed during the RCT became less apparent at Year 10. Still, patients who initially received adalimumab + MTX had significantly lower mean ΔmTSS at Year 10 compared with patients who initially received placebo + MTX. No new safety signals arose following up to 10 years of adalimumab + MTX exposure. Conclusion. During up to 10 years of treatment with adalimumab + MTX, patients with longstanding RA experienced effective disease control with no change to the expected safety profile. A 1-year delay in receipt of adalimumab + MTX was associated with reduced effectiveness, suggesting that a window of opportunity to prevent irreversible damage exists even in a population with established RA.

Clinical, Functional, and Radiographic Implications of Time to Treatment Response in Patients With Early Rheumatoid Arthritis: a Posthoc Analysis of the PREMIER Study

Objective. Rheumatoid arthritis (RA) treatment recommendations suggest target attainment within the first 3 months of therapy, yet delayed clinical responses can occur. This analysis assessed the longterm clinical, functional, and radiographic outcomes associated with delayed responses to methotrexate (MTX) monotherapy or to the combination of adalimumab (ADA) + MTX. Methods. In this posthoc analysis, patients with early RA who received MTX monotherapy or ADA + MTX in the PREMIER study were categorized based on clinical responses at 3 and 6 months [American College of Rheumatology response, 28-joint Disease Activity Score (DAS28)-C-reactive protein (CRP) improvement and targets]. “Month 3” responders met the clinical measure at both months 3 and 6, and “Month 6” responders met the clinical measure only at Month 6. The odds of achieving longterm outcomes [remission (DAS28-CRP < 2.6), normal function (Health Assessment Questionnaire-Disability Index < 0.5), or rapid radiographic progression (Δ modified total Sharp score > 3 U/yr)] were modeled using logistic regression, including treatment, response, and interaction. Results. A delayed or low-level response was associated with poorer longterm outcomes. Generally, MTX Month 6 responders demonstrated worse clinical, functional, and radiographic outcomes than Month 3 MTX and Month 3 or 6 ADA + MTX responders. Although similar longterm benefit was observed for ADA + MTX responders, delayed (Month 6) responders exhibited downward trends in clinical, functional, and radiographic outcomes that were comparable with those experienced by Month 3 MTX responders. Conclusion. Response speed and magnitude predict longterm outcomes in patients with early RA treated with MTX or ADA + MTX. MTX-treated patients failing to demonstrate a Month 3 clinical response have less-favorable outcomes than other groups, while outcomes in ADA + MTX Month 3 and Month 6 responders tended to be comparable.

Safety and effectiveness of adalimumab in a clinical setting that reflects Canadian standard of care for the treatment of rheumatoid arthritis (RA): Results from the CanACT study

BackgroundThis multicenter, open-label, prospective, single cohort study evaluated the effectiveness and safety of adalimumab in a clinical setting reflecting the Canadian standard of care for the treatment of patients with rheumatoid arthritis (RA).MethodsPatients ≥ 18 years of age with a history of active RA ≥ 3 months and fulfilling Canadian requirements for biological therapy received adalimumab 40 mg subcutaneously every other week for 12 weeks. Pre-study DMARD treatment regimens, corticosteroids, or NSAIDs were allowed throughout the study. The primary effectiveness outcome measure was the mean change in 28-joint disease activity score (DAS28) from baseline to Week 12. Secondary measures included the proportion of patients achieving joint remission (DAS28 < 2.6) and low-disease activity (DAS28 < 3.2) at Week 12, and European League Against Rheumatism (EULAR: moderate and good) and American College of Rheumatology (ACR: ACR20, 50, and 70) responses, as well as responses in ACR core components at Weeks 4, 8, and 12. Subgroup analysis included a comparison of patients naïve to biological DMARD (BDMARD) therapy versus BDMARD-experienced patients. Safety was assessed in terms of adverse and serious adverse events.ResultsA total of 879 patients (mean disease duration > 12 years) were enrolled; 772 (87.9%) completed the 12-week period. Adalimumab treatment was associated with rapid and sustained improvements in the signs and symptoms of RA. Significant improvements in mean DAS28 score were observed as early as Week 4. After 12 weeks of adalimumab treatment, 15.3% and 28.9% of patients achieved clinical remission and low-disease activity, respectively. Similarly, significant improvements in ACR core components were observed as early as Week 4, with continued improvements occurring through 12 weeks. Patients naïve to BDMARD therapy demonstrated numerically greater clinical responses when compared with patients who had experienced prior BDMARD therapy, although both subgroups were associated with significant improvements from baseline. The rates and types of adverse events, as well as the results of laboratory measures, demonstrated that adalimumab was generally safe and well-tolerated.ConclusionsThis study demonstrated that, under conditions reflective of the normal clinical practice in Canada, adalimumab is an effective and safe treatment for patients with RA.Trial registrationNCT00649545.

