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Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.
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Predisposição Genética para Doença , Escleroderma Sistêmico , Humanos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Receptores de IgG/genética , Estratificação de Risco Genético , Escleroderma Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Fatores Reguladores de Interferon/genética , Loci GênicosRESUMO
OBJECTIVES: The aim of this article is to investigate the efficacy and safety of tocilizumab in Japanese patients with systemic sclerosis. METHODS: Post hoc subgroup analysis of a global, randomised, controlled trial in patients treated with weekly tocilizumab 162 mg or placebo subcutaneously in a 48-week double-blind period (tocilizumab and placebo groups) followed by tocilizumab for 48 weeks in an open-label extension (continuous-tocilizumab and placebo-tocilizumab groups). RESULTS: Among 20 patients, 12 were randomised to tocilizumab (all had interstitial lung disease) and eight were randomised to placebo (six had interstitial lung disease). The modified Rodnan skin score improved in both treatment groups. The mean change in percent-predicted forced vital capacity was 3.3% [95% confidence interval (CI), -2.5 to 9.0] for tocilizumab and -3.8% (95% CI, -9.9 to 2.2) for placebo in the double-blind period and 2.0% (95% CI, -0.7 to 4.6) for continuous-tocilizumab and -1.4% (95% CI, -6.7 to 4.0) for placebo-tocilizumab in the open-label extension. Rates of serious adverse events per 100 patient-years were 19.3 for tocilizumab and 26.8 for placebo in the double-blind period and 0.0 for continuous-tocilizumab and 13.6 for placebo-tocilizumab in the open-label period. CONCLUSIONS: The efficacy and safety of tocilizumab in patients with systemic sclerosis were consistent between the Japanese subpopulation and the global trial population.
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Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Humanos , Japão , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/induzido quimicamente , Método Duplo-Cego , Resultado do TratamentoRESUMO
OBJECTIVES: We previously reported that heating of the neck or elbows alleviated Raynaud's phenomenon in patients with systemic sclerosis and upregulated capillary extension factor angiopoietin-1 (Angpt-1) in the fingertips. Here, we investigated which cases responded better to the effect of heating of the neck or elbows. METHODS: The pre- to post-heating change in the visual analogue scale for Raynaud's phenomenon (ΔVAS) was examined for correlation with age, disease duration, autoantibodies, disease types, corticosteroid dose, capillaroscopic nailfold capillary damage, fingertip Angpt-1 concentrations at baseline, and increased rate of Angpt-1 concentration. RESULTS: The ΔVAS for elbow heating correlated positively with the baseline Angpt-1 concentration, whereas the opposite correlation was observed for neck heating. The other items were not significantly correlated with the ΔVAS; however, the ΔVAS for elbow heating tended to be larger in patients with advanced capillary damage, whereas the opposite trend was observed for neck heating. CONCLUSIONS: Elbow and neck heating alleviated Raynaud's phenomenon to a similar extent, but their mechanism was different. Heating the elbows had a greater effect on patients with advanced capillary damage and lower fingertip Angpt-1 concentrations.
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Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases.
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Síndrome de Behçet , Exossomos , Humanos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Síndrome de Behçet/genética , Síndrome de Behçet/metabolismo , Exossomos/genética , Mitocôndrias/genética , Inflamação/metabolismo , Caspases/metabolismoRESUMO
Introduction: Intravesical Bacillus Calmette-Guerin administration is the standard therapy for high-risk nonmuscle invasive bladder cancer and is usually well tolerated. However, some patients experience severe, potentially fatal, complications including interstitial pneumonitis. Case presentation: A 72-year-old female with scleroderma was diagnosed with bladder carcinoma in situ. She developed severe interstitial pneumonitis with the first administration of intravesical Bacillus Calmette-Guerin after the cessation of immunosuppressive agents. Six days after the first administration, she experienced dyspnea at rest, and computed tomography revealed scattered frosted shadows in the upper lung. The following day, she required intubation. We suspected drug-induced interstitial pneumonia and started steroid pulse therapy for 3 days, resulting in a complete response. No exacerbation of scleroderma symptoms or recurrence of cancer was observed 9 months after Bacillus Calmette-Guerin therapy. Conclusion: For patients receiving intravesical Bacillus Calmette-Guerin therapy, close observation of the respiratory condition is necessary for early therapeutic intervention.
