Can synovial biopsies predict RA treatment response?

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A landmark clinical trial has found RA patients with few or no immune cells in their synovial tissue respond better to tocilizumab than rituximab.

A landmark clinical trial has found RA patients with few or no immune cells in their synovial tissue respond better to tocilizumab than rituximab, opening the door to biopsy-guided treatment decisions.

The multisite trial, involving close to 165 patients and published in The Lancet, was designed to evaluate if the IL-6 receptor blocker, tocilizumab, is superior to B-cell depleting rituximab, in RA patients with few or no B cells in their synovial tissue.

“This is the first study that [has] investigated whether the treatment decision in rheumatoid arthritis can be guided by the results of the synovial biopsy,” German rheumatologist Denis Poddubnyy wrote in an accompanying comment.

Previous observational studies have correlated treatment response with synovial tissue traits among RA patients. Another identified markers associated with early and late responders to rituximab.

But there are no markers that can be used in practice to predict an RA patient’s response to therapy. 

Plus, around half of RA patients all but lack the target of rituximab, CD20-expressing B cells, in their joint synovium.

In this randomised clinical trial, aiming to improve clinical outcomes in patients lacking synovial B cells, synovial biopsies were taken at baseline to classify 161 patients who had failed prior anti-TNF therapy as either B-cell rich or poor.

Participants were then randomly assigned to receive two rituximab injections two weeks apart or monthly tocilizumab infusions.

To classify patients as B-cell rich or poor, two methods were used: first, routine immunohistochemistry, then RNA sequencing.

In patients with low or absent B cells, as characterised by RNAseq only, treating with tocilizumab was superior at 16 weeks to targeting B cells with rituximab.

In patients with a B-cell rich synovium, rituximab appeared to be just as effective as tocilizumab.

However, this secondary finding “cannot justify any change to clinical practice”, the study authors noted, because the trial was not powered to examine the efficacy of rituximab in the B-cell rich group.

“This means that we know who would be a poor candidate for rituximab therapy, but it is rather unclear who would be a good candidate for rituximab,” Professor Poddubnyy wrote in his commentary.

Rheumatologist Mihir Wechalekar, who directs the synovial tissue bank based at the Flinders Medical Centre in Adelaide, also said the choice of tocilizumab as an active comparator to rituximab might not have been optimal because tocilizumab itself modulates B-cell function and survival.

Also, some patients in the trial had long-standing disease where their synovial tissue pathology was likely altered by their prior treatment, Associate Professor Wechalekar noted.

“It is not known what the response to their failed prior biologic treatment(s) was, and how long these responses lasted,” he said.

While Associate Professor Wechalekar described the trial as a “landmark study”, he said the immediate repercussions for clinical practice were less clear, given the absence of routine synovial tissue sampling and analyses in most rheumatology clinical settings.

“It may be worthwhile considering synovial biopsy when feasible (or routinely, depending on the centre) to more accurately characterise the immunological signatures of patients with RA,” Professor Wechalekar said.

“The latter may provide data to guide decision-making in the future.”

The Lancet 2021, 23 Jan

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