BACKGROUND The role of macrophages in rheumatoid arthritis(RA)and its mechanism have attracted much attention in RA pathogenesis.Macrophages accumulate in the synoviums of RA,and the proportion of M1 type pro-inflamma...BACKGROUND The role of macrophages in rheumatoid arthritis(RA)and its mechanism have attracted much attention in RA pathogenesis.Macrophages accumulate in the synoviums of RA,and the proportion of M1 type pro-inflammatory macrophages is higher than that of M2 type anti-inflammatory macrophages,leading to the secretion of inflammatory molecules and the aggravation of inflammatory reaction,which has made macrophages a potential target of RA drugs.Iguratimod is a kind of cyclo-oxygenase-2 inhibitor that affects macrophage polarity.It is speculated that its anti-inflammatory and anti-rheumatic effects may be related to the regulation of macrophage M1/M2 ratio.AIM To investigate the effects of Iguratimod on the polarity of mononuclear macrophages in elderly patients with RA.METHODS Elderly patients with RA and joint effusion were selected,including 10 men and 25 women,with an average age of 66.37±4.42 years.Patients were treated with oral administration of 25 mg Iguratimod(Iremod,State Food and Drug Administration Approval No.H20110084)twice daily for 12 wk.Disease Activity Score 28 and Health Assessment Questionnaire score were collected according to the disease severity before and after treatment.Venous blood and joint effusion fluid were collected,mononuclear macrophages were extracted and expression of cell surface markers CD86,CD64,CD163,and CD206 was analyzed by flow cytometry.The concentration of inflammatory factors interleukin(IL)-6,IL-1β,transforming growth factor-β,and IL-4 in the joint effusion fluid was analyzed by enzyme-linked immunosorbent assay.Expression of mononuclear cells inhibitor of nuclear factor-κB(IκB)and phosphorylated IκB in peripheral blood was analyzed by western blotting.RESULTS Disease Activity Score 28 score and Health Assessment Questionnaire score of patients treated with Iguratimod decreased significantly.The percentage of cell surface markers CD86 and CD64 decreased significantly,and the percentage of CD163 and CD206 increased significantly(P<0.05).The inflammatory factors IL-6 and IL-1βdecreased significantly,and transforming growth factor-βand IL-4 increased significantly.Western blot analysis showed that mononuclear cell inhibitor of nuclear factor-κB in peripheral blood was significantly increased after treatment,and its phosphorylation level was significantly decreased(P<0.05).CONCLUSION Iguratimod can promote the transformation of mononuclear macrophages from M1 to M2 in elderly patients with RA by inhibiting the nuclear factor-κB pathway,thus improving symptoms of RA.展开更多
BACKGROUND Primary Sjögren's syndrome(pSS)concomitant with autoimmune hemolytic anemia(AIHA)but without eye and mouth dryness is exceedingly rare.Iguratimod(IGU)has been widely used in the treatment of pSS.Ho...BACKGROUND Primary Sjögren's syndrome(pSS)concomitant with autoimmune hemolytic anemia(AIHA)but without eye and mouth dryness is exceedingly rare.Iguratimod(IGU)has been widely used in the treatment of pSS.However,there are few reports about the application of IGU in pSS concomitant with AIHA.CASE SUMMARY Here,we present the case of a patient with pSS concomitant with AIHA but without eye and mouth dryness.The patient was initially diagnosed with hyperplastic anemia and AIHA while pSS was missed,and was finally diagnosed with pSS concomitant with AIHA.The patient was treated with IGU along with prednisone and hydroxychloroquine,and her hemoglobin,reticulocytes and IgG returned to normal levels.CONCLUSION IGU was effective for and well tolerated by our patient with pSS concomitant with AIHA,and may be a promising therapy for the treatment of this disease.展开更多
Introduction: The aim of this study was to observe an inhibition of bone resorption and osteoclastogenesis by iguratimod (IGU, T-614), a disease-modifying anti-rheumatic drug, using adjuvant-induced arthritis (AIA) ra...Introduction: The aim of this study was to observe an inhibition of bone resorption and osteoclastogenesis by iguratimod (IGU, T-614), a disease-modifying anti-rheumatic drug, using adjuvant-induced arthritis (AIA) rats and receptor activator of nuclear factor kappa-B ligand (RANKL)-stimulated RAW264.7 cells. Methods: The bone mineral density and 3D morphometric parameters of hind paws in AIA rats were measured using micro computed tomography (μCT) imaging. The activity of osteoclast cells was estimated based on tartrate-resistant acid