Methotrexate an Old Drug with New Tricks
Abstract
:1. Introduction
2. History
3. Pharmacokinetics of MTX
4. MTX Therapeutic Mechanisms of Action in Inflammatory Settings
4.1. Folate Antagonism
4.2. Effects on Extracellular Adenosine Accumulation
4.3. Effects on Polyamine Production
4.4. Generation of Reactive Oxygen Species
4.5. Effects on Cytokine Production
4.6. Effects on Matrix Metalloproteinases
4.7. Effects on Prostaglandin Production
4.8. MTX Inhibits NF-κB Activity
4.9. MTX is a JAK/STAT Pathway Inhibitor
4.10. MTX Inhibits Proinflammatory HMGBI Alarmin Effects
5. MTX Adverse Effects Mechanisms of Action
6. MTX Response Variability
7. MTX and Chronic Viral Arthritis
8. Conclusions and Perspectives
Conflicts of Interest
References
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Organ System | MTX Related Adverse Events | Toxic Mechanism of Action |
---|---|---|
Gastrointestinal | Nausea; Vomiting; Diarrhea; Mucositis and stomatitis | Gastrointestinal toxicities and bone marrow suppression seem to be directly related to folate antagonism, because these tissues have high cell turnover with a high requirement for purines, thymidine, and pyrimidine [37,143,144]. Supplementation of folic or folinic acid may diminish toxicity. Gastrointestinal symptoms of nausea and diarrhea may be more frequent with oral MTX [145]. Switching from oral to parental administration was shown to significantly decrease the frequency of adverse gastrointestinal events in patients with RA [146,147], suggesting that other mechanisms may account for MTX induced gastrointestinal toxicity. The pathogenic mechanism underlying gastrointestinal side effects may also be related to the change of plasma homocysteine [148]. |
Hematological | Anaemia; Leucopenia; Thrombopenia; Pancytopenia | Recently, MTX-induced thrombocytopenia was shown to be mediated by MTX-induced activation of platelet apoptosis via JNK and oxidative stress [149]. |
Hepatic | Elevated liver enzymes | Long-term MTX administration can cause accumulation of MTX polyglutamates in the liver and decreased folate levels. The depletion of hepatic folate stores by accumulated MTX poly glutamates is one possible toxic effect of MTX on the liver [150]. Folate supplementation has been associated with a reduced incidence of elevated transaminases induced by MTX treatment [15]. |
Steatosis, fibrosis, cirrhosis | MTX-related hepatic fibrosis may be mediated through an adenosine pathway. MTX was shown to enhance adenosine release from cultured hepatoma (HepG2) cells. Adenosine A2A receptor occupancy stimulates collagen production by hepatic stellate cell lines [151,152]. Unlike wild-type mice, mice deficient for the adenosine A2A receptor or treated with an adenosine A2A receptor antagonist (ZM241385) were protected from developing liver fibrosis when challenged by hepatotoxin (carbon tetrachloride or thiocetamide) [151]. MTX-related liver fibrosis may also be mediated by its capacity to interfere with the generation of methionine from homocysteine. Excess of homocysteine induces endoplasmic reticulum stress promoting fat accumulation in the liver. Homocysteine can also activate hepatic stellate cells and proinflammatory cytokines, leading to liver fibrosis [153,154]. MTX-induced hepatic damage may be related to the generation of reactive oxygen species (ROS). MTX was shown to cause oxidative tissue damage by increasing lipid peroxidation in the liver tissue and decreasing the level of antioxidant enzymes in rats [155]. | |
Pulmonary | Interstitial pneumonitis; Pneumocystis carinii pneumonia; Pulmonary fibrosis | Pulmonary toxicity has been shown to occur at both high- and low-dose MTX treatment, suggesting an idiosyncratic reaction not linked to folate antagonism [49]. Several mechanisms for the pathogenesis of MTX-induced pneumonitis have been suggested including hypersensitivity, direct drug toxicity to the lung tissue, immunosuppression or altered cytokine expression contributing to the pulmonary inflammatory response and tissue damage [156]. Typical bronchoalveolar lavage and histological findings support the concept that MTX-induced pneumonitis represents a hypersensitivity reaction [157,158,159]. MTX also induces injury to alveolar epithelial walls and pulmonary fibrosis, suggesting a direct drug toxicity route [160]. MTX pulmonary toxicity may be mediated by mitogen-activated protein kinase (MAPK) pathways activation and cytokine release [156]. MTX can compromise the immune response and increase the risk for opportunistic infections due to Pneumocystis carinii [161]. |
Renal | A decrease in glomerular filtration rate; Renal insufficiency (only in pre-existing, severely impaired renal function) | In contrast to high-dose MTX, which can lead to direct tubulus toxicity and subsequent renal failure, renal toxicities induced by low-dose MTX are rare. Low dose MTX has been associated with decrease in glomerular filtration rate (GFR) [162,163,164]. MTX and its major metabolite 7-OH-MTX are relatively insoluble in acid urine and may act as a direct toxin on the tubular epithelium, or precipitate within the tubular lumen, which can lead to intratubular obstruction resulting in a decrease in GFR (particularly at high doses) [49,165]. Evidence for a direct toxic effect of MTX on renal tubular cells has been demonstrated [166]; Low doses MTX can induce cell swelling and necrosis in renal tubular cells, which may lead to permanent tubular damage [166]. MTX associated renal toxicity may be explained by an increase in plasma adenosine concentration in extracellular fluid and subsequent activation of A1 receptors in renal tissue, reducing renal blood flow and salt and water excretion [167]. Long duration of low dose MTX administration caused severe kidney injury and renal MTX accumulation in a rat model. 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), which are reliable oxidative stress markers, were significantly increased in Long-MTX treated rats suggesting that MTX-induced kidney injury may be mediated through an increase in oxidative stress [168]. |
