Dose reduction of TNF inhibitors safe, effective for some rheumatoid arthritis patients

Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.

TNF inhibitors like adalimumab (Humira®) or etanercept (Enbrel®) have proven to be effective in RA treatment. However, these drugs may have side effects and are costly, making dose reduction, or discontinuation whenever possible, an attractive option. In a study called DRESS, or Dose Reduction Strategies of Subcutaneous TNF inhibitors, researchers in the Netherlands studied 180 RA patients who had low disease activity and were using either adalimumab or etanercept. The study's primary goal was to assess whether a strategy including carefully reducing the dose until stopping it, and increasing treatment again when the RA became more active, produces results that are just as good (or non-inferior) as continuing the regular dosing of TNF inhibitors.

"If this approach to individualized dose optimization could be proven to be as effective and safe as regular continuation of the drug, this would have large impact on adverse drug reactions and costs in the millions of patients currently using these drugs," said Noortje van Herwaarden, MD, of Sint Maartenskliniek in the Netherlands and a lead author on the study.

In the study, the patients were randomized (two to one) to either a dose-reduction strategy or usual care, both in tight control settings. The dose-reduction strategy consisted of stepwise increasing the interval between injections every three months until the patient flared or the drug was discontinued. If a patient had a flare, TNF inhibitors were either restarted or escalated, and no further dose optimization attempts were made. A flare was defined as a DAS28-CRP (a measure for disease activity) increase >1.2, or DAS28-CRP increase >0.6 and current DAS28-CRP ≥3.2, compared to baseline. A persistent flare (the primary outcome) was defined as a flare lasting 12 weeks or more.

During the 18 months of follow-up, data were collected on DAS28-CRP scores, physical function, health related quality of life, RA medication use and costs (including work loss, outpatient visits and travel costs). The primary outcome was the difference in proportions of patients with persistent flare between the two groups, with a difference of less than 20 per cent defined as non-inferiority.

In the dose reduction group, the researchers found that TNF inhibitors could successfully be stopped in 20 percent of the patients. They also found that the interval could be successfully increased in 43 percent of the patients. In 37 percent of the patients, no dose reduction was possible. Incidence and nature of serious adverse events were similar between groups. Costs were significantly lower in the dose-reduction group (mean difference per patient was estimated at €9,000, or $11,480, for the 18-month period).

The study's authors concluded that a simple, tight control, TNF inhibitor dose-reduction strategy is non-inferior to usual care in maintaining disease control, function and quality of life and radiological disease control in RA patients with low disease activity. This strategy may help reduce health-care costs in this population.

"The results from the DRESS study can have tremendous impact on optimizing RA TNF inhibitor treatment, as it has now been demonstrated that the same treatment results can be obtained with nearly 50 percent reduction in medication exposure and costs. As the yearly revenues for adalimumab and etanercept alone (not taking into account the other biologicals used in rheumatic diseases) exceeds $20 billion, and is still growing, implementation of the DRESS findings could result in improved cost effectiveness of the use of these biologics," said Dr. van Herwaarden.