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Background: Interstitial lung disease (ILD) is a critical extra-articular manifestation of rheumatoid arthritis (RA). However, little is known about the risk factors of RA-ILD. Objectives: Here, we examined the effect of demographic, clinical, therapeutic, and environmental factors on the incidence of ILD in RA patients using the Korean College of Rheumatology Biologics and Targeted Therapy (KOBIO) registry. Design: We used data from the KOBIO registry, a multi-center, prospective, observational cohort that included RA patients in South Korea. Methods: RA patients who used biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) or conventional synthetic (cs)DMARDs, and were enrolled in the KOBIO registry, were examined. Demographic, clinical, and radiographic characteristics, as well as medications, were recorded at baseline and annually thereafter. Kaplan-Meier curves and the log-rank test were used to compare the incidence of ILD between RA patients taking different b/tsDMARDs. Hazard ratios (HRs) were calculated by Cox regression analyses. Results: In total, 2492 patients (1967 in the b/tsDMARDs group and 525 in the csDMARDs group) were analyzed. The b/tsDMARDs group showed longer disease duration, higher erythrocyte sedimentation rate/C-reactive protein, and higher disease activity score-28 (DAS28) than the csDMARDs group. The incidence of ILD was significantly higher in those taking tumor necrosis factor inhibitors and abatacept than in those taking csDMARDs (log ranked p < 0.001). Multivariate Cox regression analysis identified older age (HR = 1.057, p = 0.001), male sex (HR = 2.824, p = 0.007), time-averaged DAS28 (HR = 2.241, p < 0.001), and rheumatoid factor titer (HR = 1.009, p = 0.007) as having a significantly increased HR for ILD occurrence. Conclusion: ILD is a rare but critical extra-articular symptom of RA patients. Therefore, RA patients with the above risk factors should be monitored carefully for ILD development.
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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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BACKGROUND: Tumor necrosis factor inhibitors (TNFis) have shown dramatic benefit in patients with spondyloarthritis (SpA). Tapering of TNFi medication may be considered in patients with sustained low disease activity because continued use of TNFis at standard doses may increase the risk of side effects including infections and impose an economic burden. However, the optimal TNFi tapering strategy for SpA patients with inactive disease has not been established. In the present study, we investigated whether tapering TNFi doses is associated with similar risk of disease flare to maintaining SpA patients on TNFis at the standard dosage. METHODS: The MEDLINE, Embase, and Cochrane databases were systemically searched to retrieve randomized control trials (RCTs) and observational studies published prior to August 2023, that compared disease flare in SpA (including axial SpA [axSpA], psoriatic arthritis [PsA], and SpA with IBD) patients who received standard TNFi doses and those who received a tapered dose of TNFi. Odds ratios (ORs) and 95% confidence intervals (CIs) were directly retrieved or calculated, and meta-analyses were performed. Bias was assessed using funnel plots with Begg and Mazumdar rank correlation / Egger's regression method. RESULTS: Among 2,237 SpA patients in the 12 studies (9 RCTs and 3 observational studies) retrieved, 1,301 received the standard TNFi dose, while 936 SpA patients underwent TNFi tapering. Of these, 216 (16.6%) standard-dose TNFi and 217 (23.2%) TNF-tapering patients experienced disease flares. The pooled OR for disease flare in TNFi-tapering patients was 1.601 (95% CI 1.276 - 2.008) compared with the standard-dose patients. The funnel plot showed no publication bias. CONCLUSIONS: The strategy of TNFi tapering was associated with a significantly increased risk of disease flare compared to maintaining SpA patients at the standard TNF dose. Further studies are needed to determine which patients can safely undergo tapering of TNFi and to develop safe tapering strategies.
