Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study

Bruyn, G. A. W.; Tate, Guillermo; Caeiro, Francisco; Maldonado‐Cocco, José A.; Westhovens, René; Tannenbaum, H; Bell, Mary; Førre, Ø.; Bjørneboe, Olav; Tak, Paul P.; Abeywickrama, Kamal; Bernhardt, Peter; Riel, P.L.C. van

doi:10.1136/ard.2007.078808

Cited by 92 publications

(68 citation statements)

References 23 publications

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“…Interestingly, rapamycin was shown to reduce pannus formation, and to reduce cartilage erosion and joint damage in adjuvant-induced arthritis in rats (40) through mechanisms that were as yet unknown. In addition, everolimus, another mTOR-specific inhibitor, significantly reduced disease activity (based on ACR20) in a short 12-week, double-blind and placebo-controlled study in RA patients (41). A recent study also demonstrated that FLS from arthritic joints can spread disease to unaffected joints and there invade and erode cartilage (42).…”

Section: Discussionmentioning

confidence: 99%

mTOR Regulates the Invasive Properties of Synovial Fibroblasts in Rheumatoid Arthritis

Laragione

Gulko

2010

Mol Med

100

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The invasive properties of fibroblast-like synoviocytes (FLS) correlate with radiographic and histologic damage in rheumatoid arthritis (RA) and pristane-induced arthritis (PIA). We previously determined that highly invasive FLS obtained from PIA-susceptible DA (blood type D, Agouti) rats have increased expression of genes associated with invasive cancers, including Villin-2/ezrin. Villin-2/ezrin mediates invasion via mTOR. In the present study we used the mTOR inhibitor rapamycin to assess the role of the ezrinmTOR pathway on the invasive properties of FLS. FLS were isolated from synovial tissues from arthritic DA rats, and from RA patients. FLS were treated with rapamycin or dimethyl sulfoxide (DMSO) for 24 h and then studied in a Matrigel-invasion assay. Supernatants were assayed for matrix metalloproteinase (MMP) activity, and cell lysates were used for quantification of mTOR, p70S6K1, 4EBP1 and FAK, as well as their respective phosphorylated subsets. Actin filament and FAK localization were determined by immunofluorescence. Rapamycin decreased FLS invasion in DA and RA tissues by 93% and 82%, respectively. Rapamycin treatment reduced the phosphorylation of mTOR and its substrates, p70S6K1 and 4EBP1, confirming mTOR inhibition. In conclusion, rapamycin prevented actin reorganization in both DA and RA FLS, and inhibited the directional formation of lamellipodia. Phosphorylation of the lamellipodia marker FAK was also reduced by rapamycin. MMPs were not significantly affected by rapamycin. Rapamycin significantly reduced RA and DA rat FLS invasion via the suppression of the mTOR signaling pathway. This discovery suggests that rapamycin could have a role in RA therapy aimed at reducing the articular damage and erosive changes mediated by FLS.

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Section: Discussionmentioning

confidence: 99%

mTOR Regulates the Invasive Properties of Synovial Fibroblasts in Rheumatoid Arthritis

Laragione

Gulko

2010

Mol Med

100

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“…Although using a transient knock-in MVK genetic model, our study suggests a tight link between impairment in autophagic flux and mevalonate pathway dysfunction, followed by cell death [34]. A recent work in patients with rheumatoid arthritis demonstrated that increasing autophagic flux could be beneficial toward lowering markers of inflammation [35] and a previous study also demonstrated that everolimus (inhibitor of mTor pathway) treatment, concomitant with methotrexate, could improve symptoms of patients suffering of rheumatoid arthritis [36]. Van der Burgh and co-authors have previously shown that treatment of MKD patients’ monocyte with rampamycin, inhibitor of mTor pathway, slightly diminish IL-1β secretion after LPS challenge, although not to levels similar to the control [37].…”

Section: Discussionmentioning

confidence: 99%

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

Tricarico

Romeo

Gratton

et al. 2017

Cell Physiol Biochem

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Background/Aims: Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in mevalonate kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines. Methods: SH-SY5Y cells were transiently transfected, with the pCMV-6 plasmid containing MVK wild type and the two mutated sequences. Protein prenylation levels were evaluated using GFP-RhoA-F to assess farnesylation, and GFP-RhoA to evaluate geranylgeranylation; autophagy was measured by evaluating LC3 and p62 protein levels, while Annexin V-FITC and Propidium Iodide staining allowed apoptosis detection. Results: MVK mutants’ over-expression causes decreased levels of farnesylation and geranylgeranylation, and also increased LC3 lipidation in SH-SY5Y, with concomitant p62 accumulation. Treatment with bafilomycin A1 (an inhibitor of vacuolar H+-ATPase, a late autophagy inhibitor) further increase LC3-II and p62 levels, suggesting that degradation of autophagolysosome could be impaired. SH-SY5Y, with both MVK mutants, showed apoptosis increase; the presence of N301T associated with augmented cell death. Conclusions: We hypothesize that mevalonate pathway impairment causes alteration of farnesylation and geranylgeranylation proteins and alteration of the autophagic flux; these changes can induce apoptosis, possibly more relevant in the presence of N301T mutation.

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“…Everolimus-eluting coronary stents and oral everolimus have a long history of clinical utility in solidorgan transplantation to prevent acute and chronic rejections (27). Moreover, everolimus was found to alleviate RA symptoms in patients who had an inadequate response to MTX (28) and to induce disease inactivity in severe uveitis patients who became nonresponsive to cyclosporine A (29). Structurally, everolimus is slightly more polar than rapamycin, but it still exhibits low water solubility (~1-10 μmol/L) and poor/variable oral bioavailability (30).…”

Section: Introductionmentioning

confidence: 99%

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

Parker

Kleindl

et al. 2015

Mol Med

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Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study

Abstract: The study indicates that everolimus plus MTX provides clinical benefit with an acceptable safety and tolerability profile. It may offer a new treatment option in RA patients with inadequate response to MTX.

Cited by 92 publications

References 23 publications

mTOR Regulates the Invasive Properties of Synovial Fibroblasts in Rheumatoid Arthritis

mTOR Regulates the Invasive Properties of Synovial Fibroblasts in Rheumatoid Arthritis

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

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