Individualised biological treatment in rheumatoid arthritis

Abstract

In the treatment of rheumatoid arthritis (RA), optimal individual dosing of biologic disease modifying antirheumatic drugs (bDMARDs) is warranted, because of their increased risk of (dose dependent) adverse effects and high costs. The bDMARDs available for RA have their own pharmacological characteristics and subsequently need different strategies to reach the lowest effective dose.

Different rituximab retreatment strategies are being used in clinical practice.We investigated another possible rituximab treatment strategy; retreatment when there is loss of response, and thereafter using a fixed interval based on the first response duration, in seventy RA patients treated with at least three rituximab courses. Limits of agreement between intervals were large, therefore we concluded that duration of response after the first rituximab course is not a useful parameter in timing of retreatment.

Only limited data exists on dose reduction of tocilizumab in patients with RA and low disease activity. We investigated the feasibility of reducing the dose of tocilizumab in 22 patients with RA and low disease activity from 8mg/kg to 4mg/kg every 4 weeks. After 6 months, 55% of patients had successfully reduced the dose without losing disease control. All patients who experienced worsening of disease activity after dose reduction regained low disease activity after dose escalation. Disease activity guided dose reduction of tocilizumab thus seems to be feasible in a relevant proportion of patients.

To summarise the research previously performed on dose reduction and discontinuation of anti-TNF agents, we conducted a systematic literature review of randomised controlled trials and controlled clinical trials comparing down titration of anti-TNF agents to usual care/no down titration in RA patients and a low disease activity state.Based on the results of this systematic review, we designed and conducted a pragmatic, non-inferiority, randomised controlled trial on tapering and discontinuation of the subcutaneous anti-TNF agents adalimumab and etanercept in RA patients with low disease activity (the DRESS study). 180 RA patients in low disease activity using adalimumab or etanercept were randomised to a disease activity guided tapering strategy or usual care. Dose reduction consisted of stepwise increases of injection intervals 3 monthly until flare in disease activity or discontinuation, with the possibility to escalate or restart in case of flare of disease activity. The primary outcome was the difference in proportions of patients with major flare (flare > 3 months) between the two groups at 18 months.

Dose reduction was shown to be non-inferior to usual care, with the difference in major flare being 2% (95% CI -12% to 12%). Anti-TNF agent could successfully be stopped in 20% of patients, the interval successfully increased in 43%. Functional status, quality of life and clinically relevant radiographic progression were not different between the groups. Mean costs were €9,038 lower per patient in the dose reduction group. A disease activity guided tapering strategy of adalimumab and etanercept is therefore non-inferior to usual care for major flare and other clinical outcomes, while being clearly superior in cost-effectiveness. No predictors for successful tapering were found, including (anti) drug levels.