The goal is to investigate whether a strategy of attempting to discontinue of MTX or LEF (and restart when necessary) in RA patients treated with an optimal dose (allowed dose or lower, tapered to the maximum, or according to patient preference) TNFi is not worser to a continuation of combination therapy. The study will also examine the disease-related effects of treatment that attempts to discontinue MTX or LEF, how patients experience it, its safety, and its impact on medication usage and healthcare costs.
The main outcome is the difference between treatments in average disease activity over 24 months. The study will compare whether disease activity remains similar between patients who attempt to discontinue MTX or LEF and those who continue combination therapy.
Patients will be followed for 24 months with scheduled hospital visits at baseline, after 3, 6, 12, 18, and 24 months, remote visits, and additional visits for disease flares. X-rays of the hands and feet will be taken at baseline and after 24 months. During some visits, additional blood samples will be taken to measure inflammation markers and medication levels.
Age ≥ 18 years.
Diagnosis of RA, according to the 2010 ACR/EULAR and/or 1987 RA classification criteria or clinical diagnosis by a rheumatologist.
Stable disease activity for ≥ 6 months, defined as DAS28-CRP ≤ 2.9 or DAS28-CRP ≤ 3.5 combined with clinical judgment of LDA.
Current combination therapy consisting of TNFi and either MTX or LEF.
A previous attempt within the last 12 months prior to screening to taper or discontinue MTX or LEF that required reintroduction or dose increase of the csDMARD due to a disease flare.
Current MTX or LEF treatment for other indications than RA.
Current treatment with prednisolone (equivalent) of > 5 mg per day.
Current severe comorbidity or serious life-shortening condition that could interfere with adherence to the study protocol or completion of the 24-month follow-up period.
Parallel
Strategy to attempt discontinuation of MTX or LEF (and restart when necessary)
DrugParticipants will discontinue their csDMARD (MTX or LEF) immediately following randomization and continue TNFi monotherapy at their current stable dose.
Continuation of MTX or LEF
DrugParticipants will aim to continue combination therapy with csDMARD (MTX or LEF) and TNFi at their current stable doses.
The between-group difference in mean time-weighted DAS28-CRP during 24 months of follow-up.
The between-group difference in mean time-weighted DAS28-CRP during 24 months of follow-up. A mean time-weighted DAS28-CRP is chosen to balance the limitations of assessing disease activity at a single timepoint with solely considering the occurrence of flare. The time-weighted DAS28-CRP consists of a weighted average of a patient's DAS28-CRP scores, calculated using the trapezoid method and weighed by the time interval between measurements.
Between-group difference in disease activity
Disease activity measured by DAS28-CRP at 3, 6, 12, 18 and 24 months.
Between-group difference at specific timepoint disease activity
Proportion of patients in remission (DAS28-CRP ≤ 2.4) or LDA (DAS28-CRP ≤ 2.9) at 3, 6, 12, 18, and 24 months.
Between-group difference in PROM
Fatigue and pain are measured by the Numeric Pain Rating Scale (NRS 0-10), where the minimum value is 0 and the maximum value is 10, meaning higher scores indicate a worse outcome of greater pain intensity and more severe fatigue. This scale is administered at baseline, 3, 6, 12, 18, and 24 months, as well as at flare visits.
Between-group difference in PROM
Disease impact is measured by the Rheumatoid Arthritis Impact of Disease (RAID) Questionnaire, where the minimum value is 0 and the maximum value is 10, meaning higher scores indicate a worse outcome of greater overall disease impact on the patient's life. This questionnaire is administered at baseline, 3, 6, 12, 18, and 24 months, as well as at flare visits.
Cost-effectiveness
Healthcare resource utilization and related expenses are evaluated by medical costs measured using the institute for Medical Technology Assessment Medical Consumption Questionnaire (iMTA MCQ), where the minimum value is 0 euros and the maximum value is unbounded, meaning higher scores indicate a worse outcome of higher economic burden and increased healthcare consumption. This questionnaire is administered at baseline, 3, 6, 12, 18, and 24 months.
Cost-effectiveness
Economic impact and work limitations are evaluated by productivity losses and participation measured using the institute for Medical Technology Assessment Productivity Cost Questionnaire (iMTA PCQ), where the minimum value is 0 hours or euros and the maximum value is unbounded, meaning higher scores indicate a worse outcome of greater productivity loss, higher societal costs, and lower work participation. This questionnaire is administered at baseline, 3, 6, 12, 18, and 24 months.
Predictors of successful csDMARD discontinuation
Prediction modelling using baseline pharmacological factors (TNFi levels and ADA levels) and drug and ADA levels after discontinuation of csDMARDs (3 months).
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Sint Maartenskliniek
Lead sponsor
ZonMw: The Netherlands Organisation for Health Research and Development
Collaborator
