Evaluating Drug-free Remission With Abatacept in Early RA
Objectives To evaluate clinical remission with subcutaneous abatacept plus methotrexate (MTX) and abatacept monotherapy at 12 months in patients with early rheumatoid arthritis (RA), and maintenance of remission following the rapid withdrawal of all RA treatment.
Methods In the Assessing Very Early Rheumatoid arthritis Treatment phase 3b trial, patients with early active RA were randomised to double-blind, weekly, subcutaneous abatacept 125 mg plus MTX, abatacept 125 mg monotherapy, or MTX for 12 months. Patients with low disease activity (Disease Activity Score (DAS)28 (C reactive protein (CRP)) <3.2) at month 12 entered a 12-month period of withdrawal of all RA therapy. The coprimary endpoints were the proportion of patients with DAS28 (CRP) <2.6 at month 12 and both months 12 and 18, for abatacept plus MTX versus MTX.
Results Patients had <2 years of RA symptoms, DAS28 (CRP) ≥3.2, anticitrullinated peptide-2 antibody positivity and 95.2% were rheumatoid factor positive. For abatacept plus MTX versus MTX, DAS28 (CRP) <2.6 was achieved in 60.9% versus 45.2% (p=0.010) at 12 months, and following treatment withdrawal, in 14.8% versus 7.8% (p=0.045) at both 12 and 18 months. DAS28 (CRP) <2.6 was achieved for abatacept monotherapy in 42.5% (month 12) and 12.4% (both months 12 and 18). Both abatacept arms had a safety profile comparable with MTX alone.
Conclusions Abatacept plus MTX demonstrated robust efficacy compared with MTX alone in early RA, with a good safety profile. The achievement of sustained remission following withdrawal of all RA therapy suggests an effect of abatacept's mechanism on autoimmune processes.
Rheumatoid arthritis (RA) is a progressive disease characterised by chronic joint inflammation and subsequent structural damage. There may be a 'window of opportunity' in early RA to alter the course of the disease if tightly controlled, which diminishes once the inflammatory processes are more established. If so, this could aid decisions on the use of a combination of biological disease-modifying antirheumatic drugs (DMARD) and conventional synthetic (cs)DMARDs versus step-up therapy in early RA. Once RA is well controlled, the ability to sustain remission following the withdrawal of immunomodulatory medications would be an indication of disease modification.
Abatacept, a fusion protein of cytotoxic T lymphocyte-associated antigen-4 and immunoglobulin G1, selectively modulates the CD80/CD86:CD28 costimulatory signal required for full T-cell activation. Due to a greater impact on naive T cells, there is a rationale for the use of abatacept in early RA; the unique upstream mechanism of abatacept impacts downstream inflammatory mediators and autoantibodies, and may allow removal of drug therapy. In the Abatacept study to Gauge Remission and joint damage progression in methotrexate naïve patients with Early Erosive rheumatoid arthritis (AGREE), after all patients had completed 2 years of abatacept treatment, 50 patients had a dose reduction from 10 mg/kg to 5 mg/kg without change in efficacy. In patients with undifferentiated and early RA in the Abatacept study to Determine the effectiveness in preventing the development of rheumatoid arthritis in patients with Undifferentiated inflammatory arthritis and to evaluate Safety and Tolerability (ADJUST), abatacept was withdrawn following 6 months of monotherapy, and maintained inhibition of joint damage progression for 6 months after withdrawal. Similarly, in a study of patients with type 1 diabetes, the treatment effect observed with abatacept was maintained for a year following drug withdrawal.
In this phase 3b trial, we evaluated the efficacy and safety of subcutaneous (SC) abatacept plus methotrexate (MTX), and abatacept monotherapy versus MTX in inducing clinical remission after 12 months in patients with early RA, and their ability to sustain drug-free remission at 18 months. Whereas a few studies have examined the strategy of achieving disease control followed by various de-escalation approaches reducing either steroids, MTX or biologicals, this is the first study to investigate the possibility of achieving absolute drug-free remission after removing all RA therapies.
