Recruiting

Discontinuation of methotrexate (drug combination) in rheumatoid arthritis patients using TNF inhibitors

Verified siteRegistered drugNo placebo

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This study involves adults with Rheumatoid arthritis who are already receiving a biologic medication that blocks tumor necrosis factor (a type of TNF inhibitor). The usual treatment also includes a pill called methotrexate or another drug called leflunomide. The purpose of the study is to determine whether stopping the pill while continuing the biologic is not worse than keeping both treatments together.

Participants are randomly assigned to either continue both the pill and the biologic or to stop the pill after a short period. If disease activity rises (a flare), the stopped medication can be started again. All participants keep receiving their regular biologic injections. The study follows each person for up to two years, with clinic visits scheduled at about 3, 6, 12, 18 and 24 months.

At each visit, doctors will check how active the disease is using a score called DAS28-CRP, ask about pain, fatigue and daily function, and record any side effects. Patients will also fill out questionnaires about quality of life and work ability. Blood samples may be taken to measure drug levels. The study aims to compare overall disease control, safety and cost between the two approaches.

The research process

The trial runs in 10 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Baseline assessment
On the day you join the trial you attend a baseline visit where your health status is recorded. this includes a physical exam, blood tests, and questionnaires that measure pain, fatigue, and overall disease impact.
Your current tnf inhibitor (for example etanercept 25 mg subcutaneous weekly, adalimumab 40 mg subcutaneous every 2 weeks, certolizumab pegol 200 mg subcutaneous monthly, or golimumab 100 mg subcutaneous monthly) is continued at the same dose throughout the study.
The dose of methotrexate is recorded as 25 mg given by subcutaneous injection once a week, and the dose of leflunomide is recorded as 20 mg taken orally once daily. folic acid supplementation, if used, is noted.
Step 2
Randomisation
After baseline data are collected you are randomly assigned to one of two strategies:
• continuation group – you keep taking your methotrexate or leflunomide as before.
• discontinuation group – you stop taking methotrexate or leflunomide immediately after the visit.
Step 3
Medication plan – continuation group
If you are in the continuation group you continue the same weekly subcutaneous methotrexate 25 mg or daily oral leflunomide 20 mg for the full 24‑month period.
Your tnf inhibitor dose remains unchanged and is administered according to its usual schedule.
Step 4
Medication plan – discontinuation group
If you are in the discontinuation group you stop methotrexate or leflunomide right after the baseline visit.
You continue your tnf inhibitor at the same dose and schedule as before.
If a disease flare occurs you may restart the stopped drug according to the study protocol.
Step 5
Month‑3 follow‑up
Three months after the baseline visit you attend a follow‑up appointment.
Your disease activity is measured with the DAS28‑CRP score, pain and fatigue are recorded on a 0‑10 scale, and questionnaires on disease impact (RAID, PASS, transition scale) are completed.
Blood samples are taken to measure tnf inhibitor levels; this measurement is required only for participants in the discontinuation group.
The investigator checks for any flare. if a flare is present, the stopped methotrexate or leflunomide may be restarted.
Step 6
Month‑6 follow‑up
Six months after baseline you repeat the same assessments as at month 3.
The same blood test for tnf inhibitor levels is performed in the discontinuation group.
Any required medication adjustments are made based on disease activity.
Step 7
Month‑12 follow‑up
At twelve months you undergo the full set of evaluations again, including DAS28‑CRP, pain and fatigue scales, RAID, PASS, transition scale, and health‑related quality‑of‑life questionnaires (EQ‑5D‑5L).
Blood is drawn for tnf inhibitor levels in the discontinuation group.
If you experienced a flare and restarted methotrexate or leflunomide, the medication use is recorded.
Step 8
Month‑18 follow‑up
Eighteen months after baseline the same clinical and questionnaire assessments are performed.
Blood sampling for tnf inhibitor levels continues in the discontinuation group.
The decision to continue, stop, or restart any csdmard (methotrexate or leflunomide) follows the same criteria as earlier visits.
Step 9
Month‑24 final visit
Twenty‑four months after the start of the trial you attend the final visit.
All outcome measures are repeated, including DAS28‑CRP, pain and fatigue scores, RAID, PASS, transition scale, HAQ‑DI, EQ‑5D‑5L, and medication adherence questionnaire (MARS).
Blood is drawn for tnf inhibitor levels in both groups.
The use of methotrexate, leflunomide, and folic acid during the whole study period is summarised, and any adverse events are recorded.
Step 10
Flare‑related visits
If at any time your disease activity increases markedly (a DAS28‑CRP rise of more than 1.2, or more than 0.6 when the score is already above 2.9), you are instructed to contact the study team for an unscheduled flare visit.
During a flare visit disease activity is reassessed, and the stopped csdmard (methotrexate or leflunomide) may be restarted according to the protocol.
All flare visits are documented and contribute to the analysis of flare incidence and time to first flare.