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.

OP0309 Characterisation of clinical benefits in subjects classified as acr20 non-responders at week 104 of apremilast treatment: subanalysis of 3 long-term, phase iii trials

Background The PALACE 1, 2, and 3 trials evaluated the efficacy and safety of apremilast (APR) in subjects with active psoriatic arthritis (PsA) despite prior conventional disease-modifying anti-rheumatic drugs and/or biologics. Objectives The aim of this analysis is to further characterise the clinical benefits associated with long-term APR exposure in subjects who failed to achieve an ACR20 response at Week 104. Methods Subjects were randomised (1:1:1) to receive placebo (PBO), APR 30 mg BID (APR30), or APR 20 mg BID at baseline. Subjects who were randomised to APR30 at baseline and classified as ACR20 non-responders (ACR20NRs) at Week 104 were considered for this analysis. At Weeks 24, 52, and 104, ACR core components were examined as well as the proportions of subjects achieving PASI-75/PASI-50 among those with psoriasis involvement ≥3% of the body surface area at baseline, and dactylitis count and MASES of 0 among those with dactylitis or enthesitis at baseline. Safety is described for the overall PALACE 1–3 population. Results A total of 109 subjects randomised to APR30 treatment at baseline were ACR20NRs at Week 104. Baseline ACR core components were similar for ACR20NRs and ACR20 responders at Week 104. Among these ACR20NRs, several core components of ACR response, including swollen/tender joint counts and Physician’s Global Assessment of Disease Activity (visual analogue scale) scores, showed sustained improvements from baseline through Week 104 (table 1). Importantly, of the 109 ACR20NRs at Week 104, 50.0% achieved a PASI-50 response after continued treatment with APR30 through Week 104 (table 1). Among ACR20NRs with baseline dactylitis (n=44) or enthesitis (n=74), 68.2% achieved a dactylitis count of 0% and 33.8% achieved a MASES of 0 at Week 104. More limited improvements in Subject’s Global Assessment of Disease Activity, Subject’s Assessment of Pain, Health Assessment Questionnaire-Disability Index, and C-reactive protein outcomes most commonly had an impact on subjects’ ability to achieve an ACR20 response. In the overall subject population, no new safety concerns were identified through 104 weeks.Abstract OP0309 – Table 1 Conclusions ACR20NRs receiving APR30 demonstrated significant improvements in core PsA domains. The data may explain why subjects who failed to achieve an ACR20 response remained on long-term APR treatment. These findings suggest that some subjects with PsA may experience meaningful clinical improvement that is not completely captured by the assessment of ACR20 response criteria. Outcome measures specifically designed for PsA subjects, may be more suitable to evaluate treatment response in PsA subjects. Disclosure of Interest P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Consultant for: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Genentech, Janssen, Eli Lilly, Pfizer, UCB, D. Gladman Grant/research support from: AbbVie, Amgen, BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB, Consultant for: AbbVie, Amgen, BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB, A. Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB, P. Nakasato Employee of: Celgene Corporation, B. Guerette Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, P. Nash Grant/research support from: Celgene Corporation

