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The William Harvey Research Institute - Barts and The London

Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): outcomes of a stratified, biopsy-driven, multicentre, RCT

A new study published today in The Lancet is the first stratified, biopsy-driven, multicentre, open-label, randomised controlled trial that takes the first steps in the integration of molecular pathology into treatment decision making in Rheumatoid Arthritis. 

In this Q&A Professor Costantino Pitzalis from the Centre for Experimental Medicine and Rheumatology at Queen Mary's William Harvey Research Institute explains why the R4RA trial represents the first step towards precision medicine.

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Professor Costantino Pitzalis

Background

There have been dramatic changes in the treatment of rheumatoid arthritis (RA) in the last 20 years with the introduction of hugely effective new classes of drugs (Biologics) and with a more aggressive treatment at an early stage to limit the damaging inflammatory process of this disease. However, in the midst of all these exciting medical advances there is still a big question that has not yet been solved - which patients will respond best to which drugs? Current treatment is still a frustrating process of trial and error for the patient with potential unwanted side-effects, joint damage and worse outcomes, a reality of the waiting process.

What is stratified medicine?

There are particular markers within a person’s genetic makeup that may suggest that particular drug treatments will work better than others for them. Stratified medicine allows us to identify and develop therapies with the aim to treat patients with the right drug for them, the first time, avoiding cycling from one drug to the next. 

What is new about the study?

In cancer it is common to take small fragments (biopsy) of the diseased tissues to be analysed in order to select a treatment that is likely to work for the patient (personalised or precision medicine). The R4RA trial is the first biopsy-based, multicentre, randomised controlled trial in RA, conducted in order to move towards the goal of precision medicine for RA patients who currently experience a trial and error method to get the right treatment.

What did we hypothesize?

Rituximab reduces inflammation by attacking a specific type of immune cells (B-cells). However, in about half of patients it has been found that, when the joint lining is examined under a microscope, B-cells are present in only low numbers or are absent or low. We reasoned that these patients, defined to be B-cell poor, would respond better to another drug, tociluzimab, which works by a different mechanism. If this is the case, then it might be possible, by examining a small piece of tissue from the lining of the joint (biopsy), to predict which patients will respond better to each drug.

How did you carry out the study?

The study recruited 164 patients from sites across the UK, Belgium, Italy, Portugal, and Spain. Patients underwent a biopsy of inflamed joint tissue (synovium) and were randomly assigned to receive either rituximab or tocilizumab. The biopsy tissue was then analysed at laboratories in the Centre for Experimental Medicine and Rheumatology and at Barts Health NHS Trust. Patients were followed up monthly in clinic for a year to assess how they were responding to treatment. We used a score called CDAI (Clinical Disease Activity Index) to assess the change in patient’s disease activity throughout the study and determine whether patients were responding to their treatment or not.

Is there anything surprising about the results?

We found that disease improvement in histologically classified B-cell-poor patients (i.e. classified by studying the tissue under the microscope) was slightly better with tocilizumab than with rituximab, but the difference was not enough to be sure that it did not arise by chance, when response was defined as 50% improvement of the CDAI score (CDAI50%). However, when we used a much stricter outcome, including CDAI 50% improvement but also low disease activity (called CDAI Major Treatment Response -MTR), tocilizumab was clearly superior to rituximab in B cell poor patients.

Furthermore, when we assessed the joint tissue using newer molecular methods to identify B cells, the results were much more promising, showing that tocilizumab was superior to rituximab in B cell poor patients, according to several endpoints, including both CDAI 50% improvement and CDAI MTR.  

Why is the study important?

Currently RA patients are treated on a “trial and error” approach, and approximately 40% of RA patients are non-responsive to therapy. These therapies can have unwanted side-effects as well as being costly. This study represents the first step towards a better understanding of the reason why some drugs work for some patients and others do not, so that treatment can be targeted to the individual patient.  

What are the wider implications?

Although it is too early to know which drugs should be offered to which patients, the results of this study will pave the way for further research to improve how we test and then treat RA patients to achieve the best improvement in their disease. In particular, the molecular classification of joint tissue seems to be very promising and future studies will hopefully help to identify specific molecular signatures that will allow us to choose the best drug for each patient. 

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