phosphatase (TRAP) staining in specimens from the rats. In vitro TRAP activity was investigated using RANKL-stimulated RAW264.7 cells. The amount of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) protein was measured by western blot analysis. The expression of Nfatc1, its regulator genes, its upstream factors, and osteoclast-functional genes were investigated. Results: In addition to the suppression of bone resorption and lesions of bone trabeculae of AIA rats, IGU significantly decreased the number of TRAP-positive cells in the calcaneal bones. Moreover, this drug inhibited the differentiation of RANKL-stimulated RAW264.7 cells into osteoclasts, which were identified morphologically and functionally. IGU decreased the amount of NFATc1 protein and improved the altered expression of NFATc1-associated genes and osteoclast-functional genes. Conclusions: IGU suppressed osteoclastogenesis and bone resorption via the RANKL-NFATc1 pathway, suggesting such effect would be expected in clinical use.展开更多
Background:Rheumatoid arthritis(RA)is a systemic autoimmune disease characterized by chronic inflammation and joint destruction.Iguratimod(IGU)is a novel conventional synthetic disease-modifying antirheumatic drugs(cs...Background:Rheumatoid arthritis(RA)is a systemic autoimmune disease characterized by chronic inflammation and joint destruction.Iguratimod(IGU)is a novel conventional synthetic disease-modifying antirheumatic drugs(csDMARD)with good efficacy and safety for the treatment of active RA in China and Japan.However,the long-term effects of IGU on the progression of bone destruction or radiographic progression in patients with active RA remain unknown.We aimed to investigate the efficacy and safety of iguratimod(IGU),a combination of methotrexate(MTX)and IGU,and IGU in patients with active rheumatoid arthritis(RA)who were naïve to MTX.Methods:This multicenter,double-blind,randomized,non-inferiority clinical trial was conducted at 28 centers for over 52 weeks in China.In total,911 patients were randomized(1:1:1)to receive MTX monotherapy(10–15 mg weekly,n=293),IGU monotherapy(25 mg twice daily,n=297),or IGU+MTX(10–15 mg weekly for MTX and 25 mg twice daily for IGU,n=305)for 52 weeks.The patients'clinical characteristics,Simplified Disease Activity Index(SDAI),Clinical Disease Activity Index(CDAI),disease activity score in 28 joints-C-reactive protein(DAS28-CRP)level,and disease activity score in 28 joints-erythrocyte sedimentation rate(DAS28-ESR)were assessed at baseline.The primary endpoints were the proportion of patients with≥20%improvement according to the American College of Rheumatology(ACR20)response and changes in the van der Heijde-modified total Sharp score(vdH-mTSS)at week 52.Results:The proportions of patients achieving an ACR20 response at week 52 were 77.44%,77.05%,and 65.87%for IGU monotherapy,IGU+MTX,and MTX monotherapy,respectively.The non-inferiority of IGU monotherapy to MTX monotherapy was established with the ACR20(11.57%;95%confidence interval[CI],4.35–18.79%;P<0.001)and vdH-mTSS(-0.37;95%CI,-1.22–0.47;P=0.022).IGU monotherapy was also superior to MTX monotherapy in terms of ACR20(P=0.002)but not the vdH-mTSS.The superiority of IGU+MTX over MTX monotherapy was confirmed in terms of the ACR20(11.18%;95%CI,3.99–18.37%;P=0.003),but not in the vdH-mTSS(-0.68;95%CI,-1.46–0.11;P=0.091).However,the difference in the incidence rates of adverse events was not statistically significant.Conclusions:IGU monotherapy/IGU+MTX showed a more favorable clinical response than did MTX monotherapy.IGU may have some clinical benefits over MTX in terms of radiographic progression,implying that IGU may be considered as an initial therapeutic option for patients with active RA.展开更多
Background The mechanism by which iguratimod(IGU)attenuates Sjögren's syndrome(SS)remains elusive.In this study,we aimed to investigate the relationship between the therapeutic effect of IGU and macrophage po...Background The mechanism by which iguratimod(IGU)attenuates Sjögren's syndrome(SS)remains elusive.In this study,we aimed to investigate the relationship between the therapeutic effect of IGU and macrophage polarization in SS mice.Methods Female nonobese diabetic(NOD)mice were selected as the model of SS.Forty-five female NOD mice(8-week-old)and five female Institute of Cancer Research(ICR)mice(8-week-old)were applied in this study.Five ICR mice served as control group.Five NOD mice served as model group.The remaining 40 NOD mice were randomly divided into four groups and were administrated with IGU(10,20,and 40 mg/kg)or vehicle(model control group).After 