Molecular mechanisms and clinical application of Iguratimod: A review

Jiang, Huihui; Gao, Hongbo; Wang, Qin; Wang, Miao; Wu, Bin

doi:10.1016/j.biopha.2019.109704

Cited by 46 publications

(36 citation statements)

References 53 publications

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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: 51%

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: 51%

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

Xue

et al. 2020

Preprint

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“…The superiority of IGU in improving eye dryness and mouth dryness might result from its inhibition of pro-inflammatory lymphocytes and immunoglobulin. IGU is generally considered as an anti-inflammatory and immunoregulatory drug that can improve symptoms and disease activities of patients with pSS by regulating the subpopulation of B cells, reducing the production of immunoglobulin, and inhibiting the proliferation of proinflammatory T cells and their influence on tissues (Jiang H. et al, 2020). BAFF (B cells activation factors), secreted by the secretion glands of pSS patients, binds to three different cell surface receptors: the BAFF receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI).…”

Section: Discussionmentioning

confidence: 99%

“…Iguratimod (IGU), a small-molecule compound that is being widely used in China and Japan, is a potential anti-rheumatic drug and is used for the treatment of several rheumatic diseases (Jiang H. et al, 2020). An advantage of IGU is its inhibition of the functions of B cells by reducing the production of immunoglobulin and various inflammatory cytokines, including interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF) (Xu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Effectiveness and Safety of Iguratimod in Treating Primary Sjögren’s Syndrome: A Systematic Review and Meta-Analysis

Wang

Riaz

et al. 2021

Front. Pharmacol.

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Objectives: We aimed to assess the effectiveness and safety of iguratimod (IGU) in treating primary Sjögren’s syndrome (pSS) by meta-analysis.Methods: Eight databases and two clinical trial websites were searched from conception to August 10, 2020, for relevant randomized controlled trials (RCTs) on outcomes of patients with pSS treated with IGU. Revman 5.4 was used for statistical analysis and creating plots.Results: A total of 1,384 patients with pSS from 19 RCTs were included in this meta-analysis. Pooled results demonstrated that patients treated with IGU + hydroxychloroquine (HCQ) + glucocorticoid (GC) showed significant differences in erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) level, platelet (PLT) count, immunoglobulin G (IgG) level, salivary flow rate, Schirmer’s test result, EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), and efficacy rate (p ≤ 0.01) compared to patients treated with HCQ + GC. Compared to treatment with HCQ and GC, co-administration of IGU with GC showed significant differences in ESR and RF level (p ≤ 0.01); however, no significant differences were noted in IgG level. Conversely, the IgG level showed a significant improvement in the IGU + HCQ + GC group compared to the HCQ + GC group. The results of safety analysis revealed that seven trials showed no significant differences in adverse events (AEs) between the IGU + HCQ + GC and HCQ + GC groups (p = 0.15). Although no severe AEs were noted, gastrointestinal discomfort was the most common AE in the IGU group. No significant differences in AEs were observed between the IGU + GC and HCQ + GC groups.Conclusion: IGU improved the clinical symptoms of patients with pSS, including inflammatory indicators (ESR, IgG, and RF levels), PLT count, secretion function of the salivary and lacrimal glands (salivary flow rate and Schirmer’s test result), and disease indexes (ESSDAI and ESSPRI), when co-administered with HCQ + GC therapy without increasing the risks of AEs. Therefore, IGU can be considered as an effective and safe drug for clinical therapy of pSS. Considering the limitations of the present trials, more long-term, multicenter, and high-quality RCTs are required to assess the effectiveness and safety of IGU for treating patients with pSS.

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“…IGU is widely used in the treatment of RA; both monotherapy and combination therapy suggest good efficacy and safety. In addition, the clinical studies suggest that IGU has a good effect on other rheumatic diseases, such as Sjögren’s syndrome, ankylosing spondylitis, and IgG4-related diseases [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of iguratimod and conventional cyclophosphamide with sequential azathioprine as treatment of active lupus nephritis: study protocol for a multi-center, randomized, controlled clinical trial (iGeLU study)

Yan

Kang

et al. 2021

Trials

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Background Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up. Methods/design This study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test. Discussion Most patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20–35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients. Trial registration ClinicalTrials.govNCT 02936375. Registered on October 18, 2016.

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Molecular mechanisms and clinical application of Iguratimod: A review

Cited by 46 publications

References 53 publications

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

Iguratimod Inhibits Renal Interstitial Fibrosis in Lupus Nephritis

Effectiveness and Safety of Iguratimod in Treating Primary Sjögren’s Syndrome: A Systematic Review and Meta-Analysis

Comparison of iguratimod and conventional cyclophosphamide with sequential azathioprine as treatment of active lupus nephritis: study protocol for a multi-center, randomized, controlled clinical trial (iGeLU study)

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