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Optimizing biologic tapering in patients with rheumatoid arthritis using tocilizumab, drug combination, and olfactory placebo conditioning

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What is this trial about?

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

The condition being studied is Rheumatoid Arthritis, a chronic disease that causes joint pain, swelling and stiffness. Standard care often includes injectable biologic medicines that target the immune system. In this trial the following biologic agents are used: tocilizumab, adalimumab, abatacept, certolizumab pegol, etanercept, sarilumab, and infliximab. These drugs are given under the skin and belong to a class called bDMARD, which means they are biologic disease‑modifying antirheumatic drugs that help reduce inflammation.

The purpose of the study is to see whether an expectation training program, either alone or combined with a conditioning regimen that uses a harmless scent as a placebo, can improve the ability to taper, or gradually reduce, the biologic medication compared with usual care.

Participants will continue their regular injections and attend regular clinic visits for about a year. Some will receive the expectation training only, others will receive the training plus the scent conditioning, while a control group will receive usual care without the extra program. Over the study period the injection interval may be lengthened stepwise, and doctors will monitor joint symptoms, possible flares, and any side effects to ensure safety.

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 visit
After joining the study you attend a baseline visit where a health professional records your current rheumatoid arthritis status, medication use, and completes several questionnaires about symptoms and quality of life.
The information collected at this visit serves as the reference point for all later comparisons.
Step 2
Expectation training
You receive a short educational session called expectation training that explains how positive expectations about treatment can influence outcomes.
The session uses simple language and does not require any special preparation from you.
Step 3
Conditioning regimen (if assigned)
Participants who are assigned to the conditioning group experience an olfactory cue (a specific scent) that is presented together with each medication injection.
The scent is intended to become associated with the medication effect over time.
Step 4
Medication administration
You continue to receive your prescribed biologic disease‑modifying anti‑rheumatic drug (bdmard) by subcutaneous injection.
The study includes the following drugs, each given at the listed dose:
tocilizumab: 162 mg injected under the skin.
adalimumab: 40 mg injected under the skin.
abatacept: 125 mg injected under the skin.
certolizumab pegol: 200 mg injected under the skin.
etanercept: 50 mg injected under the skin.
sarilumab: 200 mg injected under the skin.
infliximab: 120 mg injected under the skin.
The specific drug you receive is based on your current treatment plan and is administered at the same frequency you were using before the study started.
Step 5
First tapering step (dress step 1)
After the initial period, the study protocol increases the interval between your injections – for example, changing from weekly to every two weeks.
This is called the first tapering or dress step 1 and is intended to reduce the total amount of medication you receive.
You continue to monitor your symptoms and report any changes to the study team during regular visits.
Step 6
Regular monitoring visits
Throughout the trial you attend scheduled visits where disease activity is measured, side effects are recorded, and questionnaires are completed.
These visits occur at intervals recommended by the study protocol and help determine whether tapering can continue safely.
Step 7
Second tapering step (dress step 2)
If your disease remains stable after the first step, the injection interval is increased again – for example, from every two weeks to every three weeks.
This second increase is referred to as dress step 2**.
You continue the same medication at the new interval and keep attending monitoring visits.
Step 8
Nine‑month assessment (t3)
At nine months you undergo a comprehensive assessment called the t3 visit.
The team evaluates whether you have successfully maintained the longer injection interval without returning to your original dosing schedule.
Additional measurements include the percentage reduction in your total bdmard dose, disease activity scores, occurrence of flares, and patient‑reported outcomes such as side‑effect intensity and quality‑of‑life questionnaires.
Step 9
Fifteen‑month assessment (t4)
At fifteen months you attend the final scheduled assessment, referred to as the t4 visit.
The same set of measurements performed at t3 are repeated to determine the longer‑term effects of tapering and the conditioning regimen.
The results from t4 are used to compare the expectation training, conditioning, and regular‑care groups.
Step 10
Study completion
After the t4 visit the study concludes for you.
You receive a summary of your individual results and any final instructions regarding ongoing medication management.

Who can join the trial?

8 criteria

Be at least 18 years old (an adult).
Be able to understand the study information and sign the consent form (this is called informed consent).
Speak, read, and understand Dutch.
Have a diagnosis of rheumatoid arthritis made by a specialist doctor called a rheumatologist.
Currently use a biologic disease‑modifying anti‑rheumatic drug (bDMARD) that is given with an injection pen either every week or every two weeks, at the full dose or after a short adjustment called a DRESS step.
Have a rheumatologist who believes you are suitable to begin reducing the dose of your bDMARD (called bDMARD tapering).
Be willing to try lowering the dose of your bDMARD as part of the study.
Own or have access to a device with internet, such as a computer, smartphone, or tablet.

Who cannot join the trial?