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Espondilartrite , Inibidores do Fator de Necrose Tumoral , Humanos , Espondilartrite/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Exacerbação dos Sintomas , Redução da Medicação , Antirreumáticos/uso terapêutico , Antirreumáticos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND/AIMS: We evaluated nailfold capillaroscopy (NFC) of interstitial pneumonia with autoimmune features (IPAF) and compared it with that of patients with connective tissue disease-interstitial lung disease (CTD-ILD) and idiopathic interstitial pneumonia (IIP). METHODS: Patients with newly diagnosed as ILD were evaluated using NFC. Baseline demographic, clinical, serological, and high-resolution CT findings were collected. NFC was semi-quantitatively scored with six domains ranging from 0 to 18. In addition, the overall patterns (scleroderma/non-scleroderma patterns) were determined. RESULTS: A total of 81 patients (31 with CTD-ILD, 18 with IPAF, and 32 with IIP) were included. The non-specific interstitial pneumonia pattern was the most common ILD pattern in the CTD-ILD and IPAF groups, whereas the usual interstitial pneumonia pattern was the most common in the IIP group. The semi-quantitative score of the CTD-ILD group was higher than that of the IPAF or IIP groups (5.8 vs 4.2 vs 3.0, p < 0.001, respectively). Giant capillaries and haemorrhages were more frequently present in the CTD-ILD and IPAF groups than in the IIP group. A scleroderma pattern was present in 27.8% of the IPAF group, whereas none of the IIP patients showed a scleroderma pattern. CONCLUSION: NFC findings may be useful in classifying patients with ILD into CTD-ILD/IPAF/IIP.
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Doenças do Tecido Conjuntivo , Pneumonias Intersticiais Idiopáticas , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Humanos , Angioscopia Microscópica , Tomografia Computadorizada por Raios X , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Pneumonias Intersticiais Idiopáticas/diagnóstico , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/diagnóstico por imagemRESUMO
OBJECTIVES: This study investigated whether Janus kinase inhibitors (JAKis) raise the risk of cardiovascular disease (CVD), venous thromboembolism (VTE), and cancer in patients with rheumatoid arthritis (RA). METHODS: We conducted a real-world retrospective observational study using data obtained from the Korean National Health Insurance Service database. Two data sets were analyzed: tumor necrosis factor inhibitor (TNFi)/JAKi-naive RA patients (set 1) and all RA patients who used TNFis or JAKis (set 2). The incidence rate ratios (IRRs) and hazard ratios (HRs) for acute myocardial infarction (AMI), stroke, cardiovascular (CV)-related mortality, major adverse cardiovascular events (MACE), VTE, arterial thromboembolism (ATE), cancer, and all-cause mortality were compared between the JAKi and TNFi groups. RESULTS: Set 1 included 1,596 RA patients (JAKi group: 645; TNFi group: 951), and set 2 included 11,765 RA patients (JAKi group: 2,498; TNFi group: 9,267). No adverse events (AEs) showed significantly higher IRRs in the JAKi groups than in the TNFi groups of sets 1 and 2. The HRs for MACE in the JAKi groups of sets 1 and 2 were 0.59 (95% confidence [CI], 0.35 to 0.99) and 0.80 (95% CI, 0.67 to 0.97), respectively. The JAKi group of set 2 showed a significantly higher risk of all-cause mortality (HR, 1.71; 95% CI, 1.32 to 2.20), but the other AEs did not demonstrate increased risks in the JAKi groups. CONCLUSIONS: In this study, JAKis did not increase the risk of AMI, stroke, CV-related mortality, MACE, VTE, ATE, or cancer in Korean RA patients relative to TNFis.
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Antirreumáticos , Artrite Reumatoide , Doenças Cardiovasculares , Inibidores de Janus Quinases , Infarto do Miocárdio , Neoplasias , Tromboembolia Venosa , Humanos , Inibidores de Janus Quinases/uso terapêutico , Antirreumáticos/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/induzido quimicamente , Tromboembolia Venosa/tratamento farmacológico , Fator de Necrose Tumoral alfa/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Infarto do Miocárdio/epidemiologia , Seguro Saúde , Neoplasias/tratamento farmacológico , República da Coreia/epidemiologiaRESUMO
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
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
The present study evaluated the predictive role of baseline radiographic change and disease activity on drug retention and clinical response in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor inhibitor (TNFi). Korean Observational Study Network for Arthritis (KORONA) registry was evaluated to identify RA patients treated with a TNFi. Disease activity score-28 (DAS28) was evaluated at baseline and 1 year after TNFi initiation or at termination of TNFi due to inefficacy (within 1 year). The retention rate of TNFi was compared in patients with and without bony erosions. The hazard ratio (HR) for drug retention was evaluated by Cox regression analysis, as was the odds ratio (OR) for achieving remission (DAS28 < 2.6). This study included 109 RA patients, including 97 (89%) women and 30 (27.5%) with erosions, who were treated with a TNFi. Higher baseline DAS28 was negatively associated with achievement of remission (OR = 0.56, 95% CI 0.35-0.88). The TNFi retention rate was significantly lower in RA patients with than in those without erosions (p = 0.04). Factors significantly associated with drug discontinuation included the presence of erosions (HR = 2.45, 95% CI 1.08-5.51) and higher time-averaged DAS28 (HR = 2.17, 95% CI 1.47-3.20), whereas concomitant methotrexate was associated with lack of drug discontinuation (HR = 0.40, 95% CI 0.17-0.95). The presence of erosions and high time-averaged disease activity could predict poor retention of TNFi by RA patients. Higher baseline DAS28 was associated with a reduced clinical response in patients with RA.Trial registration Clinical Research Information Service of South Korea https://cris.nih.go.kr : KCT0000086, registered May 26, 2009.
