Continued Structural Benefits Seen with MRI Following Abatacept Withdrawal in Early, Progressive RA

Chronic joint inflammation characterizes the progressive nature of rheumatoid arthritis (RA). Once RA is well controlled, the ability to sustain remission following the withdrawal of immunomodulatory medications is a topic that has been of recent clinical research.  Speculation exists over the “window of opportunity” in early RA, during which control of inflammatory cascades with disease-modifying antirheumatic drugs (DMARDs) can possibly sustain remission after withdrawal of medication in the future.

The efficacy of abatacept (ABA) plus methotrexate (MTX) and ABA monotherapy vs MTX in inducing clinical remission after 12 months of drug treatment in patients with early RA was evaluated in a phase 3b trial, entitled Assessing Very Early Rheumatoid arthritis Treatment (AVERT).¹  This trial also assessed the ability to sustain drug-free remission 18 months after medication discontinuation.  This study demonstrated that remission can be maintained after withdrawal of drug therapy (including DMARDs and corticosteroids) in patients with early RA who received ABA plus MTX.

The authors of this trial postulated that patients with early RA who had a very short symptom duration and mild disease activity may be presenting within a critical ”window of opportunity” and may be able to achieve sustained and complete drug-free remission following treatment with ABA. The authors further suggest that, “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.”¹

To further investigate if structural benefits of ABA-MTX combination therapy or ABA monotherapy can be maintained 6 months after the discontinuation of treatments, Charles Peterfy, MD, PhD, and colleagues further analyzed subgroup results from the AVERT trial.²  Patients were randomly assigned 1:1:1 to receive ABA 125 mg/wk plus MTX (n=119), ABA 125 mg/wk monotherapy (n=116), or MTX alone (n=116).  Evaluation was conducted 12 months following treatment initiation. At 12 months, patients with a Disease Activity Score-28 using C-reactive protein (DAS28-CRP) less than 3.2 could enter the withdrawal phase of the trial, and all treatments for RA were stopped after a period of tapering.

ABA-MTX combination therapy resulted in significantly greater decreases from baseline in synovitis and osteitis scores.  Progression of erosion was statistically less with ABA-MTX vs MTX at month 12 (−2.35 vs −0.68, −2.58 vs −0.68, and 0.19 vs 1.53, respectively; P<.01 for each) and month 18 (−1.34 vs −0.49, −2.03 vs 0.34, and 0.13 vs 2.0, respectively; P<.01 for erosion).

A statistically higher percentage of patients receiving ABA-MTX achieved DAS-defined remission together with magnetic resonance imaging (MRI) nonprogression in synovitis, osteitis, and erosion compared with those receiving MTX alone.

ABA-MTX dual therapy also resulted in greater decreases from baseline in the inflammatory marker CRP during the treatment period and following the withdrawal of all therapies compared with MTX alone.  In all treatment groups, a small number of patients still had MRI progression.

Post-hoc analyses revealed that the MRI benefits achieved after 12 months of drug treatment were maintained up to month 18 (ie, 6 months after withdrawal of all therapies) in all 3 drug treatment groups in patients with DAS-defined remission at month 18.

These data are consistent with the maintenance of MRI benefits for 6 months following the withdrawal of ABA in patients with early RA reported in the ADJUST (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) trial.³

Summary and Clinical Applicability

In this substudy of the AVERT (Assessing Very Early Rheumatoid Arthritis Treatment) trial, MRI measures of disease activity in patients with early RA and DAS-defined remission (DAS28-CRP <2.6) following 12 months of treatment and then subsequent withdrawal of all RA medication were reported.

ABA reduced inflammation and structural damage progression as assessed by changes in MRI (synovitis, osteitis, and bone erosions) in patients with early and progressive RA.  Structural benefits with ABA-MTX or ABA were maintained 6 months after withdrawal of all treatment in patients who achieved remission or low disease activity.  In patients with reappearance of inflammatory activity in the joints after withdrawal of medication, disease was defined as low and correlating with maintenance of inflammation control.

The approach to discontinuing or tapering biologic medication after remission is achieved is of great clinical significance, especially if patients who are likely to maintain remission following drug withdrawal can be identified prospectively.   Specific tapering strategies and cut-off criteria that identify patients who are more likely to remain in remission need to be identified.

References

1.     Emery P, Burmester GR, Bykerk VP, et al. Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann Rheum Dis. 2015;74(1):19-26.

2.     Peterfy C, Burmester GR, Bykerk VP, et al. Sustained improvements in MRI outcomes with abatacept following the withdrawal of all treatments in patients with early, progressive rheumatoid arthritis. Ann Rheum Dis. 2016;Feb 10.  [Epub ahead of print]

3.     Emery P, Durez P, Dougados M, et al. Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann Rheum Dis. 2010;69:510-516.