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OBJECTIVES: Mast cell activation induces pathological responses, including increased osteoclastogenesis in rheumatoid arthritis (RA). Interleukin (IL)-18 binding protein (IL-18BP) has anti-inflammatory effects. In this study, we evaluated the effect of IL-18BP on mast cell activation and mast cell induced osteoclastogenesis. METHODS: Mast cells were activated by IL-33 (100 ng/mL) and cultured with IL-18BP (10, 50, and 100 ng/mL). The proliferation, apoptosis, and necroptosis of mast cells were measured using flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of mast cell enzymes, matrix metalloproteinase (MMP), soluble RANKL (sRANKL), and pro-inflammatory cytokines in the culture media. Monocytes from patients with RA patients (n=5) were cultured with activated mast cells with various concentrations of IL-18BP. TRAP+ multinucleated osteoclasts, bone resorption area, and osteoclast differentiation-related genes were measured. RESULTS: Proliferation of tryptase+chymase+c-kit+FcεR1+ mast cells was suppressed following incubation with IL-18BP (10, 50, and 100 ng/mL). RNA expression levels of tryptase and chymase were reduced by 100 ng/mL IL-18BP. Additionally, the levels of MMP-3/9, IL-17A, IL-6, TNF-α, and sRANKL were significantly inhibited by 100 ng/mL IL-18BP. Annexin V+ and annexin V-PI+ mast cells were reduced following incubation with 100 ng/mL IL-18BP. The addition of IL-33 significantly stimulated mast cell and increased TRAP+ multinucleated cells and bone resorption area, and these effects were suppressed by IL-18BP. The osteoclast-related genes (TRAP, ATP6v0d2, RANK, and cathepsin K) expression were suppressed by IL-18BP. CONCLUSIONS: IL-18BP suppressed mast cell activation and mast cell induced osteoclastogenesis. This suggests a potential anti-arthritic role for IL-18BP in patients with RA.
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OBJECTIVES: To evaluate the role of Fcγ receptors (FcγR) and peptidyl arginine deiminase (PAD) in anti-citrullinated protein antibody (ACPA)-induced fibroblast-like synoviocytes (FLSs)-mediated osteoclastogenesis in patients with rheumatoid arthritis (RA). METHODS: FLSs and peripheral blood mononuclear cells were collected from patients with RA. We stimulated RA-FLS with ACPA (100 ng/ml) with and without anti-cluster of differentiation (CD)32a/CD64 (FcγRIIA/FcγRI) antibody and PAD-2/4 inhibitors. Flow cytometry and enzyme-linked immunosorbent assay were also performed. CD14+ monocytes were cultured with receptor activator of nuclear factor kappa beta (RANKL) and macrophage colony-stimulating factor, and ACPA-stimulated RA-FLSs were added. These cells were cultured for 14 days, and osteoclastogenesis was quantified using tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: ACPA increased RANKL+ and tumour necrotic factor-alpha (TNF-α+) FLS, which decreased dose-dependently by adding 5 and 10 ug/mL anti-CD64 antibody rather than anti-CD32a antibody. In PAD inhibitor experiments, the proportion of RANKL+ and TNF-α+ FLS decreased in 50 µM condition containing PAD-2 inhibitor rather than PAD-4 inhibitor. The co-culture of ACPA-stimulated RA-FLSs and osteoclast precursors increased the TRAP+ multinucleated osteoclast count, which was decreased by anti-CD64 antibody and PAD2 inhibitor. CONCLUSIONS: The present study showed that ACPA increased RANKL and pro-inflammatory cytokine expression in RA-FLSs, and ACPA-activated RA-FLSs could augment osteoclastogenesis. These processes were inhibited by treatment with anti-CD64 antibody and PAD-2 inhibitors. These results show that CD64 and PAD-2-induced pathways may be involved in ACPA-induced FLS activation and osteoclastogenesis in patients with RA. Therefore, regulating the CD64 and PAD-2 pathways may improve RA treatment.