AB0946 Improvements in work productivity with up to 104 weeks of apremilast monotherapy: results from a phase 3b, randomised, controlled study in biologic-naÏve subjects with active psoriatic arthritis

Background Psoriatic arthritis (PsA) patients may experience disease manifestations across multiple domains and impaired functioning in daily activities at home and work. The phase 3b ACTIVE study is evaluating the efficacy of apremilast (APR) monotherapy in biologic-naïve subjects with active PsA who may have had exposure to 1 prior conventional DMARD. Objectives To assess work productivity through Week 104. Methods Subjects were randomised (1:1) to receive APR 30 mg BID or placebo (PBO). Subjects who did not improve by ≥10% in swollen and tender joint counts at Week 16 were eligible for early escape. At Week 24, all remaining PBO subjects were switched to APR. Work productivity and activity impairment were assessed at baseline (BL) and Week 16 using the 6-item, self-administered Work Productivity and Activity Impairment Questionnaire: Psoriatic Arthritis (WPAI:PsA). WPAI:PsA includes 4 subscale scores (Absenteeism, Presenteeism, Work Productivity Loss, and Activity Impairment), each ranging from 0% to 100%; higher scores indicate greater impairment. Work-related subscales were evaluated only among employed subjects, while activity impairment was evaluated among all subjects, regardless of employment. Correlations were examined at Week 16 between WPAI:PsA subscale scores and the SF-36v2 domain scores for Physical Functioning (PF), Bodily Pain (Pain), and Vitality (VIT), as well as associations with ACR20 response. Improvement in work productivity was assessed through Week 104. Results BL characteristics were similar between APR and PBO subjects with WPAI:PsA scores included in this analysis. At Week 16, APR significantly improved work productivity and the ability to carry out daily activities vs PBO, with significantly greater mean improvements observed in the overall Work Productivity Loss (p=0.001) and Activity Impairment (p<0.001) scores (table 1). Estimated mean change in the Absenteeism score was similar with APR vs PBO (p=0.679). By contrast, the Presenteeism score showed significant improvement with APR vs worsening with PBO (−10.8% vs 4.1%; p=0.002). At Week 16, statistically significant correlations were observed between WPAI:PsA subscale scores (except Absenteeism) and the SF-36v2 domain scores for PF, Pain, and VIT, as were associations with ACR20 response. Among subjects randomised to APR at BL, improvements in Week 16 WPAI:PsA subscale score were generally maintained through Week 104 in those continuing APR.Abstract AB0946 – Figure 1 Results are from an analysis of covariance model, adjusted with BL WPAI: PsA subscale score, BL prednisone use (yes/no), and previous DMARD use (yes/no). LS mean is estimated using the observed margins of the covariates. WPAI: PsA scores were evaluated for subjects with values at both BL and Week 16. Absenteeism, Presenteeism, and Work Productivity Loss were evaluated only among employed subjects. Activity Impairment scores were evaluated among all randomised subjects with scores at BL and Week 16, regardless of employment status. CI=confidence interval; LS=least square. Conclusions In biologic-naïve subjects with PsA, APR monotherapy contributed to an overall improvement in work productivity at Week 16, which correlated with SF-36v2 PF, Pain, and VIT scores and was associated with ACR20 response; improvements in WPAI:PsA subscale scores were generally maintained to Week 104. Disclosure of Interest P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Consultant for: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Genentech, Janssen, Eli Lilly, Pfizer, UCB, D. Gladman Grant/research support from: AbbVie, Amgen, BMS, Celgene Corporation, Janssen, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, BMS, Celgene Corporation, Janssen, Novartis, Pfizer, and UCB, E. Davenport: None declared, X. Zhou: None declared, B. Guerette Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, S. Kaura Employee of: Celgene Corporation, P. Nash Grant/research support from: Celgene Corporation