Rheumatology Practice Changers 2014

Bret S. Stetka, MD; Stephen A. Paget, MD


December 18, 2014

In This Article

Reducing or Stopping Therapy

Reducing or stopping biologic and nonbiologic DMARDs in a patient with RA who is doing well is always fraught with trepidation. The fear is that in doing so, the disease will flare and cannot be controlled if the drugs are restarted. The RETRO trial[9] from Germany, presented at the 2014 ACR meeting, was a real-life study addressing different DMARD reduction strategies in RA.

The aim of RETRO was to evaluate the possibility of tapering and even discontinuing DMARD therapy in RA patients with stable, long-lasting remission and to determine predictors of disease recurrence. This was a phase 3, multicenter, randomized, controlled, open, prospective, parallel-group trial. Patients who fulfilled the ACR/EULAR 2010 criteria for RA with disease history ≥ 12 months were enrolled if they were in clinical remission (DAS28 ESR < 2.6) on a stable dose of DMARDs for more than 6 months.

Patients on one or more conventional or biologic DMARDs were included and randomly assigned to one of three trial arms: Arm 1 (control group) continued to receive full-dose conventional or biologic DMARD treatment for 12 months; in arm 2, the dose of all conventional or biologic DMARDs was reduced by 50% for 12 months; and in arm 3, the dose of all conventional or biologic DMARD treatment was reduced by 50% for 6 months, then stopped entirely.

Of 101 patients, 66.3% were still in remission at 12 months. Trial arms 2 and 3 significantly differed from the control group in terms of patients experiencing disease flare (15.8% flare rate). However, there was no significant difference between the two reduction arms. Multivariate logistic regression analysis identified anti-citrullinated protein antibody (ACPA) positivity as a predictor of subsequent flares.

This study showed that neither remission depth nor disease duration at baseline or biologic DMARD therapy predicted the recurrence of disease. Presence of ACPA, but not rheumatoid factor, was the only predictor of disease recurrence. The data indicate that treatment reduction and even discontinuation is feasible in a subset of patients with RA in stable remission.

Another important study[10] published in the New England Journal of Medicine addressed the fact that we do not yet know whether remission achieved with biologic therapy can be maintained after doses are reduced or therapy is withdrawn. The PRIZE trial, a state-of-the-art biologic treatment trial in adults with early untreated RA, was designed to fill this knowledge gap. The trial included three phases: (1) induction therapy with full-dose combination etanercept/methotrexate therapy; (2) maintenance therapy with a reduced-dose etanercept/methotrexate regimen, methotrexate alone, or no treatment; and (3) complete treatment withdrawal.

After clinical remission was induced, remission was shown to be effectively maintained with the reduced-dose combination regimen but not with the biologic-free regimens. Significantly more patients who had received the reduced-dose regimen were in remission after therapy was withdrawn than patients who received no therapy after remission induction. Of note, however, after remission was induced with the full-dose combination regimen, no substantial progression of joint damage was seen on radiography in patients receiving the reduced-dose regimen, methotrexate only, or no treatment. In patients with early RA who had remission while receiving full-dose etanercept/methotrexate, continuing combination therapy at a reduced dose resulted in better disease control than switching to methotrexate alone or placebo, but no significant difference was observed in radiographic progression.

Paul Emery, the lead author, stated that results of the PRIZE trial suggest that some patients who achieve remission with early, aggressive biologic treatment may be candidates for subsequent treatment reduction or withdrawal. This was felt to be good news for clinicians and patients who may prefer reduced-dose, step-down, or treatment-free options after remission induction with biologics because of safety or cost concerns. However, if such an approach is chosen, clinicians need to closely monitor their patients for signs of worsening disease activity or function, or radiographic progression, which would signal the need for reassessment and possible retreatment.


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