New research from Queen Mary University of London, published in natural medicine, showed that molecular profiling of diseased joint tissue can have a significant impact on the effectiveness of specific drug therapies to treat patients with rheumatoid arthritis (RA). Researchers have also identified specific genes associated with resistance to most available drug therapies, commonly referred to as refractory diseases, that may hold the key to developing effective new drugs to help these people.
Although many advances have been made in recent decades in the treatment of arthritis, a significant number of patients (about 40%) do not respond to specific drug treatments, and 5-20% of people with arthritis disease are resistant to all current forms of arthritis. medication.
The researchers conducted a biopsy-based clinical trial, involving 164 arthritis patients, in which their responses to rituximab or tocilizumab – two drugs commonly used to treat rheumatoid arthritis – were tested. The results of the original trial published in The Lancet in 2021 demonstrated that in patients with a low molecular synovial B-cell signature, only 12% responded to a B-cell targeting drug (rituximab), while 50% responded to an alternative drug (tocilizumab). When patients had high levels of this genetic signature, the two drugs were similarly effective.
In the first study of its kind, funded by the Efficacy and Mechanism Evaluation (EME) program, a partnership between the MRC and NIHR, the Queen Mary team also looked at cases where patients did not respond to treatment with any of the drugs and discovered that there were 1,277 genes unique to them.
Based on this, the researchers applied a data analysis technique called machine learning models to develop computer algorithms that could predict drug response in individual patients. Machine learning algorithms, which included genetic profiling from biopsies, were significantly better at predicting which treatment would work best compared to a model that only used tissue pathology or clinical factors.
The study strongly supports the need to perform genetic profiling of arthritic joint biopsies before prescribing expensive biological targeted therapies. It could save the NHS and society time and money and help avoid the potential unwanted side effects, joint damage and worse outcomes that are common in patients. As well as influencing the prescription of treatment, such tests could also shed light on people who may not respond to any of the drugs currently on the market, highlighting the need to develop alternative drugs.
Integrating molecular information before prescribing arthritis treatments to patients could forever change the way we treat the disease. Patients would benefit from a personalized approach that has a much greater chance of success, rather than the trial-and-error prescribing of drugs that is currently the norm.
These results are incredibly exciting to demonstrate the potential at hand, however, the field is still in its infancy and further confirmatory studies will be needed to fully realize the promise of precision medicine in RA.
The results are also important in finding solutions for people who unfortunately do not have treatment that currently helps them. Knowing which specific molecular profiles impact this and which pathways continue to drive disease activity in these patients can help develop new drugs to provide better outcomes and much-needed relief from pain and suffering.
Professor Costantino Pitzalis, Versus Arthritis Professor of Rheumatology at Queen Mary University of London
Incorporating these signatures into future diagnostic tests will be a necessary step in translating these findings into routine clinical care.
Queen Mary University of London
Rivellese, F. et al. (2022) Rituximab versus tocilizumab in rheumatoid arthritis: biomarker analysis based on synovial biopsy from the randomized phase 4 R4RA trial. natural medicine. doi.org/10.1038/s41591-022-01789-0.