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OBJECTIVES: The incidence of herpes zoster (HZ) in rheumatoid arthritis (RA) patients is greater than that in healthy controls (HC), particularly in RA patients treated with Janus kinase inhibitors (JAKi). Here, we examined the effect of JAKi on CD4+/CD8+ T cells, cytokine production, and regulation of transcriptional factors in RA patients and HC. METHODS: Peripheral blood mononuclear cells (PBMCs) obtained from RA patients (n=14) and HCs (n=7) were stimulated with varicella zoster virus lysates and exposed to three JAKi inhibitors (ruxolitinib [JAK1/2 inhibitor]; AG490 [JAK2 inhibitor]; and WHI-P154 [JAK3 inhibitor]) in the presence/absence of methotrexate. The CD4+ and CD8+ T cell populations were measured by flow cytometry. Cytokine levels in culture medium were measured by ELISA. Transcription factor expression was examined by RT-qPCR. RESULTS: There was a reduction in the CD4+IFN-γ+, CD4+CD69+IFN-γ+, CD8+IFN-γ+, and CD8+CD69+IFN-γ+ populations, and an increase in the CD4+CD25highFoxp3+ cell population, in PBMCs from RA patients and HCs after exposure to the three JAKi. ELISA revealed a reduction in IFN-γ and granzyme B levels in the presence of JAKi. JAKi reduced expression of mRNA encoding STAT1 and T-bet, but increased that of mRNA encoding STAT5 and Foxp3. Methotrexate plus the highest dose of each JAKi did not affect the Th1, cytotoxic T cell, or Treg populations, the levels of IFN-γ and granzyme B, or expression of transcription factors, significantly. CONCLUSIONS: JAKi reduce the Th1/cytotoxic T cell population and increase the Treg population in both RA patients and HC patients.
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Artrite Reumatoide , Herpes Zoster , Inibidores de Janus Quinases , Humanos , Metotrexato/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Granzimas/metabolismo , Herpesvirus Humano 3/metabolismo , Leucócitos Mononucleares/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos , Citocinas/metabolismo , Herpes Zoster/metabolismoRESUMO
OBJECTIVES: Interleukin (IL)-18 plays a pro-inflammatory role in rheumatoid arthritis (RA), and its soluble inhibitor IL-18 binding protein (IL-18BP) has a potential therapeutic role. We investigated the role of IL-18BP on the joint destruction process of RA by accessing the effects of IL-18BP on fibroblast-like synoviocytes (FLSs) and chondrocytes. METHODS: Peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy controls were cultured under T cell proliferative conditions with 10, 50, or 100 ng/mL of IL-18BP. After three days of culture, flow cytometry for CD4+ T cells was performed using various IL-18BP concentrations. The apoptosis and necroptosis of FLSs and chondrocytes were measured by flow cytometry using annexin V and propidium iodide (PI) and western blot under TNF-α stimulation with IL-18BP (10, 50, and 100 ng/mL). RESULTS: Differentiation of CD4+ IL-17A+ and CD4+ IL-4+ cells decreased and that of CD4+ CD25high Foxp3+ and CD4+ interferon (IFN)-γ+ cells increased on addition of IL-18BP to cultured RA patient-driven PBMCs. RA-FLS migration ability was not suppressed by IL-18BP after 12 or 24 h. IL-18BP increased annexin V+ FLS level and reduced annexin V+ chondrocyte level in a dose-dependent manner, whereas PI+ annexin V- FLS and chondrocyte levels were suppressed by 50, 100 ng/mL IL-18BP in culture. CONCLUSIONS: The administration of IL-18BP regulated the type 17 helper T cell/ regulatory T cell imbalance and attenuated the production of pro-inflammatory cytokines. IL-18BP further increased FLS apoptosis and decreased the necroptosis of FLS/chondrocytes and apoptosis of chondrocytes suggesting the joint preservative potential of IL-18BP.
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Artrite Reumatoide , Sinoviócitos , Humanos , Condrócitos/metabolismo , Leucócitos Mononucleares/metabolismo , Necroptose , Anexina A5/farmacologia , Anexina A5/metabolismo , Anexina A5/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Células Cultivadas , Fibroblastos/metabolismo , Apoptose , Proliferação de CélulasRESUMO
OBJECTIVES: To compare the drug retention times and clinical efficacy of alternative tumour necrosis factor inhibitors (TNFi) and secukinumab in primary and secondary non-responders with ankylosing spondylitis (AS). METHODS: AS patients treated with biologics and enrolled in the Korean College of Rheumatology Biologics registry were examined. Patients who did not respond to previous TNFi treatment were defined as primary and secondary non-responders. Data regarding drug discontinuation and clinical efficacy were collected after 1 year. Kaplan-Meier and Cox regression analyses were performed to compare drug survival and associated factors. Logistic regression analyses were conducted to compare the clinical efficacy secukinumab with that of alternative TNFi. RESULTS: In total, 124 patients (83 receiving alternative TNFi and 41 receiving secukinumab) had biologic changes due to clinical inefficacy. Drug retention rates in the alternative TNFi and secukinumab groups were similar (P = 0.096). However, subgroup analyses including only secondary non-responders revealed that secukinumab users showed a higher hazard ratio (HR) for drug discontinuation (HR = 3.77, P = 0.045). In addition, secukinumab was negatively associated with achieving BASDAI50 or a major improvement in the ASDAS. CONCLUSION: Alternative TNFi showed better drug retention and clinical efficacy in AS patients experiencing previous TNFi failure, in secondary non-responders. Therefore, alternative TNFi may be a more suitable treatment for secondary non-responders.