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Background: Autoimmune inflammatory rheumatic disease (AIRD) patients are at high risk of the coronavirus disease 2019 (COVID-19), but the medium-term effects of immunosuppressants on vaccine efficacy are unknown. We investigated the duration of humoral responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type and Omicron variant in AIRD patients administered with two doses of the BNT162b2 (Pfizer-BioNTech) vaccine. Methods: Serum-neutralizing antibody (NAb) and anti-receptor-binding domain (RBD)/spike antibody levels were measured. Short- and medium-term effects of immunosuppressants were analyzed pre-vaccination (Term 1) and 14-42 days (Term 2) and 100-200 days (Term 3) after the second vaccination. Findings: From Feb 1, 2021, to Feb 28, 2022, 439 AIRD patients and 146 healthy controls were investigated. The seropositivity rate and log10-NAb titers were significantly lower in AIRD patients than in controls at Terms 2 and 3. In rheumatoid arthritis patients, tumor necrosis factor-α inhibitors (TNFis) at Term 3, and older age, glucocorticoids, and abatacept at Terms 2 and 3 were risk factors for reduced responses. Anti-Omicron RBD/spike IgG levels strongly correlated with NAb titers. Interpretation: Glucocorticoids, TNFis, and abatacept treatments negatively affect the longevity of humoral responses to SARS-CoV-2, including Omicron, after two vaccine doses. These findings may inform the timing of additional vaccination for AIRD patients. Funding: Cloud Funding of Peace Winds Japan; Center of Innovation Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Society for the Promotion of Science KAKENHI; Japan Agency for Medical Research and Development; Kansai Economic Federation; Mitsubishi Zaidan; and Research Grant from Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology.
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OBJECTIVE: B-cell activating factor (BAFF) is implicated in SLE pathogenesis. Blocking BAFF signalling has contributed to reducing glucocorticoid dosage and preventing organ damage. However, clinical characteristics of patients who may benefit from this therapy are not yet fully elucidated. Therefore, we identified patients with high BAFF-bioactivity to investigate their clinical characteristics and BAFF-producing cells. METHODS: We established the reporter cell for BAFF and investigated the clinical characteristics of SLE patients with high BAFF-bioactivity. We identified BAFF-expressing kidney cells using publicly available scRNA-seq data and immunohistological analysis. SLE patients were stratified based on the bioactivity of BAFF and type-I IFN (IFN-I) to identify associated characteristic clinical manifestations. RESULTS: SLE patients, especially patients with LN, had significantly higher serum BAFF-bioactivity than healthy controls (HC) and non-LN patients. Additionally, single-cell-RNA-seq data and immunohistological analysis of kidney samples from LN patients revealed that BAFF is expressed in glomerular macrophages and mesangial cells. Notably, BAFF bioactivity was elevated in the urine of LN patients compared with that of non-LN patients, while no IFN-I bioactivity was detected in the urine. Furthermore, SLE stratification based on bioactivities of serum BAFF and IFN-I revealed the clinical characteristics of patients: high BAFF represented patients with LN and high IFN-I represented patients with blood and skin manifestations. CONCLUSIONS: Monitoring urinary BAFF-bioactivity may be valuable in diagnosing LN. Furthermore, stratification based on serum BAFF and IFN-I bioactivities may allow the identification of appropriate patients for biologics targeting BAFF and IFN-I.
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Produtos Biológicos , Interferon Tipo I , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Nefrite Lúpica/patologia , Fator Ativador de Células B , Rim/patologia , Glomérulos Renais/patologia , Lúpus Eritematoso Sistêmico/patologiaRESUMO
OBJECTIVES: Raynaud's phenomenon, one of the major symptoms of systemic sclerosis (SSc), is difficult to treat. Although it is empirically considered that warming is a beneficial technique, there is no supportive evidence. We conducted a multicentre study to evaluate whether continuous heating of the arm alleviates Raynaud's phenomenon in SSc. METHODS: A pair of disposable warmers was applied to the upper arm near the elbow of patients with SSc. Two weeks of non-warmer application were followed by 2 weeks of warmer application, which was repeated twice. The Raynaud Condition Score (RCS), number of episodes, and duration of Raynaud's phenomenon were recorded. The differences in the mean RCS, frequency, and duration of Raynaud's phenomenon between the warmer application and non-application periods were analysed. RESULTS: Twenty-eight patients were included in the analysis. The average RCS was 1.98 and 2.66 during the warmer application and non-application periods, respectively. The change between the two periods was statistically significant by paired t-test. In addition, the frequency and total duration of Raynaud's phenomenon in the warmer application period were significantly lower than those in the non-application period. CONCLUSIONS: Heating of the upper arm near the elbow is effective in alleviating Raynaud's phenomenon in SSc.