4 weeks,the salivary flow rate of mice in each group was measured.The histopathology of submandibular glands(SG)was determined by hematoxylin and eosin staining.The markers of polarization of M1 and M2 macrophages in the SG of NOD mice were detected by quantitative real time-polymerase chain reaction(qRT-PCR)and Western blot analysis.The polarization of M1 and M2 macrophages in the spleen of NOD mice was detected by flow cytometric analysis.Lipopolysaccharide and interleukin-4 were used to stimulate RAW264.7 cells,qRT-PCR and flow cytometry analysis were used to detect the mRNA expression of M1 and M2 macrophage markers.The activation of key proteins in mitogen-activated protein kinases(MAPKs)signaling pathway was determined by Western blot analysis.Results Compared to ICR mice,NOD mice exhibit SS-like symptoms,lymphocyte infiltration in SG,macrophage polarization in SG.After IGU treatment,SS-like symptoms and lymphocyte infiltration were reduced,along with a decreased proportion of M1 macrophages and an increased proportion of M2 macrophages in the SGs.Compared with the vehicle-treated model control group,IGU reduced percentages of M1 macrophages(20 mg/kg,40 mg/kg vs.vehicle,21.42±1.79%,21.03±1.79%vs.28.68±2.23%),whereas increased M2 macrophages(20 mg/kg vs.vehicle,15.84±0.77%vs.11.99±1.03%)in NOD mice.IGU(1µg/mL)also suppressed M1 macrophage polarization(IGU vs.vehicle,29.01±3.70%vs.59.67±1.30%),whereas promoted M2 macrophage polarization(IGU vs.vehicle,67.33±4.78%vs.52.30±3.68%)in RAW264.7 cells.IGU also significantly regulated macrophage polarization in vitro and IGU significantly reduced the phosphorylation levels of p38,extracellular regulated protein kinase 1/2,and c-Jun N-terminal kinase proteins in macrophages.Conclusions IGU might alleviate SS-like symptoms and regulate macrophage polarization through inhibiting the MAPKs pathway in SS mice.These findings clarified the mechanism underlying the therapeutic effects of IGU on SS,and provided new evidence for the further application of IGU in the treatment of SS patients.展开更多
文摘BACKGROUND The role of macrophages in rheumatoid arthritis(RA)and its mechanism have attracted much attention in RA pathogenesis.Macrophages accumulate in the synoviums of RA,and the proportion of M1 type pro-inflammatory macrophages is higher than that of M2 type anti-inflammatory macrophages,leading to the secretion of inflammatory molecules and the aggravation of inflammatory reaction,which has made macrophages a potential target of RA drugs.Iguratimod is a kind of cyclo-oxygenase-2 inhibitor that affects macrophage polarity.It is speculated that its anti-inflammatory and anti-rheumatic effects may be related to the regulation of macrophage M1/M2 ratio.AIM To investigate the effects of Iguratimod on the polarity of mononuclear macrophages in elderly patients with RA.METHODS Elderly patients with RA and joint effusion were selected,including 10 men and 25 women,with an average age of 66.37±4.42 years.Patients were treated with oral administration of 25 mg Iguratimod(Iremod,State Food and Drug Administration Approval No.H20110084)twice daily for 12 wk.Disease Activity Score 28 and Health Assessment Questionnaire score were collected according to the disease severity before and after treatment.Venous blood and joint effusion fluid were collected,mononuclear macrophages were extracted and expression of cell surface markers CD86,CD64,CD163,and CD206 was analyzed by flow cytometry.The concentration of inflammatory factors interleukin(IL)-6,IL-1β,transforming growth factor-β,and IL-4 in the joint effusion fluid was analyzed by enzyme-linked immunosorbent assay.Expression of mononuclear cells inhibitor of nuclear factor-κB(IκB)and phosphorylated IκB in peripheral blood was analyzed by western blotting.RESULTS Disease Activity Score 28 score and Health Assessment Questionnaire score of patients treated with Iguratimod decreased significantly.The percentage of cell surface markers CD86 and CD64 decreased significantly,and the percentage of CD163 and CD206 increased significantly(P<0.05).The inflammatory factors IL-6 and IL-1βdecreased significantly,and transforming growth factor-βand IL-4 increased significantly.Western blot analysis showed that mononuclear cell inhibitor of nuclear factor-κB in peripheral blood was significantly increased after treatment,and its phosphorylation level was significantly decreased(P<0.05).CONCLUSION Iguratimod can promote the transformation of mononuclear macrophages from M1 to M2 in elderly patients with RA by inhibiting the nuclear factor-κB pathway,thus improving symptoms of RA.