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Antirreumáticos , Produtos Biológicos , Espondilite Anquilosante , Humanos , Espondilite Anquilosante/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Antirreumáticos/uso terapêutico , Resultado do Tratamento , Produtos Biológicos/uso terapêutico , Fator de Necrose Tumoral alfaRESUMO
OBJECTIVE: To compare findings on salivary gland ultrasonography (SGUS) and salivary gland scintigraphy (SGS) in patients with primary SS (pSS). METHODS: The study cohort included patients newly diagnosed with pSS who underwent SGUS and SGS at the same time at our tertiary care hospital. Baseline demographics, laboratory data, clinical data and SGUS and SGS findings were collected. An SGUS cut-off score ≥14 defined positive SGUS findings and was used to classify patients in SGUS+ and SGUS- groups. SGS findings were quantified by the parotid:submandibular uptake ratio (PU:SU) and percentage parotid/submandibular excretion (%PE/%SE). The correlation between SGUS and SGS findings was evaluated. RESULTS: For analysis, 18 patients with SGUS+ findings and 18 with SGUS- findings were recruited, for a total study cohort of 36 patients. There were no between-group differences in baseline demographics and clinical and laboratory data. The PU, %PE, SU and %SE were significantly lower in the SGUS+vs SGUS- group. The SGUS score for the parotid gland was negatively correlated to the PU (r = -0.36, P = 0.03) and %PE (r = -0.35, P = 0.04). The SGUS score of the submandibular gland was negatively correlated to the SU (r = -0.42, P = 0.01) and %SE (r = -0.39, P = 0.02). CONCLUSIONS: Patients with a higher SGUS score had lower salivary gland function. The SGUS score showed a significant correlation with PU, %PE, SU and %SE. These findings are indicative of a possible predictive role of SGUS to diagnose salivary gland dysfunction.
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Síndrome de Sjogren , Humanos , Glândula Parótida/diagnóstico por imagem , Cintilografia , Glândulas Salivares/diagnóstico por imagem , Síndrome de Sjogren/diagnóstico , Glândula Submandibular/diagnóstico por imagem , UltrassonografiaRESUMO
OBJECTIVES: This study focused on distinguishing the characteristic ultrasonographic findings of lacrimal glands in primary Sjögren's syndrome (pSS) from those in idiopathic sicca syndrome. We aimed to set up a semi-quantitative scoring system of lacrimal gland ultrasonography (LGUS) for patients with pSS. METHODS: Fifty-six patients with pSS and 40 patients with idiopathic sicca syndrome were evaluated. Lacrimal glands were examined with ultrasonography using area, major/minor axis length, and five components (presence of intraglandular branch of lacrimal artery, inhomogeneity, hyperechoic bands, hypoechoic areas, and delineation). Except for the area and maximal/minimal length of lacrimal glands, other components were classified as dichotomous variables (present or absent). Using the receiver operating characteristics curve, we inferred the most appropriate combination of LGUS scoring for pSS diagnosis. RESULTS: Patients with pSS had a higher proportion of intraglandular branch of lacrimal artery (70.5% vs. 42.5%, p<0.001), inhomogeneity (72.3% vs. 46.3%, p<0.001), and hyperechoic bands (56.2% vs. 37.5%, p=0.016) than patients with idiopathic sicca syndrome. LGUS A, which represents the summation of one point assigned for the presence of intraglandular branch of lacrimal artery and one for inhomogeneity, was the most suitable diagnostic criterion (area under curve = 0.724, 95% confidence interval 0.620-0.828). If both sides have a score of 2, it results in a total of 4 points. With a cut-off value of 3 out of 4 points, LGUS A had 60.7% sensitivity, 71.1% specificity, 60.7% positive predictive value, and 72.5% negative predictive value. CONCLUSIONS: Semi-quantitative scoring of LGUS was useful when distinguishing patients with pSS from those with idiopathic sicca syndrome. The combination of intraglandular branch of lacrimal artery and inhomogeneity on both sides was most suitable for classifying pSS using LGUS.
