"We believe this study is a paradigm shift in precision medicine in RA," Dr. Costantino Pitzalis and Dr. Myles Lewis, both of Queen Mary University of London, UK, told Reuters Health by email. "We envisage that routine use of synovial biopsies could facilitate a patient-centered approach to the management of RA, thus moving away from the current trial-and-error drug prescribing towards an emergent era in which selection of the optimal drug is based on synovial biopsy gene signatures."
"The results will not directly change clinical practice immediately, as further development and additional clinical studies are needed to turn our results into a truly practical diagnostic test," they said, "and more research is needed to identify new drugs that can treat resistant RA."
"One of the surprises of the study was the identification of a synovial RNA-Seq gene signature associated with patients being refractory to the three most common classes of biologics (anti-TNF, anti-IL6 and anti-CD20)," they added. "(This) drug refractory signature was linked to the DKK3- positive subclass of fibroblasts identified by previous single-cell RNA-Seq studies (and) is likely to contain novel therapeutic targets to kickstart development of entirely new classes of drugs to help treat the most recalcitrant RA patients."
As reported in Nature Medicine, the team's original randomized trial tested the responses of 164 RA patients to either rituximab or tocilizumab. Patients with low or absent synovial B cell molecular signature had a lower response to rituximab (an anti-CD20 monoclonal antibody) compared with tocilizumab (an anti-IL6R monoclonal antibody) (https://bit.ly/3xi1NHO).
For the current study, the team conducted detailed histological/molecular analyses of the synovial biopsies from the original trial and identified humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to both medications.
Post-treatment changes in synovial gene expression and cell infiltration showed divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms, whereas an analysis of patients refractory to both drugs yielded 1,277 genes unique to this group.
Building on these findings, the team developed machine learning algorithms predictive of response to rituximab (area under the curve, 0.74), tocilizumab (AUC, 0.68) and multidrug resistance (AUC, 0.69).
The authors note that no clinical features were selected for use in the final models and that predictive models built using clinical and histology parameters alone performed "quite poorly" compared with the patient's RNA-seq models.
The authors write, "This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment-response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients."
Dr. Kathryn Dao, associate professor in the division of rheumatology at UT Southwestern Medical Center in Dallas, commented in an email to Reuters Health, "This is an exciting study that gives us a glimpse of the future of how RA will be treated."
"Currently, clinicians are selecting the next drug based on familiarity, availability, safety profile, cost, and patient preferences, but they don't really know how effective the drug will be for that individual patient," she said. "Selecting a drug that might not work is costly and delays the time to remission for patients - so the study is a step forward for precision medicine."
"My concern is that the biomarkers of the synovium can change with time and with different treatments and different environments (use of prednisone/combination csDMARD, comorbidities, infections), so cycling treatment may still be necessary," she noted. "Additional studies are needed to confirm the results."
SOURCE: https://go.nature.com/3MigaQt Nature Medicine, online May 19, 2022.
By Marilynn Larkin
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