基金Supported by the Lanzhou Science and Technology Plan Project,No.2018-3-48Lanzhou Talent Innovation and Entrepreneurship Project,No.2019-RC-35and 2019 Special Fund for Doctoral Training of Lanzhou University Second Hospital,No.YJS-BD-15.
文摘BACKGROUND Primary Sjögren's syndrome(pSS)concomitant with autoimmune hemolytic anemia(AIHA)but without eye and mouth dryness is exceedingly rare.Iguratimod(IGU)has been widely used in the treatment of pSS.However,there are few reports about the application of IGU in pSS concomitant with AIHA.CASE SUMMARY Here,we present the case of a patient with pSS concomitant with AIHA but without eye and mouth dryness.The patient was initially diagnosed with hyperplastic anemia and AIHA while pSS was missed,and was finally diagnosed with pSS concomitant with AIHA.The patient was treated with IGU along with prednisone and hydroxychloroquine,and her hemoglobin,reticulocytes and IgG returned to normal levels.CONCLUSION IGU was effective for and well tolerated by our patient with pSS concomitant with AIHA,and may be a promising therapy for the treatment of this disease.
文摘Introduction: The aim of this study was to observe an inhibition of bone resorption and osteoclastogenesis by iguratimod (IGU, T-614), a disease-modifying anti-rheumatic drug, using adjuvant-induced arthritis (AIA) rats and receptor activator of nuclear factor kappa-B ligand (RANKL)-stimulated RAW264.7 cells. Methods: The bone mineral density and 3D morphometric parameters of hind paws in AIA rats were measured using micro computed tomography (μCT) imaging. The activity of osteoclast cells was estimated based on tartrate-resistant acid phosphatase (TRAP) staining in specimens from the rats. In vitro TRAP activity was investigated using RANKL-stimulated RAW264.7 cells. The amount of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) protein was measured by western blot analysis. The expression of Nfatc1, its regulator genes, its upstream factors, and osteoclast-functional genes were investigated. Results: In addition to the suppression of bone resorption and lesions of bone trabeculae of AIA rats, IGU significantly decreased the number of TRAP-positive cells in the calcaneal bones. Moreover, this drug inhibited the differentiation of RANKL-stimulated RAW264.7 cells into osteoclasts, which were identified morphologically and functionally. IGU decreased the amount of NFATc1 protein and improved the altered expression of NFATc1-associated genes and osteoclast-functional genes. Conclusions: IGU suppressed osteoclastogenesis and bone resorption via the RANKL-NFATc1 pathway, suggesting such effect would be expected in clinical use.