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Aparelho Lacrimal , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico por imagem , Glândulas Salivares/diagnóstico por imagem , Aparelho Lacrimal/diagnóstico por imagem , Índice de Gravidade de Doença , Ultrassonografia/métodosRESUMO
OBJECTIVES: Patients with ankylosing spondylitis (AS) have a heterogenic disease course and treatment response. Cluster-based phenotypes are useful for predicting AS disease course. Here, we compared drug retention and clinical efficacy of biologic disease-modifying anti-rheumatic drugs (bDMARDs) in AS patients with cluster A and cluster B phenotypes. METHODS: AS patients enrolled in the Korean College of Rheumatology BIOlogics registry were divided into cluster A (axial symptoms predominant) and cluster B (both axial and peripheral symptoms). Retention of bDMARDs was measured using Kaplan-Meier curve and Cox regression analyses. Clinical efficacy (BASDAI50, ASAS20, ASAS40, ASDAS inactive state, and clinically important improvement/major improvement of ASDAS) at 1-year follow-up was measured by logistic regression analysis. Also, propensity score (PS)-matched analyses were conducted. RESULTS: 1600 AS patients (1468 for cluster A, 132 for cluster B) were included. Kaplan-Meier curve analysis revealed that the drug retention rate was lower in cluster B patients (p=0.03). PS-matched analyses showed that the hazard ratio (HR) for drug discontinuation was signi cantly higher in cluster B patients (HR=1.568; 95% con dence interval =1.055-2.329). The odds ratio for BASDAI50 at 1-year was comparable between cluster A and cluster B patients in PS-matched and multivariate logistic regression analyses. A similar result was obtained in other clinical efficacy assessments. CONCLUSIONS: The drug retention rate was lower in cluster B patients than in cluster A patients; clinical efficacy was comparable between the two groups at 1-year follow-up. These results may help predict drug retention and clinical efficacy in AS patients.
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Antirreumáticos , Produtos Biológicos , Espondilite Anquilosante , Antirreumáticos/uso terapêutico , Produtos Biológicos/efeitos adversos , Humanos , Fenótipo , Sistema de Registros , República da Coreia/epidemiologia , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVES: CD4+ T cells are crucial for the pathogenesis of rheumatoid arthritis (RA). Here, we evaluated gene expression in CD4+ T cells in early RA, and main purpose of present study was to seek the changes in CD4+ T-cell-related cytokines according to RA progression. METHODS: Early RA was defined as methotrexate (MTX)-naïve patients. Established RA was defined as patients with more than 6 months of DMARDs. Patients with osteoarthritis were evaluated as controls. Microarray analysis was used to identify overexpressed genes in CD4+ T cells, and RT-qPCR was used to validate. Plasma cytokine were measured in patients with early and established RA, and correlations with disease activity were assessed in patients with early RA, whereas clinical prognosis was assessed in established patients with RA. RESULTS: Thirty-four genes showed overexpression in CD4+ T cells from patients with early RA compared with OA controls. Nineteen were related to interferon (IFN)-γ, and eight were related to interleukin (IL)-17A. Plasma levels of IL-17A, IL-6, IL-12, and TNF-α correlated with IFN-γ, and correlation coefficient was highest between DAS28-ESR and plasma IFN-γ levels in patients with early RA (Rho=0.553, p=0.0025). In established RA with low disease activity, drug reduction group showed lower plasma IFN-γ and IL-17A than drug maintenance/relapse group (13.61±5.75 vs. 29.89±18.72, p<0.001; and 10.91±3.92 vs. 21.04±12.81 pg/mL, p<0.001, respectively). CONCLUSIONS: The IFN-γ and IL-17 gene signature in CD4+ T cells was significantly increased in early RA. Patients with established RA with low levels of IFN-γ and IL-17A could be eligible for dose reduction.
