Discontinuation of methotrexate or leflunomide in rheumatoid arthritis patients on TNF inhibitors: a randomized non‑inferiority trial

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What is this study about?

The study involves people with Rheumatoid arthritis, a condition that causes joint pain, swelling and stiffness. All participants are already receiving a TNF inhibitor, a type of medicine that blocks inflammation. The trial will compare two approaches: continuing the usual combination of the TNF inhibitor with another drug such as methotrexate or leflunomide, versus stopping the additional drug and only restarting it if symptoms get worse. The purpose is to find out whether stopping the extra medication is not worse than keeping it.

Participants will be randomly placed into one of the two groups. Those in the continuation group will keep taking their current medicines, while those in the discontinuation group will stop the extra drug and may begin it again only if needed. Over the next two years, they will attend regular clinic visits where doctors will check how the disease is doing, ask about pain and fatigue, and perform simple blood tests and X‑rays to look at joint health.

The main way the disease activity is measured is with a score called DAS28-CRP, which combines information about joint swelling, tenderness and a blood marker of inflammation. A higher score means more active disease, while a lower score indicates that the disease is under control. The study will also record any worsening of symptoms, called a “flare,” as well as side‑effects, quality of life, and how well participants stick to their medication schedule.

1 baseline visit and start of medication

after joining the study you attend a baseline visit. disease activity is measured with the das28‑crp score and questionnaires for pain, fatigue, disease impact, health‑related quality of life and medication adherence are completed.

you begin the study medication. the tnfi is given at the optimal dose (examples: etanercept 25 mg subcutaneous injection, adalimumab 40 mg subcutaneous injection, certolizumab pegol 200 mg subcutaneous injection, golimumab 100 mg subcutaneous injection, or infliximab 7.5 mg/kg intravenous infusion). in addition you receive either methotrexate 25 mg subcutaneous injection or leflunomide 20 mg oral tablet. the medication is taken for the entire 24‑month study period.

2 randomization to treatment strategy

you are randomly assigned to one of two strategies. in the continuation strategy you keep taking the csdmard (methotrexate or leflunomide) together with the tnfi. in the discontinuation strategy you stop the csdmard while continuing the tnfi. the tnfi dose remains unchanged in both groups.

3 regular follow‑up visits

you attend follow‑up visits at month 3, month 6, month 12, month 18 and month 24. at each visit das28‑crp, pain, fatigue, disease impact questionnaires, health assessment questionnaire‑disability index and eq‑5d‑5l are repeated. medication adherence is evaluated with the mars questionnaire.

blood samples are taken to measure tnfi serum levels at baseline, at month 3 (only for the discontinuation group) and at month 24. anti‑drug antibody levels are also measured at these time points.

4 flare monitoring and possible restart of csdmard

if das28‑crp increases by more than 1.2 (or more than 0.6 when baseline das28‑crp is above 2.9) a flare visit is scheduled. during a flare you may restart the csdmard that was stopped, according to the study protocol. the decision to restart is recorded and subsequent visits continue as scheduled.

5 final assessment at month 24

at the end of the 24‑month period a final assessment is performed. das28‑crp, all questionnaires, radiographic joint damage (sens), medication usage, and tnfi serum levels are recorded. the proportion of patients still using the tnfi, the proportion who restarted a csdmard, and any adverse events are documented.

Who Can Join the Study?

Be 18 years of age or older.
Have a diagnosis of rheumatoid arthritis confirmed by a rheumatologist or by the official classification criteria used for this disease.
Have stable disease activity for at least 6 months, meaning the disease is well‑controlled. This is measured by the DAS28‑CRP score (a number that combines joint counts and a blood test called C‑reactive protein). A score of 2.9 or less, or a score of 3.5 or less together with a doctor’s judgment of low disease activity, is required.
Be currently taking a combination of either methotrexate (MTX) or leflunomide (LEF) at the same dose for at least 3 months, along with a tumor necrosis factor inhibitor (TNFi) at an optimal dose (the approved dose or a lower dose that has been reduced because of previous flare or personal preference).
Be able to follow all study procedures, attend scheduled visits, and complete follow‑up assessments.
Provide written informed consent before any study‑related activities begin.