Dermatologic | Nodulosis (rare); Alopecia; Rash; Anaphylactic reactions | MTX-induced nodulosis may be mediated by adenosine through the adenosine A1 receptor [169]. MTX was shown to induce the generation of multinucleated giant cells, as does adenosine A1 receptor occupancy. This effect of MTX was reversed by a specific adenosine A1 receptor antagonist. Alopecia related to MTX treatment seems to be related to folate antagonism. In low dose MTX treatment, alopecia is rare and generally resolves several months after discontinuation [17,170]. |
Central nervous system (CNS) | Lethargy and fatigue; Headache, vertigo (less frequent) | Neurotoxicity of MTX may be related to MTX induced adenosine release and accumulation in the CNS. By acting at the A1 receptor on the perifornical lateral hypothalamus, adenosine may regulate wakefulness and somnolence and so potentially explaining asthenia and sleepiness experienced by some patients after MTX intake [171,172]. Other possible mechanisms of MTX-induced neurotoxicity are increased homocysteine levels and their excitatory amino acid neurotransmitter metabolites as homocysteic acid and cysteinesulfinic acid [173] and impairment of biopterin regerenating system in the brain, resulting in a reduced monoamine neurotransmitters availability [174]. |
Urogenital | Teratogenecity; oligospermia; gynecomastia (rare) | Use of MTX should be avoided before or during pregnancy because of its documented embryotoxicity and teratogenicity [175]. |
Musculoskeletal | Osteopathy; Osteoporosis | The effect of low dose MTX on bone was described in rats. Prolonged administration of low dose MTX in rats caused significant osteopenia with reduced osteoblast activity and increased osteoclast recruitment, which results in increased bone resorption [176]. However, no detrimental impact of MTX on the skeleton has been reported in patients treated with low dose MTX. MTX seems to have no clinically significant effect on bone mineral density (BMD) or on the osteoblast lineage [177,178]. |
Immunologic | Opportunistic infections | There is a belief amongst rheumatologists that MTX, as an immunosuppressant drug, is asssociated with the development of opportunistic infections. Weekly low-doses MTX can affect T cell activity [58], and cases of Pneumocystis pneumonia, nocardiosis, aspergillum, cryptococcosis, herpes zoster, herpes simplex and listeria-meningitis have been reported [170,179]. Despite some studies suggesting an increased risk of infection with MTX [180,181], several other studies have found that low-dose MTX does not appear to significantly increase the risk of infections in RA patients [182,183,184,185]. This risk appears to be associated with disease activity, comorbidities (diabetes, alcoholism) and the use of glucocorticoids, but not directly with MTX treatment [182]. It is well recognized that RA patients have significant increased risk of infection possibly due to chronic immune activation and inflammation which may impair immune function [185]. An increased risk of infection associated with MTX is possibly offset by the improvement of the immunological function secondary to the control of inflammation [185]. |
Others | Lymphoproliferative disorders | Lymphoproliferative disorders occur with increased frequency in RA patients compared to the general population, especially in the setting of high disease activity [170,184,186,187]. A relationship between MTX treatment and the occurrence of lymphoproliferative disorders in RA has been suggested. Long-term MTX therapy was associated with Epstein–Barr virus-related lymphoproliferative disorders with spontaneous regression after MTX withdrawal [188]. Despite its association with Epstein–Barr-associated lymphomas, there is currently no clear evidence that MTX provides additional risk of lymphoproliferative disorders to that of RA itself [184,189]. |
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Bedoui, Y.; Guillot, X.; Sélambarom, J.; Guiraud, P.; Giry, C.; Jaffar-Bandjee, M.C.; Ralandison, S.; Gasque, P. Methotrexate an Old Drug with New Tricks. Int. J. Mol. Sci. 2019, 20, 5023. https://doi.org/10.3390/ijms20205023
Bedoui Y, Guillot X, Sélambarom J, Guiraud P, Giry C, Jaffar-Bandjee MC, Ralandison S, Gasque P. Methotrexate an Old Drug with New Tricks. International Journal of Molecular Sciences. 2019; 20(20):5023. https://doi.org/10.3390/ijms20205023
Chicago/Turabian StyleBedoui, Yosra, Xavier Guillot, Jimmy Sélambarom, Pascale Guiraud, Claude Giry, Marie Christine Jaffar-Bandjee, Stéphane Ralandison, and Philippe Gasque. 2019. "Methotrexate an Old Drug with New Tricks" International Journal of Molecular Sciences 20, no. 20: 5023. https://doi.org/10.3390/ijms20205023