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Antirreumáticos , Artrite Reumatoide , Interferon gama , Interleucina-17 , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Citocinas , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , PrognósticoRESUMO
AIM: This study investigated whether a vitronectin-derived peptide (VnP-16) prevents and/or reverses alveolar bone resorption induced by ligature-induced periodontitis in rodents and identified the underlying mechanism. MATERIALS AND METHODS: We evaluated the effects of VnP-16 on osteogenic differentiation in human periodontal ligament cells (hPDLCs), lipopolysaccharide-induced inflammatory responses in gingival fibroblasts, and immune response in T lymphocytes. Ligature-induced periodontitis was induced by ligating the bilateral mandibular first molars for 14 days in rats and for 7 days in mice (n = 10/group). VnP-16 (100 µg/10 µl) was applied topically into the gingival sulcus of rats via intra-sulcular injection, whereas the peptide (50 µg/5 µl) was administered directly into the gingiva of mice via intra-gingival injection. To evaluate the preventive and therapeutic effects of VnP-16, micro-computed tomography analysis and histological staining were then performed. RESULTS: VnP-16 promoted osteogenic differentiation of periodontal ligament cells and inhibited the production of lipopolysaccharide-induced inflammatory mediators in gingival fibroblasts. Concomitantly, VnP-16 modulated the host immune response by reducing the number of receptor activator of NF-κB ligand (RANKL)-expressing lipopolysaccharide-stimulated CD4+ and CD8+ T cells, and by suppressing RANKL and interleukin (IL)-17A production. Furthermore, local administration of VnP-16 in rats and mice significantly prevented and reversed alveolar bone loss induced by ligature-induced periodontitis. VnP-16 enhanced osteoblastogenesis and simultaneously inhibited osteoclastogenesis and suppressed RANKL and IL-17A expression in vivo. CONCLUSIONS: Our findings suggest that VnP-16 acts as a potent therapeutic agent for preventing and treating periodontitis by regulating bone re-modelling and immune and inflammatory responses.
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Perda do Osso Alveolar , Periodontite , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/prevenção & controle , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Humanos , Interleucina-17/uso terapêutico , Ligantes , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B , Osteogênese , Periodontite/tratamento farmacológico , Periodontite/metabolismo , Periodontite/prevenção & controle , Ligante RANK/metabolismo , Ratos , Vitronectina/uso terapêutico , Microtomografia por Raio-XRESUMO
Targeting specific pathologic pro-inflammatory cytokines or related molecules leads to excellent therapeutic effects in inflammatory arthritis, including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Most of these agents, known as biologic disease-modifying anti-rheumatic drugs (bDMARDs), are produced in live cell lines and are usually monoclonal antibodies. Several types of monoclonal antibodies target different pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-17A, IL-6, and IL-23/12. Some bDMARDs, such as rituximab and abatacept, target specific cell-surface molecules to control the inflammatory response. The therapeutic effects of these bDMARDs differ in different forms of inflammatory arthritis and are associated with different adverse events. In this article, we summarize the therapeutic utility and adverse effects of bDMARDs and suggest future research directions for developing bDMARDs.
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Antirreumáticos , Artrite Psoriásica , Produtos Biológicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Antirreumáticos/efeitos adversos , Artrite Psoriásica/tratamento farmacológico , Fator de Necrose Tumoral alfa , Anticorpos Monoclonais/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Produtos Biológicos/efeitos adversosRESUMO
BACKGROUND: Patients with rheumatoid arthritis (RA) have increased levels of interleukin-18 (IL-18) and decreased levels of IL-18 binding protein (IL-18BP) in the serum and synovial fluid (SF) compared to those in patients with osteoarthritis (OA) or in healthy controls. In this study, we evaluated the effects of IL-18BP on osteoclastogenesis and T cell differentiation in RA in vitro. METHODS: Serum and SF of patients with RA and OA were collected to compare IL-18 and IL-18BP levels by the enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMCs) and SF mononuclear cells (SFMCs) of RA patients were cultured under type 17 helper T cell (Th17) polarisation conditions with or without IL-18BP. In addition, PBMCs were cultured in the presence of receptor activator of nuclear factor kappa-Β ligand (RANKL) or IL-17A with or without IL-18BP, and tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative polymerase chain reaction for expression levels of osteoclast-related genes were performed. RESULTS: IL-18 levels were higher in the serum and SF of patients with RA, whereas IL-18BP was lower in the SF of patients with RA than in the control group. Treatment of patients' PBMCs with IL-18BP decreased the differentiation of CD4+ IL-17A+ and CD4+ RANKL+ T cells, whereas the differentiation of CD4+CD25highFOXP3+ T cell population increased in a dose-dependent manner. These changes in CD4+ T cell differentiation were also observed in the SFMCs of patients with RA. The levels IL-17A and soluble RANKL in the culture medium were significantly decreased by IL-18BP. IL-18BP administration decreased TRAP+ cell counts in a dose-dependent manner on the background of stimulation with RANKL-and IL-17A. In addition, expression levels of TRAP, NFATC1, CTSK, and TNFRSF11A (RANK) genes were lower in the IL-18BP treated cells. CONCLUSION: We showed that IL-18BP can rectify the Th17/Treg imbalance and decrease IL-17-induced osteoclastogenesis in PBMCs from patients with RA. Therefore, IL-18BP may have therapeutic potential for RA treatment.