Abstract and Introduction
Abstract
Objectives To evaluate clinical remission with subcutaneous abatacept plus methotrexate (MTX) and abatacept monotherapy at 12 months in patients with early rheumatoid arthritis (RA), and maintenance of remission following the rapid withdrawal of all RA treatment.
Methods In the Assessing Very Early Rheumatoid arthritis Treatment phase 3b trial, patients with early active RA were randomised to double-blind, weekly, subcutaneous abatacept 125 mg plus MTX, abatacept 125 mg monotherapy, or MTX for 12 months. Patients with low disease activity (Disease Activity Score (DAS)28 (C reactive protein (CRP)) <3.2) at month 12 entered a 12-month period of withdrawal of all RA therapy. The coprimary endpoints were the proportion of patients with DAS28 (CRP) <2.6 at month 12 and both months 12 and 18, for abatacept plus MTX versus MTX.
Results Patients had <2 years of RA symptoms, DAS28 (CRP) ≥3.2, anticitrullinated peptide-2 antibody positivity and 95.2% were rheumatoid factor positive. For abatacept plus MTX versus MTX, DAS28 (CRP) <2.6 was achieved in 60.9% versus 45.2% (p=0.010) at 12 months, and following treatment withdrawal, in 14.8% versus 7.8% (p=0.045) at both 12 and 18 months. DAS28 (CRP) <2.6 was achieved for abatacept monotherapy in 42.5% (month 12) and 12.4% (both months 12 and 18). Both abatacept arms had a safety profile comparable with MTX alone.
Conclusions Abatacept plus MTX demonstrated robust efficacy compared with MTX alone in early RA, with a good safety profile. The achievement of sustained remission following withdrawal of all RA therapy suggests an effect of abatacept's mechanism on autoimmune processes.
Introduction
Rheumatoid arthritis (RA) is a progressive disease characterised by chronic joint inflammation and subsequent structural damage. There may be a 'window of opportunity' in early RA to alter the course of the disease if tightly controlled, which diminishes once the inflammatory processes are more established. If so, this could aid decisions on the use of a combination of biological disease-modifying antirheumatic drugs (DMARD) and conventional synthetic (cs)DMARDs versus step-up therapy in early RA. Once RA is well controlled, the ability to sustain remission following the withdrawal of immunomodulatory medications would be an indication of disease modification.
Abatacept, a fusion protein of cytotoxic T lymphocyte-associated antigen-4 and immunoglobulin G1, selectively modulates the CD80/CD86:CD28 costimulatory signal required for full T-cell activation. Due to a greater impact on naive T cells, there is a rationale for the use of abatacept in early RA; the unique upstream mechanism of abatacept impacts downstream inflammatory mediators and autoantibodies, and may allow removal of drug therapy. In the Abatacept study to Gauge Remission and joint damage progression in methotrexate naïve patients with Early Erosive rheumatoid arthritis (AGREE), after all patients had completed 2 years of abatacept treatment, 50 patients had a dose reduction from 10 mg/kg to 5 mg/kg without change in efficacy. In patients with undifferentiated and early RA in the Abatacept study to Determine the effectiveness in preventing the development of rheumatoid arthritis in patients with Undifferentiated inflammatory arthritis and to evaluate Safety and Tolerability (ADJUST), abatacept was withdrawn following 6 months of monotherapy, and maintained inhibition of joint damage progression for 6 months after withdrawal. Similarly, in a study of patients with type 1 diabetes, the treatment effect observed with abatacept was maintained for a year following drug withdrawal.
In this phase 3b trial, we evaluated the efficacy and safety of subcutaneous (SC) abatacept plus methotrexate (MTX), and abatacept monotherapy versus MTX in inducing clinical remission after 12 months in patients with early RA, and their ability to sustain drug-free remission at 18 months. Whereas a few studies have examined the strategy of achieving disease control followed by various de-escalation approaches reducing either steroids, MTX or biologicals, this is the first study to investigate the possibility of achieving absolute drug-free remission after removing all RA therapies.