Non‑inferiority of methotrexate or leflunomide discontinuation versus continuation in rheumatoid arthritis patients on TNF‑inhibitor therapy

The primary objective of the trial is to determine whether a strategy of discontinuing methotrexate or leflunomide, with the option to restart the drug if required, in patients with Rheumatoid arthritis receiving an optimal dose TNF inhibitor is non-inferior to maintaining the conventional combination therapy, thereby assessing the feasibility of reducing csDMARD exposure without compromising disease control.

Secondary objectives evaluate additional clinical outcomes, including:

• Between‑group difference in disease activity overall and at predefined time points.
• Between‑group difference in patient‑reported outcome measures (PROM).
• Between‑group difference in radiographic progression.
• Between‑group difference in physical functioning.
• Between‑group difference in quality of life.
• Between‑group difference in pharmacokinetic and immunogenicity parameters.
• Between‑group difference in flare rates.
• Between‑group difference in safety.
• Between‑group difference in medication use.
• Between‑group difference in cost‑effectiveness.
• Identification of predictors of successful csDMARD discontinuation.

The trial enrolled adult individuals (≥ 18 years) of both sexes diagnosed with Rheumatoid arthritis according to the 2010 ACR/EULAR or 1987 classification criteria, or by clinical assessment of a rheumatologist. All participants had stable disease activity for at least six months, defined by a DAS28‑CRP ≤ 2.9 or ≤ 3.5 combined with clinical judgment of low disease activity, and were receiving a stable dose of methotrexate (MTX) or leflunomide (LEF) together with an optimally dosed TNF inhibitor. Eligibility required the ability to adhere to study procedures and provision of written informed consent. The sponsor did not provide information on the total number of participants enrolled in the study.

The DISCO‑RA trial is a phase IV, randomized, parallel‑group, non‑inferiority study evaluating a strategy of discontinuing methotrexate or leflunomide in patients with rheumatoid arthritis who are receiving a tumor‑necrosis‑factor inhibitor at an optimal dose; participants are allocated to either a csDMARD‑discontinuation arm with protocol‑directed re‑initiation or a continuation arm maintaining combination therapy. The study enrolment period begins with a screening visit to confirm eligibility criteria, followed by a baseline visit (day 0) that initiates the assigned intervention. Subsequent scheduled assessments occur at months 3, 6, 12, 18 and 24 and include disease‑activity scoring (DAS28‑CRP), patient‑reported outcomes, radiographic evaluation, laboratory safety tests, and pharmacokinetic sampling of TNF‑inhibitor and anti‑drug antibodies. Additional unscheduled flare visits are triggered by predefined increases in DAS28‑CRP and are used to document flare incidence, manage rescue therapy, and capture relevant outcome measures. The end‑of‑study visit at month 24 concludes the 24‑month follow‑up period, after which final data collection is performed. Participants remain in the trial for approximately 26 weeks of active treatment plus the screening phase, with overall involvement of up to 24 months. Early termination may occur if a participant experiences a serious adverse event, requires prohibited concomitant medication, fails to meet compliance standards, withdraws consent, or is lost to follow‑up, in which case data up to the point of discontinuation are retained for analysis.

Etanercept, a TNF inhibitor, is supplied as a solution for injection in pre‑filled syringes or pens. The study uses 25 mg and 50 mg single‑dose vials administered by subcutaneous injection.

Adalimumab, another TNF inhibitor, is provided as a solution for injection in pre‑filled syringes or pens. Doses of 40 mg and 80 mg are administered subcutaneously.

Certolizumab pegol, a pegylated fragment of a monoclonal antibody targeting TNF‑α, is given as a 200 mg solution for injection in pre‑filled syringes or pens via the subcutaneous route.

Golimumab, a fully human monoclonal antibody against TNF‑α, is administered as a 100 mg solution for injection in pre‑filled syringes or pens, subcutaneously.

Infliximab, a chimeric monoclonal antibody against TNF‑α, is supplied as a powder for concentrate for solution for infusion. After reconstitution, it is given intravenously at a dose of 7.5 mg per kilogram of body weight.

Methotrexate, a disease‑modifying antirheumatic drug, is used in both subcutaneous and oral formulations. Subcutaneous preparations are supplied as solutions for injection in pre‑filled devices with a fixed dose of 25 mg per injection; oral tablets are also dosed at 25 mg per administration.

Leflunomide, a disease‑modifying antirheumatic drug, is administered orally as film‑coated tablets at a daily dose of 20 mg.

The primary efficacy assessment is the between‑group difference in mean time‑weighted DAS28-CRP over 24 months. Individual DAS28‑CRP scores are collected at each study visit and combined using the trapezoid method to produce a weighted average that reflects disease activity across the entire follow‑up period.

Secondary efficacy outcomes include disease activity measured by DAS28‑CRP at months 3, 6, 12, 18 and 24; the proportion of patients achieving remission (≤ 2.4) or low disease activity (≤ 2.9) at the same timepoints; and patient‑reported measures of fatigue and pain using the Numeric Pain Rating Scale (0–10) at baseline, each scheduled visit and during flare assessments. Additional patient‑reported outcomes comprise the Rheumatoid Arthritis Impact of Disease questionnaire, the Patient Acceptable Symptom State, a transition scale, and the Medical Adherence Rating Scale, all recorded at baseline, the scheduled visits and flare visits. Radiographic progression is evaluated by change in the Simple Erosion Narrowing Score from baseline to month 24. Functional status is measured with the HAQ‑DI, and health‑related quality of life with the EQ‑5D‑5L questionnaire at the same intervals. Serum concentrations of the TNF inhibitor and anti‑drug antibodies are quantified at baseline, at month 3 for the csDMARD discontinuation arm, and at month 24.

All assessments employ validated instruments or laboratory assays. Disease activity scores are obtained by trained clinicians using standardized joint counts and CRP values. Patient‑reported outcomes are completed electronically or on paper according to instrument instructions. Radiographs are read centrally by blinded readers applying the SENS methodology. Serum drug and antibody levels are measured with validated immunoassays. Adverse events are classified according to CTCAE version 5. Data are captured at baseline, months 3, 6, 12, 18, 24, and at any flare visit, enabling longitudinal analysis of efficacy and safety endpoints.