A Randomized, Double-Blind, Parallel, Single-Site Pilot Trial to Compare Two Different Starting Doses of Methotrexate in Methotrexate-Naïve Adult Patients with Rheumatoid Arthritis

Hobl, Eva‐Luise; Mader, Robert M.; Jilma, Bernd; Duhm, Bernhard; Mustak, Monika; Bröll, H; Högger, Petra; Erlacher, L

doi:10.1016/j.clinthera.2012.03.059

Cited by 20 publications

(21 citation statements)

References 13 publications

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“…When methotrexate is given intravenously in chemotherapy regimes, plasma concentrations peak at around 50μM [ 33 ]. Following oral administration of low- dose methotrexate for the treatment of rheumatoid arthritis the peak plasma concentration of methotrexate is around one hundred times lower at 0.4–0.8μM [ 34 ]. Although care must be taken when comparing ex vivo and in vivo levels, we observe strong suppression of STAT5 phosphorylation at 1μM drug concentrations, levels approximately equivalent to those seen in patients taking low-dose oral methotrexate.…”

Section: Resultsmentioning

confidence: 99%

Methotrexate Is a JAK/STAT Pathway Inhibitor

et al. 2015

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BackgroundThe JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains.Methods & FindingsWe used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin.ConclusionsAminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential.

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Section: Resultsmentioning

confidence: 99%

Methotrexate Is a JAK/STAT Pathway Inhibitor

et al. 2015

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“…First, there is no compelling evidence that the adverse events associated with oral MTX are linked to dosage 49,51,77. Second, there is a relationship, albeit weak, between oral MTX dosage and clinical response.…”

Section: Pathways For Optimizing Mtx Treatmentmentioning

confidence: 99%

Recommendations for optimizing methotrexate treatment for patients with rheumatoid arthritis

Bello

Perkins²,

Jay

et al. 2017

OARRR

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Methotrexate (MTX) remains the cornerstone therapy for patients with rheumatoid arthritis (RA), with well-established safety and efficacy profiles and support in international guidelines. Clinical and radiologic results indicate benefits of MTX monotherapy and combination with other agents, yet patients may not receive optimal dosing, duration, or route of administration to maximize their response to this drug. This review highlights best practices for MTX use in RA patients. First, to improve the response to oral MTX, a high initial dose should be administered followed by rapid titration. Importantly, this approach does not appear to compromise safety or tolerability for patients. Treatment with oral MTX, with appropriate dose titration, then should be continued for at least 6 months (as long as the patient experiences some response to treatment within 3 months) to achieve an accurate assessment of treatment efficacy. If oral MTX treatment fails due to intolerability or inadequate response, the patient may be “rescued” by switching to subcutaneous delivery of MTX. Consideration should also be given to starting with subcutaneous MTX given its favorable bioavailability and pharmacodynamic profile over oral delivery. Either initiation of subcutaneous MTX therapy or switching from oral to subcutaneous administration improves persistence with treatment. Upon transition from oral to subcutaneous delivery, MTX dosage should be maintained, rather than increased, and titration should be performed as needed. Similarly, if another RA treatment is necessary to control the disease, the MTX dosage and route of administration should be maintained, with titration as needed.

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“…The literature search related to MTX toxicities identified 15 case reports and case series. Adverse events encountered with MTX therapy included elevated liver enzyme at least one time above upper limit of normal (ULN) (2.5–42%) and two times above ULN (3–20%), leucopenia (11%), thrombocytopenia (0.9–2%), pancytopenia (1.4–2.1%), elevated blood urea nitrogen (BUN) and creatinine (2–4%), and abnormal chest radiograph (0.9–3.4%) …”

Section: Recommendationsmentioning

confidence: 99%