7 criteria

Inability to smell at all or having a severely reduced sense of smell (olfactory function = sense of smell).
Allergy or sensitivity to inhaled essential oils (concentrated plant extracts).
Cannot open the smell stick (similar to opening a small bottle or marker) and no support person is available to help once a week.
Any vision (sight) or hearing problems that prevent taking part in the training.
Insufficient thinking ability (cognitive function) or lacking basic computer/phone abilities (digital skills) and no support person is available to assist.
Planning to become pregnant within the next year.
Currently participating in, or planning to join, another rheumatoid arthritis (RA) medication trial.

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Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
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Rotterdam, The Netherlands

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Investigated drugs

Tocilizumab is a medication that blocks a protein called interleukin‑6, which can cause inflammation and joint damage in rheumatoid arthritis. In this study it is given under the skin to see if patients can safely reduce the amount of medicine they need while keeping their disease under control. Adalimumab is a drug that blocks tumor necrosis factor (TNF), another substance that drives inflammation in the joints. Participants receive it by a subcutaneous injection, and the trial tests whether tapering the dose is possible when combined with special training and conditioning techniques. Abatacept works by interfering with the activity of certain immune cells that contribute to rheumatoid arthritis. It is administered under the skin, and the study examines if patients can lower their use of this drug while maintaining disease control through the trial’s behavioral interventions. Certolizumab pegol is a medication that also blocks TNF, helping to reduce joint swelling and pain. In the trial it is given as a subcutaneous injection, and researchers are checking whether patients can taper off it more effectively when they receive expectation training and conditioning. Etanercept is a biologic that binds to TNF, preventing it from causing inflammation in the joints. It is given by subcutaneous injection, and the study looks at whether patients can safely reduce their dose when they are taught to expect positive outcomes and undergo conditioning. Sarilumab blocks interleukin‑6 receptors, reducing the inflammatory signals that lead to joint damage. It is administered under the skin, and the trial evaluates if tapering this medication is easier when participants receive specific psychological training and conditioning. Infliximab is a drug that neutralizes TNF, helping to control inflammation and pain in rheumatoid arthritis. In this study it is given by subcutaneous injection, and the researchers are testing whether patients can lower their dose when they participate in expectation training and conditioning programs. Expectation training is a behavioral program that teaches participants to develop positive expectations about reducing their medication. By shaping how they think about tapering, the training aims to make it easier for patients to lower their drug doses without worsening their arthritis. The conditioning regimen pairs the medication with a harmless sensory cue (like a smell) so that the body learns to associate the cue with the drug’s effects. Over time, the cue alone may help maintain disease control, allowing patients to taper the actual medication more safely.

What is already known about the treatment

TOCILIZUMAB
This medication is given as a subcutaneous injection of 162 mg. It is an approved drug that is widely studied and used in medical practice. It is mainly prescribed for rheumatoid arthritis and works by blocking the interleukin‑6 (IL‑6) receptor, which reduces inflammation. It belongs to the class of IL‑6 receptor antagonists.
ADALIMUMAB
This medication is administered by a subcutaneous injection of 40 mg. It is an approved biologic with extensive clinical data supporting its use. It is used to treat rheumatoid arthritis and works by binding to tumor necrosis factor‑alpha (TNF‑α), preventing it from causing inflammation. It is classified as a TNF inhibitor.
ABATACEPT
This medication is given as a subcutaneous injection of 125 mg. It is an approved therapy that has been well documented in the medical literature. It is used for rheumatoid arthritis and works by interfering with the CD80/86 costimulatory signal needed for T‑cell activation, which lowers immune activity. It is classified as a selective costimulation modulator.
CERTOLIZUMAB PEGOL
This medication is administered by a subcutaneous injection of 200 mg. It is an approved drug with solid evidence from clinical studies. It is used to treat rheumatoid arthritis and works by attaching to TNF‑α, stopping it from driving inflammation. It belongs to the class of TNF inhibitors (pegylated Fab’ fragment).
ETANERCEPT
This medication is given as a subcutaneous injection of 50 mg. It is an approved biologic that has been studied for many years. It is used for rheumatoid arthritis and acts as a “decoy” receptor that captures TNF‑α, reducing inflammation. It is classified as a TNF inhibitor.
SARILUMAB
This medication is administered by a subcutaneous injection of 200 mg. It is an approved drug with a strong presence in medical research. It is prescribed for rheumatoid arthritis and works by blocking the IL‑6 receptor, which helps control inflammation. It belongs to the IL‑6 receptor antagonist class.

Investigated diseases

Rheumatoid arthritis - Rheumatoid arthritis is a chronic inflammatory condition that primarily affects the joints. It typically starts with pain, swelling, and stiffness in small joints such as those of the hands and feet. Over time the inflammation can spread to larger joints and lead to joint damage. The disease often follows a pattern of flare‑ups and periods of reduced activity. Persistent inflammation may cause the joint lining to thicken and erode bone and cartilage. Joint function can gradually decline if the disease remains active.