Researchers at UCSF have developed methods of treating Rheumatoid arthritis and for predicting the response of patients to methotrexate.
Rheumatoid arthritis (RA) is an autoimmune disease that leads to inflammation and destruction of joints, as well as other organs. Nearly all newly diagnosed RA patients are initiated on methotrexate (MTX); however, up to 50% of patients do not achieve a clinically adequate outcome. The major target of MTX, dihydrofolate reductase (DHFR), is conserved across all domains of life. In addition to mammalian DHFR, MTX can directly bind DHFR from multiple bacteria. The potential for MTX to act therapeutically by inhibiting gut microbiome remains unexplored, despite the broad impacts of the gut microbiome on immunity. Further, emerging evidence suggests the microbiome is associated with RA.
The inventors have developed prognostic tools and methods of treating inflammation in the gut and/or joints of a patient based on the susceptibility of the patient’s gut microbiome to methotrexate. They employ metagenomic sequencing methods and metabolomics analysis to evaluate the association between microbiome-driven MTX depletion and clinical response. They demonstrate MTX-induced changes in microbial community structure were associated with patient response. Their work provides biomarkers for accelerating the stable initiation of therapy and a first step toward determining which bacterial taxa contribute to, or interfere with, treatment outcomes.