Iguratimod as a New Drug for Rheumatoid Arthritis: Current Landscape

Xie, Sisi; Li, Shu; Tian, Jing; Li, Fen

doi:10.3389/fphar.2020.00073

Cited by 51 publications

(35 citation statements)

References 45 publications

(46 reference statements)

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“…Iguratimod, also named T-614 (3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4one), has been considered to be a novel immunomodulator and widely used to treat RA by rheumatologists in China and Japan [39][40][41]. In present study, we observed the effect of iguratimod on RIF in LN.…”

Section: Discussionmentioning

confidence: 50%

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

Xue

et al. 2020

Preprint

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Background: Renal interstitial fibrosis (RIF) is one of the main poor prognostic factors of lupus nephritis (LN). Here, we tested whether iguratimod could inhibit RIF in LN. Methods: MRL/lpr mice, an animal model of lupus, were treated with iguratimod or vehicle solution. Pathological changes of kidney was evaluated blindly by the same pathologist. Renal type I collagen (COL-I), IgG, E-cadherin, fibroblast-specific protein 1 (FSP-1) were detected by immunofluorescence, immunohistochemical staining or quantitative real-time PCR. After treated with transforming growth factor β1 (TGF-β1) and iguratimod, E-cadherin, fibronectin, Smad2/3, p38 MAPK, p-Smad2/3 and p-p38 MAPK in HK2 cells were measured by western blotting, quantitative real-time PCR or immunofluorescence. Results: In MRL/lpr mice, iguratimod eased the renal interstitial deposition of collagen fibers, further confirmed by decreased expression of COL-I after iguratimod treatment. Moreover, upstream pathological processes of RIF, including IgG deposition along the tubular basement membrane, infiltration of inflammatory cells into renal interstitium and tubular injury, were also prevented effectively by iguratimod treatment. Furthermore, iguratimod suppressed the expression of FSP-1 and raised the expression of E-cadherin in renal tubular epithelial cells, suggesting that iguratimod reversed the process of tubular epithelial-to-mesenchymal transition (EMT). In HK2 cells induced by TGF-β1, co-treatment with iguratimod not only reversed cellular morphologic change, but also prevented down-regulation of E-cadherin and up-regulation of fibronectin. Finally, iguratimod blocked TGF-β1-induced phosphorylation of Smad2/3 and p38 MAPK in HK2 cells. Conclusions: Our results suggest that iguratimod shows an inhibitory effect on the progress of RIF in vivo and in vitro, so iguratimod may be a potential drug for the treatment of RIF in LN.

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Section: Discussionmentioning

confidence: 50%

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

Xue

et al. 2020

Preprint

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“…It could alleviate joint damage and immune abnormalities in chronic arthritis and autoimmune diseases; inhibit inflammatory cytokines (IL-1, IL-6, IL-8, and TNF) production; block the IL-17 signalling pathway and inhibit lymphocyte proliferation and immunoglobulin production ( 10 ). In terms of clinical manifestations, Iguratimod could significantly reduce the levels of ESR, C-reactive protein, immunoglobulin, IL-1, IL-6, TNF and other inflammation diagnostic parameters ( 7 , 11 ). Moreover, in clinical studies, the safety and effectiveness of Iguratimod have been verified in patients with rheumatoid arthritis ( 12 – 14 ).…”

Section: Discussionmentioning

confidence: 99%

“…Iguratimod, also known as T-614, is a new type of small molecule compound with anti-inflammatory and immunomodulatory effects; It was listed in China (2011) and Japan (2012) for the treatment of rheumatoid arthritis; its safety and effectiveness have been verified in patients with rheumatoid arthritis ( 6 ). As Iguratimod could inhibit the production of inflammatory cytokines, such as IL-1 and TNF; block the IL-17 signalling pathway and inhibit cyclooxygenase ( 7 ), Iguratimod may be effective in the treatment of SPA/AS. However, no rigorous clinical research exists to confirm this speculation.…”

Section: Introductionmentioning

confidence: 99%

Randomised, Double-Blind, Placebo-Controlled Study of Iguratimod in the Treatment of Active Spondyloarthritis

Zhang

et al. 2021

Front. Med.

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Background and Purpose: The effect of Iguratimod in the treatment of rheumatoid arthritis was confirmed in past studies. In terms of the mechanism of the effect and clinical application experience, Iguratimod has a potential value in the treatment of spondyloarthritis (SpA). This study evaluated the efficacy and safety of Iguratimod on active SpA.Methods: Subjects with active SpA were enrolled and randomly divided into two groups at a ratio of 1:2 (placebo vs. Iguratimod). On the basis of non-steroidal anti-inflammatory drugs, combined treatment with Iguratimod or placebo, followed by follow-up every 4 weeks for 24 weeks. The primary efficacy endpoint was to evaluate the alleviation rate of ASAS20; the important improvement of ASDAS and the efficacy of spinal mobility, physical function and quality of life at the 24th week.Results: A total of 48 cases in the Iguratimod group and 25 cases in the placebo group were included in the final analysis. On the 24th week, the percentage of responders to ASAS20 (80 vs. 44%) and ASAS40 (56 vs. 20%) treated with Iguratimod were significantly higher than that in the placebo group (P < 0.05). Twelve cases had gastrointestinal discomfort, of which eight were in the Iguratimod group (16.7%, one case withdrew from the study due to diarrhoea) and four were in the placebo group (16.0%). No significant difference was found between the two groups (P < 0.05). Three cases of elevated transaminase were observed in the Iguratimod group and none in the placebo group, with no significant difference (P < 0.05).Conclusion: Iguratimod could significantly reduce the symptoms and signs of patients with active SpA. It could improve the physical function and quality of life of these patients and the overall safety and tolerance are good.

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“…Iguratimod, a disease modified anti-rheumatic drug (DMARD) is known to inhibit the production of immunoglobulins and cytokines and regulate T lymphocyte subsets at the synovial joints [ 197 ]. Iguratimod was also reported [ 198 ] to inhibit nuclear translocation of NF-κB p65.…”

Section: Molecules That Can or May Be Repurposed As Nf-κb Pathway mentioning

confidence: 99%

Small Molecule NF-κB Pathway Inhibitors in Clinic

Ramadass

Vaiyapuri

Tergaonkar

2020

IJMS

148

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Nuclear factor kappa B (NF-κB) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-κB pathways for modulating expression of those genes and the diseases mediated by them. In-spite of the critical, but often promiscuous role played by this pathway and the inhibition causing adverse drug reaction, currently many biologics, macromolecules, and small molecules that modulate this pathway are in the market or in clinical trials. Furthermore, many marketed drugs that were later found to also have NF-κB targeting activity were repurposed for new therapeutic interventions. Despite the rising importance of biologics in drug discovery, small molecules got around 76% of US-FDA (Food and Drug Administration-US) approval in the last decade. This encouraged us to review information regarding clinically relevant small molecule inhibitors of the NF-κB pathway from cell surface receptor stimulation to nuclear signaling. We have also highlighted the underexplored targets in this pathway that have potential to succeed in clinic.

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Iguratimod as a New Drug for Rheumatoid Arthritis: Current Landscape

Cited by 51 publications

References 45 publications

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

Randomised, Double-Blind, Placebo-Controlled Study of Iguratimod in the Treatment of Active Spondyloarthritis

Small Molecule NF-κB Pathway Inhibitors in Clinic

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