Molecular therapeutics. Methotrexate and its mechanism of action

Cronstein, Bruce N.

doi:10.1002/art.1780391203

Cited by 240 publications

(143 citation statements)

References 93 publications

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“…53 However, when PBMC from RA patients were stimulated with phytohemagglutinin and treated with MTX, an increase in Th2 cytokines and a decrease in Th1 cytokines was observed. 16 In RA patients treated with MTX, a significant decrease in IL-6, IFN-g 54 and TNF 54,55 levels has also been seen. The same effect was obtained in the cases of IL-6 and TNF in patients treated with a combination of MTX with either etanercept 43 or abatacept.…”

Section: Discussionmentioning

confidence: 99%

Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

Aira

Hernández

Prada³

et al. 2015

mAbs

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(2016) Immunological evaluation of rheumatoid arthritis patients treated with itolizumab, mAbs, 8:1, 187-195, DOI: 10.1080/19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 Rheumatoid arthritis is an autoimmune disease characterized by joint inflammation that affects approximately 1% of the general population. Itolizumab, a monoclonal antibody specific for the human CD6 molecule mainly expressed on T lymphocytes, has been shown to inhibit proliferation of T cells and proinflammatory cytokine production in psoriasis patients. We have now assessed the immunological effect of itolizumab in combination with methotrexate in rheumatoid arthritis by analyzing clinical samples taken from 30 patients enrolled in a clinical trial. T and B cell subpopulations were measured at different time points of the study. Plasma cytokine levels and anti-idiotypic antibody response to itolizumab were also evaluated. The combined treatment of itolizumab and methotrexate led to a reduction in the frequency of T cell subpopulations, and plasma levels of proinflammatory cytokines showed a significant decrease up to at least 12 weeks after treatment ended. No anti-idiotypic antibody response was detected. These results support the relevance of the CD6 molecule as a therapeutic target for the treatment of this disease.

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Section: Discussionmentioning

confidence: 99%

Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

Aira

Hernández

Prada³

et al. 2015

mAbs

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“…Importantly, MTX also uses RFC for cellular uptake, with an affinity (K m ϭ 1-5 M) close to that of 5-methyltetrahydrofolate (29,32). Given their anionic nature, natural folates and MTX cannot traverse the plasma membrane; therefore, RFC-mediated cellular uptake should be regarded as the first critical step in any antiinflammatory/antiproliferative mode of action of MTX (33)(34)(35)(36). Consequently, diminished transport activity of RFC has been associated with loss of MTX efficacy and with folate deficiency (31,(37)(38)(39)(40).…”

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confidence: 99%

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Jansen¹,

Heijden²,

Oerlemans³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis. Conclusion. At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these diseasemodifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.

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“…Both act by suppressing cytokine production in patients with RA (11). Cyclosporin A (CSA) is also an effective DMARD in RA and has complex effects on T cell function, including inhibition of interleukin-2 release and subsequent activation of T cells (12).…”

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confidence: 99%

Treatment of poor-prognosis early rheumatoid arthritis: A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone

Proudman

Conaghan

Richardson

et al. 2000

Arthritis & Rheumatism

113

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Objective. To determine whether a regimen of methotrexate, cyclosporin A, and corticosteroids introduced at onset in poor-prognosis rheumatoid arthritis (RA) can produce a significant improvement in outcome compared with standard monotherapy with sulfasalazine (SSZ).Methods. Eighty-two consecutive patients presenting with new, untreated RA of less than 12 months' duration who fulfilled criteria for poor long-term outcome were randomized to receive either combination therapy (n ‫؍‬ 40) or SSZ alone (n ‫؍‬ 42). The primary outcome measures were remission and American College of Rheumatology (ACR) criteria for 20% improvement at 48 weeks.Results. After 48 weeks, the numbers of patients who met the ACR criteria for 20% improvement were not significantly different between the two groups (combination 58% versus SSZ 45%), and similar numbers of patients had persisting clinical remission (ϳ10% both groups). During the first 3 months, there were significantly greater reductions in parameters of disease activity in the combination group. By 24 weeks, the swollen and tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates had fallen significantly in both groups, with a greater improvement in the swollen and tender joint count in the combination group. At 48 weeks, the radiographic damage score had increased by a median of 1 (range 0-42.5) in the combination group and 1.25 (range 0-72.5) in the SSZ group (P ‫؍‬ 0.28; although there were significant differences in the scores for the right hand). There were significantly fewer withdrawals due to lack of efficacy in the combination group than in the SSZ group (1 of 40 versus 10 of 42; P ‫؍‬ 0.007). In the combination group, dose reduction was needed in 22.5% because of hypertension and in 22.5% because of elevated creatinine levels. Over 48 weeks, serum creatinine increased in both groups, but particularly in the combination arm.

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Molecular therapeutics. Methotrexate and its mechanism of action

Cited by 240 publications

References 93 publications

Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

Immunological evaluation of rheumatoid arthritis patients treated with itolizumab

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Treatment of poor-prognosis early rheumatoid arthritis: A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone

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