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Antirreumáticos , Artrite Reumatoide , Humanos , Feminino , Masculino , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Antirreumáticos/uso terapêutico , Resultado do Tratamento , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêuticoRESUMO
Herein, we investigated the effect of DJ-1 on helper T cell differentiation, fibroblast-like synoviocyte (FLS) activation, and osteoclastogenesis in rheumatoid arthritis (RA). Serum and synovial fluid (SF) of RA and osteoarthritis (OA) patients were collected, and DJ-1 and H2O2 levels were investigated. CD4+ cells from peripheral blood mononuclear cells (PBMCs) were cultured under type 17 helper T cell (Th17) polarization conditions, and CD4+ T cell differentiation, pro-inflammatory cytokine levels, and soluble receptor activator of nuclear factor kappa-Β ligand (RANKL) were assessed. RA-FLSs were stimulated with 50 µM H2O2, and DJ-1 (10, 50, 100 ng/mL) to evaluate MMP-9, VEGF, TNF-α, and sRANKL production, while RANKL+ FLSs were assessed using flow cytometry. Monocytes were cultured with RANKL or IL-17A with or without DJ-1 and H2O2-pretreated RA-FLS, and tartrate-resistant acid phosphatase (TRAP) staining and RT-qPCR of osteoclast-related genes were performed. The levels of DJ-1 and H2O2 in serum and SF of RA patients were higher than those of OA patients. Under Th17-polarizing conditions, CD4+RANKL+ and CD4+CCR4+CCR6+CXCR3- T cells decreased, whereas CD4+CD25highFoxp3+ T cell increased after DJ-1 administration. Additionally, IL-17A, TNF-α, and sRANKL levels decreased in DJ-1-treated groups. DJ-1 lowered MMP-9, VEGF, TNF-α, and sRANKL levels, and RANKL+ FLS in ROS-stimulated RA-FLS. Both RANKL and IL-17A stimulated osteoclast differentiation, DJ-1 decreased TRAP+ cell count, and the expression levels of TRAP, ATP6v0d2, NFATc1, and CTSK. These findings were also observed in in vitro osteoclastogenesis with DJ-1 pretreated RA-FLS. As DJ-1 regulates Th17/Treg imbalance, pro-inflammatory cytokine production, RA-FLS activation, and osteoclastogenesis, it holds potential for RA therapy.
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Artrite Reumatoide , Osteogênese , Proteína Desglicase DJ-1 , Linfócitos T , Artrite Reumatoide/genética , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Fibroblastos/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Interleucina-17/metabolismo , Leucócitos Mononucleares/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Osteoartrite/metabolismo , Osteoclastos/metabolismo , Proteína Desglicase DJ-1/metabolismo , Ligante RANK/metabolismo , Linfócitos T/citologia , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Nailfold capillaroscopy (NFC) is a safe and non-invasive imaging tool for evaluating microvascular abnormalities. This retrospective cross-sectional study aimed to analyze the NFC outcomes and clinical characteristics in patients and an asymptomatic carrier with transthyretin (TTR) gene mutation. The participants consist of eight patients with genetically and clinically confirmed hereditary amyloidogenic transthyretin (ATTRv) amyloidosis and one asymptomatic carrier. The TTR gene mutant forms of six male and three female participants from six families were Asp38Ala (five patients), Lys35Asn (three patients), and Ala36Pro (one patient). All participants showed decreased capillary density, dilatated capillaries, and destructed architecture in NFC. Early progression identification of a carrier to patients with symptoms is a major concern from a therapeutic viewpoint in ATTRv amyloidosis. Therefore, further studies with a larger number of subjects will be needed to determine the use of NFC as an early detection tool.
