Down-Titration of Biologics May Be an Option For Patients With RA

Biologic therapies have resulted in better treatment of rheumatoid arthritis (RA), and have allowed many patients to achieve remission. The efficacy of these therapies has allowed clinicians to consider down-titration (also referred to as dose reduction or dose tapering) for patients who have achieved remission or low disease activity (LDA), though rheumatology guidelines in the United States, Asia, and Europe all acknowledge the fact that the level of evidence guiding down-titration is moderate to very low.

A recently published systematic literature review sought to compare the effects of down-titration of biologics compared with standard dosing on clinical efficacy and health-related quality of life (HRQL), and to evaluate the impact of decreased doses on the cost of RA treatment.

The investigators, led by Chak Sing Lau, MD, conducted an electronic literature search of English-language references published from January 2000 to February 2015. Randomized controlled trials, non-randomized controlled trials, observational studies, and pharmacogenomics studies were eligible for inclusion and screened for risk of bias. The studies that qualified for inclusion evaluated adalimumab, certolizumab, etanercept, infliximab, and rituximab:

• The PRESERVE trial, which evaluated whether patients could maintain LDA after down-titration of etanercept, demonstrated that, at both standard and reduced doses, a combination of etanercept and methotrexate was more effective in maintaining LDA than methotrexate alone, following discontinuation of etanercept.
• The PRIZE study concluded that down-titration or full withdrawal of etanercept after aggressive treatment to reach remission or LDA may be acceptable in some patients, especially those who have experienced sustained remission (based on American College of Rheumatology [ACR] or European League Against Rheumatism guidelines).
• The RAPID 1 study found that improvements in DAS28-ESR, or a disease activity score in a count of 28 joints and erythrocyte sedimentation rate, and ACR response rates were maintained over 192 weeks following dose decreases of certolizumab.
• A retrospective study found that, in patients who received a reduced dose of etanercept, most were able to continue at the reduced dose, and those who had flares resumed the higher dose or switched to adalimumab and regained clinical remission.
• A cross-sectional study in patients receiving adalimumab, etanercept, or infliximab found that it is acceptable to attempt down-titration after clinical response has been achieved.
• A prospective observational study found that 16 of 18 patients with RA receiving infliximab were successfully down-titrated.
• Another prospective observational study found that the HRQL of patients before and after down-titration of infliximab had no significant difference.
• The SMART study indicated non-inferiority of a down-titrated dose of rituximab versus a higher dose.

In terms of economic outcomes, most studies reported a decrease in cost with down-titration. One retrospective US cost analysis found, however, that patients with a decreased dose had a significantly higher number of inpatient admissions, physician visits, laboratory and diagnostic tests, and prescriptions.

Based on these findings, the authors concluded that down-titration can be successful in some patients with RA, and that down-titration generally decreases costs. However, because some patients are unable to retain remission or LDA after having changed their treatment dosage, care must be exercised so that these patients do not experience joint damage.