Who can join the trial?

6 criteria

Be 18 years of age or older.
Have rheumatoid arthritis diagnosed according to the 2010 ACR/EULAR or 1987 classification criteria, or diagnosed by a rheumatologist (a doctor who treats joint diseases).
Have stable disease for at least 6 months, meaning a score called DAS28‑CRP (a test that measures joint swelling, pain and a blood marker called C‑reactive protein) is 2.9 or lower, or 3.5 or lower if the doctor judges the disease to be in low activity.
Be currently taking a combination of either methotrexate (MTX) or leflunomide (LEF) at the same dose for at least 3 months, together with a TNF inhibitor (TNFi) at an optimal dose (the approved dose or a lower dose that has been adjusted because of past flare‑ups or personal preference).
Be able to follow all study procedures, attend visits, and complete follow‑up assessments.
Provide written informed consent before any study‑related procedure.

Who cannot join the trial?

7 criteria

If you tried to lower or stop the medicines methotrexate (MTX) or leflunomide (LEF) in the past 12 months and then had to start them again or increase the dose because your arthritis got worse (a disease flare), you cannot join the study.
If you are currently taking MTX or LEF for a health problem other than rheumatoid arthritis, you cannot join the study.
If you are taking more than 5 mg per day of prednisolone (a steroid medication) or an equivalent drug, you cannot join the study.
If you have a serious additional illness (severe comorbidity) or a condition that could shorten your life and might make it hard to follow the study steps or finish the 24‑month follow‑up, you cannot join the study.
If you are a woman who is pregnant, breastfeeding, or planning to become pregnant during the study, you cannot join because MTX and LEF should not be used in pregnancy or while nursing.
If you cannot attend the required study visits or complete the follow‑up assessments, you cannot join the study.
If you are unable or unwilling to sign the informed consent form that explains the study, you cannot join the study.

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Verified sites

All sites with verified contact details – recruitment status may not be available; ask directly

Elisabeth-TweeSteden Ziekenhuis
Verified
Tilburg, The Netherlands
Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
Responsive
Rotterdam, The Netherlands
Reade revalidatie & reumatologie centrum te Amsterdam
Verified
Amsterdam, The Netherlands