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Neuropatias Amiloides Familiares , Angioscopia Microscópica , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/genética , Estudos Transversais , Feminino , Humanos , Masculino , Projetos Piloto , Pré-Albumina/genética , Estudos RetrospectivosRESUMO
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
PURPOSE: Spondyloarthritis (SpA) is a systemic inflammatory arthritis mediated mainly by interleukin (IL)-17. The vitronectin-derived bioactive peptide, VnP-16, exerts an anti-osteoporotic effect via ß1 and αvß3 integrin signaling. SpA is associated with an increased risk of osteoporosis, and we investigated the effect of VnP-16 in mice with SpA. METHODS: SpA was induced by curdlan in SKG ZAP-70W163C mice, which were treated with vehicle, celecoxib, VnP-16, or VnP-16+celecoxib. The clinical score, arthritis score, spondylitis score, and proinflammatory cytokine expression of the spine were evaluated by immunohistochemical staining. Type 17 helper T cell (Th17) and regulatory T cell (Treg) differentiation in the spleen was evaluated by flow cytometry and in the spine by confocal staining. Splenocyte expression of signal transducer and activator of transcription (STAT) 3 and pSTAT3 was evaluated by in vitro Western blotting. RESULTS: The clinical score was significantly reduced in the VnP16+celecoxib group. The arthritis and spondylitis scores were significantly lower in the VnP-16 and VnP16+celecoxib groups than the vehicle group. In the spine, the levels of IL-1ß, IL-6, tumor necrosis factor-α, and IL-17 expression were reduced and Th17/Treg imbalance was regulated in the VnP-16 alone and VnP-16+celecoxib groups. Flow cytometry of splenocytes showed increased polarization of Tregs in the VnP-16+celecoxib group. In vitro, VnP-16 suppressed pSTAT3. CONCLUSIONS: VnP-16 plus celecoxib prevented SpA progression in a mouse model by regulating the Th17/Treg imbalance and suppressing the expression of proinflammatory cytokines.
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Celecoxib/administração & dosagem , Peptídeos/administração & dosagem , Espondilartrite/tratamento farmacológico , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Vitronectina/química , beta-Glucanas/efeitos adversos , Animais , Celecoxib/farmacologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Integrina alfaVbeta3/metabolismo , Integrina beta1/metabolismo , Camundongos , Peptídeos/farmacologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Baço/imunologia , Espondilartrite/induzido quimicamente , Espondilartrite/genética , Espondilartrite/imunologiaRESUMO
The clinical data on the biologic disease-modifying antirheumatic drug (bDMARD) use in late-onset ankylosing spondylitis (LOAS) is limited. Thus, this study aimed to evaluate the drug efficacy and retention rate of bDMARDs in LOAS and compare it to young-onset ankylosing spondylitis (YOAS). Data of patients with AS receiving bDMARDs were extracted from the Korean College of Rheumatology Biologics and Targeted Therapy registry. Patients whose age of onset was > 50 years and ≤ 50 years were classified as having LOAS and YOAS, respectively. Their baseline characteristics and disease-associated parameters were evaluated. Drug efficacy [Ankylosing Spondylitis Disease Activity Score (ASDAS)-clinically important improvement (CII), ASDAS-major improvement (MI), Assessment of SpondyloArthritis International Society (ASAS) 20, and ASAS 40] at 1-year follow-up and drug retention rates were assessed. A total of 1708 patients (comprising 1472 patients with YOAS and 236 patients with LOAS) were included in this analysis. The LOAS group had a lower prevalence among males, lower HLA-B27 positivity and a higher prevalence of peripheral arthritis. Patients with LOAS were more likely to have higher disease-associated parameters (inflammatory reactants, patient global assessment, ASDAS-erythrocyte sedimentation rate, and ASDAS-C-reactive protein). LOAS was negatively associated with achieving ASDAS-CII, ASAS 20, and ASAS 40. The drug retention rate was lower in LOAS; however, the propensity score-matched and covariate-adjusted hazard ratios for bDMARD discontinuation were comparable to YOAS. There were no differences in the drug retention rates based on the type of bDMARD used in LOAS. Inferior clinical efficacy and shorter drug retention time were found in patients with LOAS receiving bDMARDs using real-world nationwide data. There were no differences among each bDMARD type.