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Artrite Reumatoide , Interleucina-17 , Células Cultivadas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Leucócitos Mononucleares , Osteoclastos , Osteogênese , Ligante RANK , Linfócitos T Reguladores , Células Th17RESUMO
OBJECTIVES: Sjögren's syndrome (SS) is an autoimmune disease caused by inflammation of the exocrine gland. The pathological hallmark of SS is the infiltration of lymphocytes into the salivary glands. Increased infiltration of T and B cells into salivary glands exacerbates symptoms of SS. Several recent studies have identified the role of gut microbiota in SS. Butyrate, one of the metabolites of the gut microbiota, regulates T cells; however, its effects on B cells and SS remain unknown. This study determined the therapeutic effect of butyrate on regulating B cells in SS. METHODS: Various concentrations of butyrate were intraperitoneally injected three times per week in NOD/ShiLtJ (NOD) mice, the prototype animal model for SS, and observed for more than 10 weeks. Whole salivary flow rate and the histopathology of salivary glands were investigated. Human submandibular gland (HSG) cells and B cells in mouse spleen were used to confirm the anti-inflammatory and immunomodulatory effects of butyrate. RESULTS: Butyrate increased salivary flow rate in NOD mice and reduced inflammation of salivary gland tissues. It also regulated cell death and the expression of circadian-clock-related genes in HSG cells. Butyrate induced B cell regulation by increasing IL-10-producing B (B10) cells and decreasing IL-17-producing B cells, through the circadian clock genes RAR-related orphan receptor alpha and nuclear receptor subfamily 1 group D member 1. CONCLUSION: The findings of this study imply that butyrate may ameliorate SS via reciprocal regulation of IL-10- and IL-17-producing B cells.
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Linfócitos B/imunologia , Linfócitos B/metabolismo , Butiratos/metabolismo , Relógios Circadianos/genética , Interleucina-10/biossíntese , Síndrome de Sjogren/etiologia , Síndrome de Sjogren/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Biomarcadores , Butiratos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Imuno-Histoquímica , Imunofenotipagem , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Modelos Biológicos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Síndrome de Sjogren/patologia , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismoRESUMO
OBJECTIVES: The choice of second-line biologics for AS patients previously treated with a TNF inhibitor (TNFi) remains unclear. Here, we compared drug retention and clinical efficacy between AS patients who switched biologics to secukinumab and those who switched to a different TNFi. METHODS: AS patients enrolled in the Korean College of Rheumatology BIOlogics registry were included, and patients with non-radiographic axial spondyloarthritis were excluded. Patients with previous TNFi exposure were divided into the secukinumab group and the TNFi switching group. Drug retention and clinical efficacy [BASDAI50, Assessment of Spondylo-Arthritis International Society (ASAS)20, ASAS40, AS disease activity score (ASDAS) <2.1, ASDAS clinically important improvement and ASDAS major improvement] were assessed at the 1 year follow-up. Propensity score (PS)-matched and covariate-adjusted logistic regression analyses were performed. RESULTS: Two hundred and forty-six had available 1 year follow-up data. Secukinumab as third- or later-line biologic was more frequent than alternative TNFi (54% vs 14%). PS-matched and multiple covariate-adjusted analyses showed that the odds ratio (OR) for drug discontinuation was comparable between the secukinumab and TNFi switching groups [OR 1.136 (95% CI 0.843, 1.531) and 1.000 (95% CI 0.433-2.308), respectively]. The proportion of patients who achieved BASDAI50 was also comparable between the two groups [OR 0.833 (95% CI 0.481, 1.441) in PS-matched analysis]. Other clinical efficacy parameters were also comparable. In the subgroup analysis of AS patients with previous TNFi discontinuation due to ineffectiveness, all clinical efficacy parameters were comparable between the two groups. CONCLUSION: In AS patients with previous exposure to a TNFi, switching biologics to secukinumab and switching to an alternative TNFi resulted in comparable drug retention and clinical efficacy.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Sistema de Registros , Retenção Psicológica/efeitos dos fármacos , Espondilite Anquilosante/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Feminino , Seguimentos , Humanos , Interleucina-17 , Masculino , Índice de Gravidade de Doença , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/psicologia , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate whether bone scintigraphy with semiquantitative analysis in patients with early axial spondyloarthritis (axSpA) has prognostic value for predicting spinal structural progression of these patients after 2 years. METHODS: The records of 53 patients with early axSpA who underwent baseline bone scintigraphy were reviewed retrospectively. The sacroiliac joint to sacrum (SIS) ratio of bone scintigraphy was measured for semiquantitative analysis, and modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and syndesmophyte growth were calculated at baseline and after 2 years. Receiver operating characteristic (ROC) curve analysis was used to determine the cut-off for the SIS ratio of bone scintigraphy. To identify factors associated with significant spinal structural progression, univariate and multivariate logistic regression analyses were performed. Significant progression of spinal structural damage over 2 years was defined as an increase of mSASSS of at least 2 units for 2 years or new syndesmophyte growth/bridging of pre-existing syndesmophytes. RESULTS: Multivariate regression analysis revealed current smoking status (p=0.010), and high SIS ratio of bone scintigraphy (p=0.016) as independent predictors for worsening mSASSS by at least 2 units over 2 years. For new syndesmophyte growth/bridging of pre-existing syndesmophytes over 2 years, current smoking (p=0.013), high SIS ratio of bone scintigraphy (p=0.025), and pre-existing syndesmophyte (p=0.036) were independent predictors. CONCLUSIONS: Semiquantitative analysis of bone scintigraphy (high SIS ratio) in patients with early axSpA may be useful for identifying patients at high risk for spinal structural progression after 2 years.
