Methotrexate an Old Drug with New Tricks

Abstract

Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses—including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus—have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients’ immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.

The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19

“…MTX thus limits the viability of highly replicating cells. Moreover, MTX-induced reactive oxygen species generation modulates different cell functions, such as suppression of cytokine production and cell proliferation decreasing TNF-α, IL-1β, and adhesion molecules (E-selectin and VCAM-1) [183].…”

The relationship of the immune response mediator genes’ polymorphic variants with the methotrexate efficacy in juvenile idiopathic arthritis

“…It has been shown that the methotrexate treatment reduces the TNFα, IL1β, and IL6 production and increases the IL10 expression in the synovial tissue of rheumatoid arthritis patients [12]. At the same time, Pawlik et al (2006) established the interrelation of a number of the cytokine genes polymorphic loci variants with the level of phytohemagglutinin-stimulated secretion of the Table 3.…”

“…An important role in the regulation of inflammation, cell survival and proliferation is played by NFκB, a family of transcription factors (RelA (p65), cRel, RelB, NFκB1 (p50 and its precursor p105), and NFκB2 (p52 and its precursor p100)), which functions as various heteroor homodimers [12,36,37]. One of the key members of this family is p50 encoded by the NFKB1 gene.…”

“…The antiinflammatory effects of methotrexate in JIA may be mediated by addition to folate antagonism mechanisms, such as adenosine release, inhibition of spermine/ spermidine production and/or alteration of cellular redox state [9]. It has been shown that methotrexate may directly or indirectly affect the expression and/or secretion of the various immune response mediators involved in the pathogenesis of JIA and other autoimmune diseases, including cytokines (such as tumour necrosis factor alpha (TNFα), interleukin 1 (IL1), IL2, IL6, IL10), nuclear factor kappa B (NFκB), cytotoxic T-lymphocyte associated protein 4 (CTLA4) and others [10][11][12][13].…”

Cardiovascular and Metabolic Protection by Vitamin E: A Matter of Treatment Strategy?

“…In contrast to the CANTOS trial, the clinical Cardiovascular Inflammation Reduction Trial (CIRT) targeted a broader range of pro-inflammatory processes using the anti-rheumatic compound methotrexate, which is known to reduce cytokine secretion and the generation of ROS [ 228 ]. After the primary prevention of rheumatoid arthritis, off-target effects such as a reduction in cardiovascular events were detected with the methotrexate treatment using the normal dosing range of 5–30 mg per week for rheumatoid arthritis [ 229 ].…”