Trial locations

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Investigated drugs

Etanercept
is a medication that blocks a protein called tumor necrosis factor (TNF). By reducing TNF activity, it helps lower inflammation and pain in the joints of people with rheumatoid arthritis. In this study, participants receive etanercept as a subcutaneous injection, either in a pre‑filled syringe or pen.
Adalimumab
is another TNF‑blocking drug that works in a similar way to etanercept. It is given by injection under the skin and is used to control joint inflammation and swelling in rheumatoid arthritis. The trial includes adalimumab in several brand forms, all delivered as pre‑filled syringes or pens.
Certolizumab pegol
is a TNF inhibitor that is slightly different because it does not have the usual antibody structure. It is injected under the skin and helps reduce joint pain and damage in rheumatoid arthritis. In the trial it is provided as a pre‑filled syringe.
Golimumab
is a TNF‑blocking medication that is also given by subcutaneous injection. It reduces inflammation and can improve joint function in rheumatoid arthritis patients. The study uses golimumab in pre‑filled syringes or pens.
Methotrexate
is a conventional disease‑modifying drug that works by suppressing the immune system to lower joint inflammation. It can be taken by injection (under the skin or into a vein) or taken orally as a tablet. In this trial methotrexate is used as the drug that may be stopped or continued while patients stay on a TNF inhibitor.
Leflunomide
is an oral medication that reduces the activity of immune cells, helping to decrease joint swelling and pain in rheumatoid arthritis. It is taken as a tablet once a day. The study examines whether patients can stop leflunomide while staying on a TNF inhibitor.

What is already known about the treatment

Etanercept
Etanercept is given as a subcutaneous injection using a pre‑filled syringe or pen, allowing patients to inject the solution under the skin. It is an approved biologic disease‑modifying antirheumatic drug (DMARD) with extensive clinical use and literature support for rheumatoid arthritis and other inflammatory conditions. The drug works by acting as a decoy receptor that binds tumor‑necrosis factor‑alpha (TNF‑α), preventing it from triggering inflammation. Pharmacologically, it is classified as a TNF‑α inhibitor and a biologic DMARD.
Adalimumab
Adalimumab is administered by subcutaneous injection with a pre‑filled syringe or pen, delivering the medication just beneath the skin. It is a widely approved and studied biologic DMARD used for rheumatoid arthritis, psoriatic arthritis, and similar diseases. The molecule is a fully human monoclonal antibody that attaches to TNF‑α, blocking its interaction with cell receptors and reducing inflammatory signals. It belongs to the class of TNF‑α inhibitors.
Certolizumab pegol
Certolizumab pegol is provided as a subcutaneous injection in a pre‑filled syringe, allowing patients to self‑inject the solution under the skin. This pegylated Fab fragment is an approved biologic DMARD indicated for rheumatoid arthritis and other autoimmune disorders. It binds to TNF‑α and neutralizes its activity, thereby lowering inflammation, while the pegylation prolongs its presence in the body. It is classified as a TNF‑α inhibitor.
Golimumab
Golimumab is delivered by subcutaneous injection using a pre‑filled pen or syringe, enabling easy self‑administration. It is an approved biologic DMARD used for rheumatoid arthritis, ankylosing spondylitis, and related conditions. The drug is a human monoclonal antibody that attaches to TNF‑α, blocking the cytokine’s inflammatory actions. Pharmacologically, it is a TNF‑α inhibitor.
Infliximab
Infliximab is given as an intravenous infusion, prepared from a powder that is mixed to create a solution for infusion. It is a well‑established biologic DMARD approved for rheumatoid arthritis, Crohn’s disease, and other inflammatory illnesses. The medication is a chimeric monoclonal antibody that binds to TNF‑α, preventing the cytokine from activating inflammatory pathways. It is classified as a TNF‑α inhibitor.
Methotrexate
Methotrexate can be taken as an oral tablet or injected subcutaneously, with the injection form supplied in pre‑filled syringes or pens for under‑skin delivery. It is the cornerstone conventional DMARD for rheumatoid arthritis and is supported by decades of clinical research. The drug works by inhibiting the enzyme dihydrofolate reductase, which slows DNA synthesis and reduces the activity of immune cells that cause joint damage. It is classified as an antimetabolite DMARD.

Investigated diseases

Rheumatoid arthritis - Rheumatoid arthritis is a chronic condition in which the immune system mistakenly attacks the lining of joints. It causes inflammation, swelling, and pain in the affected joints. Over time the inflammation can lead to damage of cartilage and bone. Joint stiffness, especially in the morning, is common. The disease often spreads from a few joints to many, including hands, wrists, and feet. Persistent inflammation may result in reduced joint function and deformities.