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Doença de Raynaud , Escleroderma Sistêmico , Humanos , Estudos Prospectivos , Calefação , Escleroderma Sistêmico/terapia , Escleroderma Sistêmico/tratamento farmacológico , Doença de Raynaud/etiologia , Doença de Raynaud/terapiaRESUMO
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, and many peripheral immune cell populations (ICPs) are thought to be altered according to the course of the disease. However, it is unclear which ICPs are associated with the clinical phenotypes of SLE. We analyzed peripheral blood mononuclear cells (PBMCs) of 28 SLE patients using mass cytometry and identified 30 ICPs. We determined the proliferative activity of ICPs by measuring the proportion of cells expressing specific markers and Ki-67 among CD45+ cells (Ki-67+ proportion). We observed an increased Ki-67+ proportion for many ICPs of SLE patients and examined the association between their Ki-67+ proportions and clinical findings. The Ki-67+ proportions of five ICPs [classical monocyte (cMo), effector memory CD8+ T cell (CD8Tem), CXCR5- naive B cell (CXCR5- nB), and CXCR5- IgD-CD27- B cell (CXCR5- DNB)] were identified as clinically important factors. The SLE Disease Activity Index (SLEDAI) was positively correlated with cMo and plasma cells (PC). The titer of anti-DNA antibodies was positively correlated with cMo, CXCR5- nB, and CXCR5- DNB. The C4 level was negatively correlated with CXCR5- DNB. The bioactivity of type I interferon was also positively correlated with these ICPs. Fever and renal involvement were associated with cMo. Rash was associated with CD8Tem and CXCR5- DNB. On the basis of the proliferative activity among five ICPs, SLE patients can be classified into five clusters showing different SLE phenotypes. Evaluation of the proliferative activity in each ICP can be linked to the clinical phenotypes of individual SLE patients and help in the treatment strategy.
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Leucócitos Mononucleares , Lúpus Eritematoso Sistêmico , Humanos , Antígeno Ki-67 , Linfócitos B , FenótipoRESUMO
OBJECTIVES: Raynaud's phenomenon (RP) is a peripheral vascular disorder that frequently occurs in systemic sclerosis (SSc). Although therapeutic heating seems reasonable given that RP is elicited by cold stimuli, the effects of heating are still unclear. We examined the effects of heating applied on various body parts in SSc patients with RP of fingers. METHODS: Fourteen SSc patients heated their neck, elbows, and wrists with disposable heating pads for 1 week each. The visual analogue scale (VAS) for RP during each heating period was compared with that of each 1-week pre-treatment interval. On the day after the expiration of each heating period, their finger temperature, the finger blood flow, and angiogenesis-related factors (vascular endothelial growth factor, endostatin, angiopoietin-1, and angiopoietin-2) obtained from the cubital vein and fingertip were measured. RESULTS: The mean VAS was significantly reduced during the heating of the neck and elbows. Fingertip blood samples showed significantly increased angiopoietin-1 after each of the heating periods and increased endostatin after wrist heating. After the termination of heating, changes in finger temperature or blood flow could not be detected. CONCLUSIONS: Heating the neck or elbows can alleviate RP in SSc. The heat up-regulates angiopoietin-1 in the fingers.
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Angiopoietina-1 , Dedos , Resposta ao Choque Térmico , Doença de Raynaud , Escleroderma Sistêmico , Angiopoietina-1/sangue , Angiopoietina-1/metabolismo , Calefação , Humanos , Projetos Piloto , Doença de Raynaud/etiologia , Doença de Raynaud/terapia , Escleroderma Sistêmico/complicações , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology. SSc causes damage to the skin and various organs including the lungs, heart, and digestive tract, but the extent of the damage varies from patient to patient. The pathology of SSc includes ischemia, inflammation, and fibrosis, but the degree of progression varies from case to case. Many cytokines have been reported to be involved in the pathogenesis of SSc: interleukin-6 is associated with inflammation and transforming growth factor-ß and interleukin-13 are associated with fibrosis. Therapeutic methods to control these cytokines have been proposed; however, which cytokines have a dominant role in SSc might differ depending on the extent of visceral lesions and the stage of disease progression. Therefore, it is necessary to consider the disease state of the patient to be targeted and the type of evaluation method when an anti-cytokine therapy is conducted. Here, we review the pathology of SSc and potential cytokine targets, especially interleukin-6, as well as the use of anti-cytokine therapy for SSc.