Assuntos
Espondilartrite , Espondilite Anquilosante , Progressão da Doença , Humanos , Projetos Piloto , Radiografia , Cintilografia , Estudos Retrospectivos , Articulação Sacroilíaca/diagnóstico por imagem , Sacro/diagnóstico por imagem , Índice de Gravidade de Doença , Espondilartrite/diagnóstico por imagem , Espondilite Anquilosante/diagnóstico por imagemRESUMO
BACKGROUND: Patient-centered management is becoming increasingly important in gout, but there are limited studies exploring patients' perspectives and preferences. We aimed to investigate patients' perspectives and preferences regarding gout and gout management, and their impacts on adherence to urate lowering therapy (ULT). METHODS: A paper-based survey was performed in patients with gout seen at the rheumatology outpatient clinics of 16 tertiary hospitals. The survey included questions regarding demographics, comorbidities, gout attacks, current treatment and adherence, and patients' perspectives and preferences regarding gout and gout management. Multivariate regression analysis was performed to determine the factors associated with ULT adherence. RESULTS: Of 809 surveyed patients with gout, 755 (94.5%) were using ULT. Among those using ULT, 89.1% had ≥ 80% adherence to ULT. Majority of the patients knew management strategies to some extent (94.8%), perceived gout as a life-long disease (91.2%), and were making efforts toward practicing at least one lifestyle modification (89.2%). Most patients (71.9%) obtained information about gout management during their clinic visits. Approximately half of the patients (53.6%) preferred managing their disease with both ULT and lifestyle modification, 28.4% preferred ULT only, and 17.4% preferred lifestyle modification only. Adherence was better in patients with older age (odds ratio [OR], 1.03), those with better knowledge of gout management strategies (OR, 3.56), and those who had preference for ULT (OR, 2.07). CONCLUSION: Patients' perspectives and management preferences had high impacts on adherence to ULT in gout. Consideration of patients' perspectives and preferences is important for achieving the desired clinical outcome in gout.
Assuntos
Supressores da Gota/uso terapêutico , Gota/tratamento farmacológico , Conhecimentos, Atitudes e Prática em Saúde , Preferência do Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Gerenciamento Clínico , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Assistência Centrada no Paciente , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Rheumatoid arthritis (RA) is a long-term autoimmune disorder that mostly affects the joints and leads to the destruction of cartilage. An RA model in non-human primates is especially useful because of their close phylogenetic relationship to humans in terms of cross-reactivity to compounds developed using modern drug technologies. METHODS: We used a collagen-induced arthritis (CIA) model in Macaca fascicularis. CIA was induced by the immunization of chicken type II collagen. Swelling was measured as the longitudinal and transverse axes of 16 proximal interphalangeal joints. RESULTS: A new system for visual evaluation was created, with a perfect score of 16. Individual behavioral analysis was also conducted. Serum was collected once a week after the first immunization. Blood chemistry and inflammatory cytokine parameters were higher in the CIA group than in the wild type group. CONCLUSION: In conclusion, we established CIA in M. fascicularis, and the results can be used for drug evaluation models.
Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Colágeno Tipo II , Macaca fascicularis , FilogeniaRESUMO
BACKGROUND: To evaluate the immunomodulatory effect of Lactobacillus sakei in a mouse model of rheumatoid arthritis (RA) and in human immune cells. METHODS: We evaluated whether L. sakei reduced the severity of collagen-induced arthritis (CIA) and modulated interleukin (IL)-17 and IL-10 levels, as well as whether it affected the differentiation of CD4+ T cells and regulatory B cells. We evaluated osteoclastogenesis after culturing bone marrow-derived mononuclear cells with L. sakei. RESULTS: The differentiation of T helper 17 cells and the serum level of IL-17 were suppressed by L. sakei in both human peripheral blood mononuclear cells and mouse splenocytes. The serum level of IL-10 was significantly increased in the L. sakei-treated group, whereas the regulatory T cell population was unchanged. The population of regulatory B cells significantly increased the in L. sakei-treated group. Oral administration of L. sakei reduced the arthritis incidence and score in mice with CIA. Finally, osteoclastogenesis and the mRNA levels of osteoclast-related genes were suppressed in the L. sakei-treated group. CONCLUSION: L. sakei exerted an anti-inflammatory effect in an animal model of RA, regulated Th17 and regulatory B cell differentiation, and suppressed osteoclastogenesis. Our findings suggest that L. sakei has therapeutic potential for RA.
Assuntos
Artrite Experimental , Linfócitos B Reguladores , Latilactobacillus sakei , Animais , Artrite Experimental/terapia , Diferenciação Celular , Camundongos , Linfócitos T Reguladores , Células Th17RESUMO
BACKGROUND: Spondyloarthritis (SpA) is chronic inflammatory arthritis, and interleukin (IL)-17 is crucial in SpA pathogenesis. Type 17 helper T (Th17) cells are one of major IL-17-secreting cells. Signal transducer and activator of transcription (STAT)-3 signaling induces Th17 differentiation. This study investigated the effects of protein inhibitor of activated STAT3 (PIAS3) on SpA pathogenesis. Curdlan was injected into SKG ZAP-70W163C mice for SpA induction. METHODS: The PIAS3 or Mock vector was inserted into mice for 10 weeks. Clinical and histologic scores of the paw, spine, and gut were evaluated. The expression of IL-17, tumor necrosis factor-α (TNF-α), STAT3, and bone morphogenic protein (BMP) was measured. Confocal microscopy and flow cytometry were used to assess Th cell differentiation. RESULTS: PIAS3 significantly diminished the histologic scores of the paw and gut. PIAS3-treated mice displayed decreased expression of IL-17, TNF-α, and STAT3 in the paw, spine, and gut. BMP-2/4 expression was lower in the spines of PIAS3-treated mice. Th cell differentiation was polarized toward the upregulation of regulatory T cells (Tregs) and the downregulation of Th17 in PIAS3-treated mice. CONCLUSION: PIAS3 had beneficial effects in mice with SpA by reducing peripheral arthritis and gut inflammation. Pro-inflammatory cytokines and Th17/Treg differentiation were controlled by PIAS3. In addition, BMPs were decreased in the spines of PIAS3-treated mice. These findings suggest that PIAS3 could have therapeutic benefits in patients with SpA.
Assuntos
Trato Gastrointestinal/patologia , Inflamação/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Transdução de Sinais , Espondilartrite/imunologia , Espondilartrite/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos BALB C , Fator de Transcrição STAT3/metabolismo , Baço/patologiaRESUMO
Rheumatoid arthritis (RA) is a type of systemic autoimmune arthritis that causes joint inflammation and destruction. One of the pathological mechanisms of RA is known to involve histone acetylation. Although the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) can attenuate arthritis in animal models of RA, the mechanism underlying this effect is poorly understood. This study was performed to examine whether SAHA has therapeutic potential in an animal model of RA and to investigate its mechanism of action. Collagen-induced arthritis (CIA) mice were orally administered SAHA daily for 8 weeks and examined for their arthritis score and incidence of arthritis. CD4+ T cell regulation following SAHA treatment was confirmed in splenocytes cultured under type 17 helper T (Th17) cell differentiation conditions. Clinical scores and the incidence of CIA were lower in mice in the SAHA treatment group compared to the controls. In addition, SAHA inhibited Th17 cell differentiation, as well as decreased expression of the Th17 cell-related transcription factors pSTAT3 Y705 and pSTAT3 S727. In vitro experiments showed that SAHA maintained regulatory T (Treg) cells but specifically reduced Th17 cells. The same results were obtained when mouse splenocytes were cultured under Treg cell differentiation conditions and then converted to Th17 cell differentiation conditions. In conclusion, SAHA was confirmed to specifically inhibit Th17 cell differentiation through nuclear receptor subfamily 1 group D member 1 (NR1D1), a factor associated with Th17 differentiation. The results of the present study suggested that SAHA can attenuate CIA development by inhibition of the Th17 population and maintenance of the Treg population through NR1D1 inhibition. Therefore, SAHA is a potential therapeutic candidate for RA.