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Antirreumáticos/uso terapêutico , Espondilite Anquilosante/diagnóstico por imagem , Adulto , Idade de Início , Idoso , Produtos Biológicos/uso terapêutico , Sedimentação Sanguínea , Índice de Massa Corporal , Proteína C-Reativa , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Prevalência , Modelos de Riscos Proporcionais , Sistema de Registros , Análise de Regressão , República da Coreia/epidemiologia , Fumar , Sociedades Médicas , Adulto JovemRESUMO
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: 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
OBJECTIVE: This study aimed to evaluate the impact of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) on lipid profile and atherogenic index of plasma (AIP) in rheumatoid arthritis (RA) patients and to compare the occurrence of dyslipidemia between patients using bDMARDs, tsDMARDs, or conventional DMARDs (cDMARDs). METHODS: Data on lipid profile, AIP, and occurrence of dyslipidemia were collected from the Korean College of Rheumatology BIOlogics registry. A comparison was conducted between patients using bDMARDs (tumor necrosis factor (TNF)-α inhibitor, tocilizumab, abatacept), Janus kinase inhibitors (JAKis), and cDMARDs. The Kaplan-Meier method was used to compare the occurrence of dyslipidemia between groups, and hazard ratios (HR) were calculated using the cox proportional hazard method. RESULTS: The data of 917, 826, 789, 691, and 520 RA patients were eligible for analysis at the baseline, 1-year, 2-year, 3-year, and 4-year follow-ups, respectively. Baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were higher in the cDMARDs group, whereas AIP was comparable. During the 4-year follow-up, AIP was comparable between the groups. The occurrence of dyslipidemia did not show a significant difference when comparing the bDMARDs/tsDMARDs and cDMARDs groups (P=0.06) or the TNF-α inhibitor, tocilizumab, abatacept, JAKi, and cDMARD user groups (P=0.3). In the multivariate cox proportional hazard model, older age (HR=1.03, P=0.005) and concomitant hypertension (HR=2.21, P=0.013) were significantly associated with dyslipidemia occurrence. CONCLUSION: Long-term use of bDMARDs and tsDMARDs is relatively safe with regard to lipid profile, AIP, and the occurrence of dyslipidemia in RA patients. Key Points ⢠The use of bDMARDs and tsDMARDs did not increase the risk of dyslipidemia than cDMARDs use in patients with RA. ⢠AIP was comparable between bDMARDs user, tsDMARDs user, and cDMARDs user group in 4-year follow-up data. ⢠Based on the present study, the long-term use of bDMARDs or tsDMARDs did not significantly deteriorate atherogenic lipid profile nor an increased risk of dyslipidemia in patients with RA.
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Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Reumatologia , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/efeitos adversos , Seguimentos , Humanos , Sistema de Registros , República da CoreiaRESUMO
Objective: Trauma has been proposed as a triggering factor of psoriatic arthritis (PsA), and the deep Koebner phenomenon was the suggested underlying mechanism The relationship between spondyloarthritis (SpA) and trauma was only observed in PsA This study investigated cases of SpA other than PsA that occurred after physical trauma and analyzed their clinical, laboratory, and radiologic features. Methods: We retrospectively reviewed the medical records of 213 patients who visited our hospital due to a suspicion of SpA and grouped them into post-traumatic-SpA (PT-SpA, n=12) and non-post-traumatic-SpA (non-PT-SpA, n=201) Baseline characteristics were compared between the two groups by cross-sectional manner. Results: Peripheral SpA was more common in PT-SpA than in non-PT-SpA Active inflammation on sacroiliac joint (SIJ) magnetic resonance imaging (MRI) was more common in non-PT-SpA (835% vs 545%, p=0046) The modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) was significantly higher in the non-PT-SpA group (20 vs 00, p=0007) Symptom duration from the first SpA symptom to diagnosis tends to be longer in the non-PT-SpA group (20 vs 05 years, p=0079). Conclusion: PT-SpA patients more frequently showed peripheral SpA, a less active inflammatory lesion on SIJ MRI, and a lower mSASSS score Further studies are needed to clarify whether physical trauma has a direct/indirect role in the pathogenesis of SpA or merely confers an opportunity to recognize SpA symptoms.
