Evaluating drug-free remission with abatacept in early rheumatoid arthritis

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SCIENCE
Evaluating drug-free remission with abatacept in early rheumatoid arthritis
Key Take-Away: 
  • Drug-free remission may be possible by following treatment with abatacept in early Rheumatoid arthritis (RA).
  • Abatacept plus methotreaxate (MTX) demonstrated robust efficacy compared with MTX alone in early RA, with a good safety profile.

Rheumatoid arthritis (RA) is a progressive disease characterized 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. 

ABSTRACT: 
Background: 

Rheumatoid arthritis (RA) is a progressive disease characterized 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 CD80/ CD86:CD28 co stimulatory signal required for full T-cell activation. Due to a greater impact on naïve 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 auto antibodies, and may allow removal of drug therapy. In Abatacept study, we determine the effectiveness in preventing the development of RA 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 Abatacept was withdrawn following 6 months of monotherapy and maintained inhibition of joint damage progression for 6 months after withdrawal.

  • Rationale behind research
  1. Alter the course of disease if tightly controlled, diminishes the inflammatory processes in early RA
  2. Abatacept unique mechanism of downstream inflammatory mediators and auto antibodies may allow removal of drug therapy in early RA
  • Objective

To evaluate clinical remission with subcutaneous abatacept plus 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: 

 *DAS = Disease Activity Score

 * CCP= Anticitrullinated peptide

 

Study outcomes

Primary outcome: DAS28 (CRP) <2.6  and the proportion of randomized and treated patients in DAS-defined remission at (A) month 12 and (B) months 12 and 18 for abatacept plus MTX versus MTX

Secondary outcomes:

  • DAS-defined remission at (A) month 12 and (B) months 12 and 18 for abatacept monotherapy versus MTX
  • Health Assessment Questionnaire-Disability Index (HAQ-DI) response (≥0.3 points reduction from baseline)
  • MRI  test evaluate osteitis, synovitis and erosion score
  • Safety and tolerability

Time-points

  •  Efficacy: Baseline, 12th and 18th month

 

Results: 

 

Baseline: Two treatment groups were well balanced with no statistically significant  difference

  • Primary outcome:
  • Abatacept plus MTX achieved statistically significantly higher rates of DAS-defined remission versus MTX at month 12 (70/115 (60.9%) patients vs 52/115 (45.2%) patients; OR (95% CI) 2.01 (1.18 to 3.43); (p=0.010). Numerically higher DAS-defined remission rates were observed in the abatacept plus MTX group versus MTX from day 57, which were maintained over time for the rest of treatment period.
  • Secondary outcome:
  • Abatacept monotherapy resulted in a similar proportion of patients achieving DAS-defined remission at month 12 compared with MTX (48/113 (42.5%) vs. 52/115 (45.2%).
  • HAQ-DI response rates at month 12 were 65.5% versus 44.0%, respectively.
  • Abatacept plus MTX and abatacept monotherapy resulted in numerically greater decreases from baseline in synovitis and osteitis scores, and abatacept plus MTX resulted in less progression of erosion score than MTX at 12 months
  • During the treatment period, adverse events (AE) occurred in 101/119 (84.9%), 93/116 (80.2%) and 96/116 (82.8%) patients treated with abatacept plus MTX, abatacept monotherapy and MTX, respectively. There were no deaths during the treatment period
  • Other outcomes:

Abatacept plus MTX and abatacept monotherapy versus MTX during withdrawal period.

  • Abatacept plus MTX achieved statistically significantly higher rates of DAS-defined remission versus MTX at both months 12 and 18 (17/115 (14.8%) patients vs 9/115 (7.8%) patients; OR (95% CI) 2.51 (1.02 to 6.18); p=0.045).
  • The proportion of patients achieving DAS-defined remission at both months 12 and 18 was 14/113 (12.4%) versus 9/115 (7.8%) for abatacept monotherapy and MTX groups, respectively (analysis included only patients with DAS28 (CRP) available at baseline.
  • Of the patients who entered the withdrawal period, 73, 50 and 53 patients in each treatment group were in DAS-defined remission at month 12. Of these, 18/73 (24.7%), 14/50 (28%) and 9/53 (17.0%) remained in DAS-defined remission at month 18
Conclusion: 

AVERT establishes the benefit of abatacept treatment in combination with MTX in an early RA population, and suggests that, in early RA, drug-free remission may be possible following treatment with abatacept. The novel achievement of sustained remission following withdrawal of all RA therapy in a small but significant number of patients is suggestive of an underlying effect of abatacept’s mechanism on autoimmune processes.

A withdrawal treatment strategy is a highly desirable goal for patients and physicians in the long-term treatment of RA, and further investigations with abatacept are warranted.

Previous studies have examined a variety of treatment withdrawal paradigms with a number of biological agents, but have not assessed the rapid withdrawal of all RA treatment. Remission following withdrawal or tapering of RA therapy is an important goal in early RA. The unique study design of AVERT included the rapid withdrawal of all RA treatment, including abatacept, MTX and corticosteroids. Abatacept plus MTX achieved robust efficacy versus MTX, as demonstrated by multiple measures of remission and HAQ-DI, and consistent structural benefits.

Ann Rheum Dis 2015; 74:19–26
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