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Researchers have yet to crack how to analyze synovial tissue biopsy specimens to predict treatment responses for patients with rheumatoid arthritis (RA).

According to new research, classifying patients by synovial fluid B-cell status was not reliable in predicting treatment response to etanercept, tocilizumab, or rituximab. More comprehensive molecular analyses may hold more promise in developing models to predict treatment of a disease as heterogeneous as RA, write the authors, led by chief investigator Costantino Pitzalis, MD, head of the Centre for Experimental Medicine and Rheumatology at Queen Mary University of London.

The article was published in the November 2023 issue of The Lancet Rheumatology.

Trial-and-Error Treatment

Because clinicians do not have a way to reliably predict how patients may respond to certain medications, sporanox z the current RA treatments involve trial and error.

“Both with regard to the first conventional synthetic disease-modifying antirheumatic drug (DMARD) for all patients and the first biologic DMARD for the subgroup of patients requiring these drugs, the choice of a drug is based on pragmatic arguments rather than on individual patient characteristics,” writes Annette H. van der Helm-van Mil, MD, PhD, professor of rheumatology at the Leiden University Medical Center, the Netherlands, in an accompanying editorial.

Most research on predicting treatment response has used clinical features and blood biomarkers, but neither approach is reliably predictive. “Precision medicine, therefore, remains elusive,” she said. Newer research has focused on synovial tissue biopsy to inform research decisions.

The STRAP Studies

In this newest study, researches combined data from two clinical studies with identical design: the Stratification of Biological Therapies by Pathobiology in Biologic-Naive Patients With Rheumatoid Arthritis (STRAP) trial, taking place in the United Kingdom, and STRAP-EU, which recruited patients from the European Union. The trials are the largest biopsy-driven trials to date, according to the researchers.

In total, researchers recruited 223 biologic-naive adult patients from 26 universities in the UK and Europe. Participants underwent ultrasound-guided synovial tissue biopsy and were then randomly assigned to receive etanercept (72 patients), tocilizumab (73 patients), or rituximab (78 patients). In a histologic analysis, 121 patients were characterized as B-cell poor (BCP), 100 patients were classified as B-cell rich (BCR), and two patients were classified as undetermined.

“We hypothesized that patients with a low synovial histological or molecular B-cell score would have a lower response to rituximab than to etanercept or tocilizumab,” the authors write.

However, among the BCP patients, there were no significant differences between responses to treatment at week 16 in the rituximab group compared with the etanercept and tocilizumab groups put together. In both groups, around 60% of patients achieved the primary endpoint of at least 20% improvement in American College of Rheumatology response criteria.

The results suggest that “a dichotomic classification into synovial B cell poor versus rich is unable to predict treatment response in patients treated with rituximab compared with etanercept or tocilizumab,” the authors write.

The findings echo work from the same group of researchers in 2021. This study ― the R4RA trial ― enrolled 164 patients who previously had an inadequate response to tumor necrosis factor blockers. Researchers then used a similar histologic approach to compare patients’ responses to tocilizumab or rituximab.

Among patients classified as BCP, there was not a significant difference in treatment response between the tocilizumab group and the rituximab group. However, classifying patients as BCP with RNA sequencing did make a difference. In this subgroup, patients given tocilizumab demonstrated a significantly higher response rate than those treated with rituximab.

Molecular-Level Analyses Needed

This 2021 study showed ― and this most recent study further confirmed ― that “histology is not the way to understand what’s going on with or be predictive with tissue,” said Harris R. Perlman, PhD, chief of rheumatology at Northwestern University Feinberg School of Medicine, in Chicago. He was not involved with the research.

Dr Harris Perlman

“Most people now believe that you really have to understand the tissue on a single-cell basis ― using the gene expression of each individual cell ― to really give you an idea of what’s happening in tissue,” he noted.

Dr Elena Myasoedova

“RA continues to tell us that it is more complex than just something dichotomous,” added Elena Myasoedova, MD, PhD, director of the Inflammatory Arthritis Subspecialty Group at the Mayo Clinic in Rochester, Minnesota. She was also not involved with the work.

“Understanding more about the heterogeneity using different ‘-omics’ approaches and introducing a two- or three-dimensional approach with spatial biology can be helpful,” she said.

Spatial transcriptomics, for example, allows scientists to measure all gene activity in a tissue sample and to map where that gene activity is occurring.

“It helps us to understand and visualize molecules and their unique context within individual cells and tissues,” Myasoedova explained.

With advanced molecular analyses already available, Perlman is adamant that synovial tissue remains the key to unlocking precision medicine.

“The tissue is the golden ticket,” he said, “but it’s how you analyze it.”

And it’s clear that older analytic methods ― such as histology – are not enough, he said.

A larger study of similar size to STRAP’s that incorporates multiple sources of patient information, from gene expression to clinical symptoms, to create a predictive model would be key to understanding how to move the field of precision treatment for RA forward, he added.

“Precision medicine for RA is close,” he said. “We still have to get the numbers.”

The STRAP and STRAP-EU trials were jointly funded by the UK Medical Research Council and Versus Arthritis. Pfizer and Roche donated the study drugs through an investigator sponsored research grant. Many authors, including Pitzalis, have multiple financial relationships with pharmaceutical companies. Van der Helm-van Mil and Myasoedova have disclosed no relevant financial relationships. Perlman consults for AbbVie, AnaptysBio, Exagen, Janssen, and Kiniksa.

Lancet Rheumatol. 2023;5:e648-e659. Full text

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