Safety and effectiveness of adalimumab in patients with rheumatoid arthritis over 5 years of therapy in a phase 3b and subsequent postmarketing observational study

Gerd R Burmester, Marco Matucci-Cerinic, Xavier Mariette, Francisco Navarro-Blasco, Sonja Kary, Kristina Unnebrink, Hartmut Kupper, Gerd R Burmester, Marco Matucci-Cerinic, Xavier Mariette, Francisco Navarro-Blasco, Sonja Kary, Kristina Unnebrink, Hartmut Kupper

Abstract

Introduction: Patients with active rheumatoid arthritis who had failed at least one disease-modifying anti-rheumatic drug (DMARD) were treated with adalimumab (ADA) in the ReAct study with the option to continue treatment for 5 years in ReAlise. The purpose of this study was to evaluate the long-term safety and effectiveness of ADA as prescribed from the first injection in ReAct to the last observation in ReAlise.

Methods: Patients received ADA alone or in combination with DMARDs according to usual clinical care practices. Adverse events (AEs) were tabulated by five time windows after the first ADA injection. Effectiveness measures included achievement of low disease activity (LDA), defined as Simplified Disease Activity Index (SDAI) ≤11, or remission, (REM), defined as SDAI ≤3.3.

Results: Of the 6,610 ReAct patients, 3,435 (52%) continued in ReAlise. At baseline in ReAct, mean age was 54 years, mean DAS28 was 6.0 and mean HAQ DI was 1.64. The mean treatment duration was 1,016 days, representing 18,272 patient-years (PYs) of ADA exposure. Overall incidence rates of serious AEs and serious infections were 13.8 and 2.8 events (E)/100 PYs, respectively. Serious AEs occurred most frequently in the first 6 months and deceased thereafter. Standardised mortality ratio was 0.71 (95% CI 0.57 to 0.87) and standardised incidence ratio for malignancies was 0.64 (95% CI 0.53 to 0.76). LDA was achieved by 50% and REM by 21% of patients at last observation.

Conclusions: Results of this large observational study of ADA in routine clinical practice were consistent with controlled trials, with no new safety concerns during a follow-up of more than 5 years. Effectiveness of ADA was maintained during long-term observation.

Trial registration: NCT00448383, NCT00234884.

Figures

Figure 1
Figure 1
Patient disposition. *ReAct was followed by ReAlise when ADA was commercially licensed, giving patients the opportunity to be further observed for safety and effectiveness over 5 years or more. †Discontinuations and completions are listed for the entire duration of the ReAlise study. ADA, adalimumab; ReAct, the Research in Active Rheumatoid Arthritis phase 3b study; ReAlise, the Registry of HUMIRA™ in RA: a Long-Term Investigation of Safety and Efficacy observational follow-up study.
Figure 2
Figure 2
Percentages of patients with (A) American College of Rheumatology (ACR) 20%, 50%, or 70% improvement; (B) European League Against Rheumatism (EULAR) responses of at least ‘moderate’ and ‘good’; and (C) low disease activity (LDA) and disease remission (REM) defined as Simplified Disease Activity Index (SDAI) ≤11 and SDAI ≤3.3, respectively. Data are shown as observed values for all evaluable patients at each time point during long-term treatment with adalimumab (ADA). LO, last observation.
Figure 3
Figure 3
Percentages of patients with (A) minimal important difference ≥0.22 on the Health Assessment Questionnaire Disability Index (HAQ DI) and (B) normal function defined as HAQ DI ≤0.5 over long-term adalimumab (ADA) treatment. Observed data are reported. LO, last observation.
Figure 4
Figure 4
Mean change of Health Assessment Questionnaire Disability Index (HAQ DI) from baseline in patients (A) with sustained low disease activity (LDA) defined as Simplified Disease Activity Index (SDAI) ≤ 11 for at least 6 months and without sustained LDA and (B) with sustained remission (REM) defined as SDAI ≤ 3.3 for at least 6 months and without sustained REM. Data are shown as observed values for all evaluable patients at each time point during long-term treatment with adalimumab (ADA). *Denotes significance from baseline, P ≤0.001. LO, last observation.

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