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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.
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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
Chronic shoulder pain is a common complication in breast cancer patients after surgery. Chronic shoulder pain after breast cancer surgery was formerly considered as neuropathic pain, however the pathophysiology including structural damages has not been assessed comprehensively. We hypothesized that the structural change could be one of the cause of shoulder pain after breast cancer surgery and evaluated various ultrasonography findings of the shoulder in breast cancer patients with chronic shoulder pain. Patients who were suffering from chronic shoulder pain on unilateral side for at least 3 months after breast cancer surgery were enrolled from a single tertiary hospital. Demographic and clinical data were collected at the baseline. Articular and adjacent structures of both shoulders (painful and contralateral side) were evaluated by ultrasonography. The ultrasonography findings were compared between painful and contralateral sides. Logistic regression analysis was performed to determine the factors associated with abnormal ultrasonography findings. Fifty-two female patients (average age of 55) were enrolled. Significantly more abnormal ultrasonography findings were observed in the painful side than in the contralateral side [39 (75.0%) vs 11 (21.2%), P < 0.001]. The coracohumeral ligament was significantly thicker in the painful side than in the contralateral side (2.48 ± 0.69 vs 1.54 ± 1.25 mm, P < 0.001); adhesive capsulitis was also more frequent in the painful side [14 (26.9%) vs 0, P < 0.001]. Furthermore, patients with a history of breast cancer surgery on the ipsilateral side were associated with abnormal ultrasonography findings and adhesive capsulitis. This study is the first to evaluate ultrasonography in patients with chronic shoulder pain after breast cancer surgery. The results showed that ultrasonography could reveal several structural problems in these patients.
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Neoplasias da Mama/cirurgia , Dor Crônica/diagnóstico por imagem , Mastectomia/efeitos adversos , Dor de Ombro/diagnóstico por imagem , Dor Crônica/etiologia , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Articulação do Ombro/diagnóstico por imagem , Dor de Ombro/etiologia , UltrassonografiaRESUMO
BACKGROUND: The present study aimed to evaluate the suppressive role of interleukin (IL)-25 in IL-22-induced osteoclastogenesis and receptor activator of nuclear factor κB ligand (RANKL) expression in rheumatoid arthritis (RA). METHODS: Serum from patients with RA and osteoarthritis (OA), and healthy controls, and synovial fluid from patients with RA and OA were collected, and the levels of IL-22 and IL-25 were measured. RA and OA synovial tissues were stained against IL-25. Fibroblast-like synoviocytes (FLSs) of patients with RA were cultured with IL-22, in the presence or absence of IL-25, and RANKL expression was measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured under IL-22/RANKL + M-CSF, with or without IL-25, and tartrate-resistant acid phosphatase (TRAP)-positive cells and osteoclast-related markers were investigated to determine osteoclastogenesis. RESULTS: Serum and synovial IL-25 levels in RA were upregulated compared to those in OA and healthy control, and elevated expression of IL-25 in RA synovial tissue was re-confirmed. IL-25 and IL-22 levels showed significant correlation in serum and synovial fluid. Pre-treatment of FLS with IL-25 reduced IL-22-induced RANKL expression at the RNA level. The suppressive effects of IL-25 were confirmed to occur through the STAT3 and p38 MAPK/IκBα pathways. IL-25 reduced osteoclast differentiation and suppressed the expression of osteoclast-related markers. CONCLUSION: In the current study, we demonstrated the regulatory effect of IL-25 on IL-22-induced osteoclastogenesis. Therapeutic approach involving augmentation of IL-25 regulatory response may serve as a novel treatment option for RA, especially by suppressing osteoclastogenesis.