Pharmacomicrobiology of Methotrexate in Rheumatoid Arthritis: Gut Microbiome as Predictor of Therapeutic Response

Abstract

Rheumatoid arthritis (RA) is a disabling autoimmune disease with invasive arthritis as the main manifestation and synovitis as the basic pathological change, which can cause progressive destruction of articular cartilage and bone, ultimately leading to joint deformity and loss of function. Since its introduction in the 1980s and its widespread use in the treatment of RA, low-dose methotrexate (MTX) therapy has dramatically changed the course and outcome of RA treatment. The clinical use of this drug will be more rational with a better understanding of the pharmacology, anti-inflammatory mechanisms of action and adverse reaction about it. At present, the current clinical status of newly diagnosed RA is that MTX is initiated first regardless of the patients’ suitability. But up to 50% of patients could not reach adequate clinical efficacy or have severe adverse events. Prior to drug initiation, a prognostic tool for treatment response is lacking, which is thought to be the most important cause of the situation. A growing body of studies have shown that differences in microbial metagenomes (including bacterial strains, genes, enzymes, proteins and/or metabolites) in the gastrointestinal tract of RA patients may at least partially determine their bioavailability and/or subsequent response to MTX. Based on this, some researchers established a random forest model to predict whether different RA patients (with different gut microbiome) would respond to MTX. Of course, MTX, in turn, alters the gut microbiome in a dose-dependent manner. The interaction between drugs and microorganisms is called pharmacomicrobiology. Then, the concept of precision medicine has been raised. In this view, we summarize the characteristics and anti-inflammatory mechanisms of MTX and highlight the interaction between gut microbiome and MTX aiming to find the optimal treatment for patients according to individual differences and discuss the application and prospect of precision medicine.

Combination of Methotrexate and Leflunomide Is Efficient and Safe for 60 Patients with Rheumatoid Arthritis

“…Methotrexate (MTX) was originally designed in the 1940s as a folate antagonist for treatment of various cancers [ 6 ]. In the management of early and established RA, MTX is recommended as a first-line drug by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) [ 7 ]. However, it has no significant effect and is accompanied by different side effects [ 8 ].…”

Gut microbiota and rheumatoid arthritis: From pathogenesis to novel therapeutic opportunities

“…DMARDs may indirectly affect and remodel the structure and function of gut microbiota to regulate systemic immunity. Studies have demonstrated that microbial differences in the gastrointestinal tract of RA patients may partially determine the bioavailability and subsequent clinical outcome of methotrexate ( 63 , 64 ). In turn, methotrexate treatment was shown to partially restore normal gut microbiota composition in RA patients ( 16 , 65 ).…”

Microbiome Changes in Connective Tissue Diseases and Vasculitis: Focus on Metabolism and Inflammation

“…Methotrexate may also influence the community of intestinal microorganisms, regulating their diversity and function. It inhibits the growth of intestinal bacterial strains in a dose-dependent manner, which results in reduced stimulation of immune system activation and decreased tolerance to Treg cell induction [ 101 ]. In addition, the use of hydroxychloroquine in SLE appears to reduce the abundance of Enterobacteriaceae [ 102 ].…”