The advances of methotrexate resistance in rheumatoid arthritis

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Inflammopharmacology

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The advances of methotrexate resistance in rheumatoid arthritis Jun Yu1   · Peng Zhou2 Received: 9 June 2020 / Accepted: 23 July 2020 © Springer Nature Switzerland AG 2020

Abstract Rheumatoid arthritis (RA) is a systemic autoimmune disease, which is characterized by a chronic fluctuating course and immune dysfunction, resulting in affecting the health and life quality of RA patients. Methotrexate (MTX), as the standard gold treatment of RA, has received more and more clinical applications and basic pharmacological research. In several observational studies, MTXR, and treatment responses in RA patients show that the ratio of MTXR and non- response is about 30%–50%, namely MTX resistance (MTXR). Extensive efforts have been made into the investigation of the mechanism and effective biomarkers in MTXR of RA. In this paper, we discuss the recent findings regarding the critical signaling pathways of MTXR in RA. Provide research targets and directions for a drug therapy that develop preventive strategies and effective treatments of MTXR. Keywords  Rheumatoid arthritis · Methotrexate resistance · Mechanism · Response

Introduction Rheumatoid arthritis (RA) is a systemic autoimmune disease, which is characterized by a chronic fluctuating course and immune dysfunction, resulting in progressive joint erosion, deformity, and disability. The prominent clinical manifestation of RA is multiple joints arthritis. The joints such as the hands, wrists, and feet are most commonly affected. Redness, swelling, heat, pain, and dysfunction appear early, and erosive deformities can perform at a later stage. It is a disease with a high disability rate (Ostrowska et al. 2018). The current clinical drugs used to treat RA include nonsteroidal anti-inflammatory drugs (NSAIDs), steroidal antiinflammatory drugs (SAIDs), and disease-modifying antirheumatic drugs (DMARDs). Still, the long-term application will cause various and even severe adverse reactions (Felson 2016).

* Peng Zhou [email protected] 1



The Fourth Affiliated Hospital of Anhui Medical University, Hefei 230012, China



School of Integrated Chinese and Western Medicine, Anhui Province Key Laboratory of Chinese Medicinal Formula, Anhui University of Chinese Medicine, Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei 230012, China

2

Methotrexate (MTX) is folic acid (folate) inhibitor that was first synthesized in the 1940s to treat childhood leukemia. It is extensively used in acute leukemia, breast cancer, and lung cancer. Research in the 1980s found that low-dose MTX can treat RA and has good therapeutic effects, and has gradually become a standard gold treatment for RA (Boerbooms et al. 1995). The American College of Rheumatology (ACR) in 2015, European League Against Rheumatism (EULAR) in 2019, and the Chinese Rheumatology Association in 2018 suggested that the patient is diagnosed with RA, MTX monotherapy is recommended. For patients with middle or high degree disease activity, MTX combination