文摘Background:Rheumatoid arthritis(RA)is a systemic autoimmune disease characterized by chronic inflammation and joint destruction.Iguratimod(IGU)is a novel conventional synthetic disease-modifying antirheumatic drugs(csDMARD)with good efficacy and safety for the treatment of active RA in China and Japan.However,the long-term effects of IGU on the progression of bone destruction or radiographic progression in patients with active RA remain unknown.We aimed to investigate the efficacy and safety of iguratimod(IGU),a combination of methotrexate(MTX)and IGU,and IGU in patients with active rheumatoid arthritis(RA)who were naïve to MTX.Methods:This multicenter,double-blind,randomized,non-inferiority clinical trial was conducted at 28 centers for over 52 weeks in China.In total,911 patients were randomized(1:1:1)to receive MTX monotherapy(10–15 mg weekly,n=293),IGU monotherapy(25 mg twice daily,n=297),or IGU+MTX(10–15 mg weekly for MTX and 25 mg twice daily for IGU,n=305)for 52 weeks.The patients'clinical characteristics,Simplified Disease Activity Index(SDAI),Clinical Disease Activity Index(CDAI),disease activity score in 28 joints-C-reactive protein(DAS28-CRP)level,and disease activity score in 28 joints-erythrocyte sedimentation rate(DAS28-ESR)were assessed at baseline.The primary endpoints were the proportion of patients with≥20%improvement according to the American College of Rheumatology(ACR20)response and changes in the van der Heijde-modified total Sharp score(vdH-mTSS)at week 52.Results:The proportions of patients achieving an ACR20 response at week 52 were 77.44%,77.05%,and 65.87%for IGU monotherapy,IGU+MTX,and MTX monotherapy,respectively.The non-inferiority of IGU monotherapy to MTX monotherapy was established with the ACR20(11.57%;95%confidence interval[CI],4.35–18.79%;P<0.001)and vdH-mTSS(-0.37;95%CI,-1.22–0.47;P=0.022).IGU monotherapy was also superior to MTX monotherapy in terms of ACR20(P=0.002)but not the vdH-mTSS.The superiority of IGU+MTX over MTX monotherapy was confirmed in terms of the ACR20(11.18%;95%CI,3.99–18.37%;P=0.003),but not in the vdH-mTSS(-0.68;95%CI,-1.46–0.11;P=0.091).However,the difference in the incidence rates of adverse events was not statistically significant.Conclusions:IGU monotherapy/IGU+MTX showed a more favorable clinical response than did MTX monotherapy.IGU may have some clinical benefits over MTX in terms of radiographic progression,implying that IGU may be considered as an initial therapeutic option for patients with active RA.
基金National Natural Science Foundation of China,Grant/Award Number:81970062。
文摘Background The mechanism by which iguratimod(IGU)attenuates Sjögren's syndrome(SS)remains elusive.In this study,we aimed to investigate the relationship between the therapeutic effect of IGU and macrophage polarization in SS mice.Methods Female nonobese diabetic(NOD)mice were selected as the model of SS.Forty-five female NOD mice(8-week-old)and five female Institute of Cancer Research(ICR)mice(8-week-old)were applied in this study.Five ICR mice served as control group.Five NOD mice served as model group.The remaining 40 NOD mice were randomly divided into four groups and were administrated with IGU(10,20,and 40 mg/kg)or vehicle(model control group).After 4 weeks,the salivary flow rate of mice in each group was measured.The histopathology of submandibular glands(SG)was determined by hematoxylin and eosin staining.The markers of polarization of M1 and M2 macrophages in the SG of NOD mice were detected by quantitative real time-polymerase chain reaction(qRT-PCR)and Western blot analysis.The polarization of M1 and M2 macrophages in the spleen of NOD mice was detected by flow cytometric analysis.Lipopolysaccharide and interleukin-4 were used to stimulate RAW264.7 cells,qRT-PCR and flow cytometry analysis were used to detect the mRNA expression of M1 and M2 macrophage markers.The activation of key proteins in mitogen-activated protein kinases(MAPKs)signaling pathway was determined by Western blot analysis.Results Compared to ICR mice,NOD mice exhibit SS-like symptoms,lymphocyte infiltration in SG,macrophage polarization in SG.After IGU treatment,SS-like symptoms and lymphocyte infiltration were reduced,along with a decreased proportion of M1 macrophages and an increased proportion of M2 macrophages in the SGs.Compared with the vehicle-treated model control group,IGU reduced percentages of M1 macrophages(20 mg/kg,40 mg/kg vs.vehicle,21.42±1.79%,21.03±1.79%vs.28.68±2.23%),whereas increased M2 macrophages(20 mg/kg vs.vehicle,15.84±0.77%vs.11.99±1.03%)in NOD mice.IGU(1µg/mL)also suppressed M1 macrophage polarization(IGU vs.vehicle,29.01±3.70%vs.59.67±1.30%),whereas promoted M2 macrophage polarization(IGU vs.vehicle,67.33±4.78%vs.52.30±3.68%)in RAW264.7 cells.IGU also significantly regulated macrophage polarization in vitro and IGU significantly reduced the phosphorylation levels of p38,extracellular regulated protein kinase 1/2,and c-Jun N-terminal kinase proteins in macrophages.Conclusions IGU might alleviate SS-like symptoms and regulate macrophage polarization through inhibiting the MAPKs pathway in SS mice.These findings clarified the mechanism underlying the therapeutic effects of IGU on SS,and provided new evidence for the further application of IGU in the treatment of SS patients.