Who Cannot Join the Study?

If you tried to lower or stop methotrexate (MTX) or leflunomide (LEF) within the last 12 months and then had to restart them or increase the dose because your arthritis got worse (a disease flare).
If you are currently taking MTX or LEF for a condition other than rheumatoid arthritis.
If you are taking more than 5 mg per day of prednisolone (or an equivalent steroid medication).
If you have a serious other illness (severe comorbidity) or a life‑shortening condition that could make it difficult to follow the study plan or finish the 24‑month follow‑up.
If you are pregnant, breastfeeding, or might become pregnant during the study (because MTX and LEF are contraindicated in pregnancy and while nursing).
If you are unable to follow the study visits, procedures, or required follow‑up assessments.
If you cannot or do not want to give written permission to take part in the research (informed consent).

Where you can join this trial?

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Other Sites

Site Name	City	Country
Sint Maartenskliniek Stichting	Ubbergen	The Netherlands
Egaldiogebldhahawbkb Zvporafkab	Tilburg	The Netherlands
Rnxlt rejpxhoefip &ehsh rtkmgbtxzekh cyvulgh tz Axfhettgl	Amsterdam	The Netherlands
Emgwbag Uqusifsnrdmv Mznnbee Cnpxlnw Rewwkokzp (mquutbn Mta	Rotterdam	The Netherlands

Trial status

Country	Status	Recruitment Start
The Netherlands	Not yet recruiting	01.05.2026

Trial locations

Investigated drugs:

Etanercept is a medication that blocks a protein called tumor necrosis factor (TNF). By blocking TNF, it reduces inflammation and pain in the joints of people with rheumatoid arthritis. In this trial it is used as the main TNF‑inhibitor drug that patients continue taking while the study tests whether other medicines can be stopped.

Adalimumab is another TNF‑blocking medicine given by a subcutaneous injection. It works in the same way as etanercept to lower joint inflammation. In the study it serves as the TNF‑inhibitor that stays on the treatment plan while the researchers try stopping other drugs.

Certolizumab pegol is a TNF inhibitor that is also injected under the skin. It helps control rheumatoid arthritis by preventing TNF from causing joint damage. In this trial it is one of the TNF‑inhibitor options that participants keep using.

Golimumab is an injectable medication that blocks TNF and reduces swelling and pain in the joints. It is included in the study as a TNF‑inhibitor that patients continue while the trial examines stopping other disease‑modifying drugs.

Infliximab is a medication given by intravenous infusion that also blocks TNF. It helps to calm the immune system and protect joints from damage. In the trial it is used as a TNF‑inhibitor that remains part of the patients’ regular therapy.

Methotrexate is a conventional disease‑modifying anti‑rheumatic drug (DMARD). It can be taken as a pill or given by injection and works by slowing down the immune response that attacks the joints. The study is testing whether patients can safely stop methotrexate while staying on a TNF inhibitor.

Leflunomide is an oral DMARD that reduces the activity of immune cells that cause joint inflammation. In this trial it is examined as a drug that might be discontinued, with patients continuing their TNF‑inhibitor treatment.

Rheumatoid arthritis – Rheumatoid arthritis is a chronic autoimmune condition that primarily attacks the lining of joints, causing swelling, pain, and stiffness. The inflammation often begins in small joints such as those of the hands and feet and can spread to larger joints over time. As the disease progresses, the joint lining thickens and may erode the bone and cartilage, leading to reduced mobility. Symptoms can vary day to day, with periods of increased activity (flares) followed by quieter phases. The condition may also involve other parts of the body, such as the skin, eyes, or lungs, as the immune response extends beyond the joints.

Trial ID:

2026-525316-33-00

Protocol code:

2025.36

Trial Phase:

Therapeutic confirmatory (Phase III)

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Discontinuation of methotrexate or leflunomide in rheumatoid arthritis patients on TNF inhibitors: a randomized non‑inferiority trial

What is this study about?

Who Can Join the Study?

Who Cannot Join the Study?