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Citocinas/metabolismo , Escleroderma Sistêmico/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Citocinas/antagonistas & inibidores , Desenvolvimento de Medicamentos , Humanos , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologiaRESUMO
TAFRO syndrome is a newly proposed disease that is characterised by thrombocytopenia, anasarca, fever, reticulin fibrosis (or renal dysfunction), and organomegaly. Generally, high doses of corticosteroids are recommended for the initial treatment of TAFRO syndrome; however, some patients experience prolonged refractory thrombocytopenia after initiating such therapies. If corticosteroid treatment alone is ineffective, additional immunosuppressive therapies such as cyclosporine A are recommended. Since long-term use of immunosuppressive therapies with TAFRO syndrome sometimes causes serious infection, it is important to recognise the time to recovery from thrombocytopenia. In this study, we investigated how long it took to recover from thrombocytopenia, to aid clinicians in decision-making regarding the need to strengthen treatment for prolonged thrombocytopenia. Here, we describe three of our patients with TAFRO syndrome exhibiting prolonged thrombocytopenia. We also investigated the median period to recovery from this complication (defined as the time to increase the platelet count above 50,000/µL) after the initiation of high-dose corticosteroid treatment in our 3 cases and 38 peer-reviewed cases. We found that it took our patients 61 days to recover from thrombocytopenia; in comparison, our investigation of the 38 peer-reviewed case reports revealed a median recovery time of 47.5 days among previously reported patients. We showed the time to recovery from thrombocytopenia in patients with TAFRO syndrome for the first time. Our findings ought to be useful for decision-making among clinicians regarding the administration of other immunosuppressive treatments in addition to corticosteroid.
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Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/diagnóstico , Trombocitopenia/complicações , Trombocitopenia/diagnóstico , Corticosteroides/uso terapêutico , Hiperplasia do Linfonodo Gigante/terapia , Ciclosporina/uso terapêutico , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Imunossupressores/uso terapêutico , Avaliação de Resultados da Assistência ao Paciente , Contagem de Plaquetas , Recidiva , Trombocitopenia/terapiaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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BACKGROUND: A phase 2 trial of tocilizumab showed preliminary evidence of efficacy in systemic sclerosis. We assessed skin fibrosis and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in a phase 3 trial to investigate the safety and efficacy of tocilizumab, an anti-interleukin-6 receptor antibody, in the treatment of systemic sclerosis. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, participants were recruited from 75 sites in 20 countries across Europe, North America, Latin America, and Japan. Adults with diffuse cutaneous systemic sclerosis for 60 months or less and a modified Rodnan skin score (mRSS) of 10-35 at screening were randomly assigned (1:1) with a voice-web-response system to receive subcutaneous tocilizumab 162 mg or placebo weekly for 48 weeks, stratified by IL-6 levels; participants and investigators were masked to treatment group. The primary endpoint was the difference in change from baseline to week 48 in mRSS. Percentage of predicted forced vital capacity (FVC% predicted) at week 48, time to treatment failure, and patient-reported and physician-reported outcomes were secondary endpoints. This trial is registered with ClinicalTrials.gov (number NCT02453256) and is closed to accrual. FINDINGS: Between Nov 20, 2015, and Feb 14, 2017, 210 individuals were randomly assigned to receive tocilizumab (n=104) or placebo (n=106). In the intention-to-treat population, least squares mean [LSM] change from baseline to week 48 in mRSS was -6·14 for tocilizumab and -4·41 for placebo (adjusted difference -1·73 [95% CI -3·78 to 0·32]; p=0·10). The shift in distribution of change from baseline in FVC% predicted at week 48 favoured tocilizumab (van Elteren nominal p=0·002 vs placebo), with a difference in LSM of 4·2 (95% CI 2·0-6·4; nominal p=0·0002), as did time to treatment failure (hazard ratio 0·63 [95% CI 0·37-1·06]; nominal p=0·08). Change in LSM from baseline to week 48 in Health Assessment Questionnaire-Disability Index and in patient-global and physician-global visual analogue scale assessments did not differ between tocilizumab and placebo. In the safety set, infections were the most common adverse events (54 [52%] of 104 participants in the tocilizumab group, 53 [50%] of 106 in the placebo group). Serious adverse events were reported in 13 participants treated with tocilizumab and 18 with placebo, primarily infections (three events, eight events) and cardiac events (two events, seven events). INTERPRETATION: The primary skin fibrosis endpoint was not met. Findings for the secondary endpoint of FVC% predicted indicate that tocilizumab might preserve lung function in people with early SSc-ILD and elevated acute-phase reactants. Safety was consistent with the known profile of tocilizumab. FUNDING: F Hoffmann-La Roche Ltd.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Estudos de Coortes , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Capacidade VitalRESUMO
A contribution of epigenetic modifications to B cell tolerance has been proposed but not directly tested. Here we report that deficiency of ten-eleven translocation (Tet) DNA demethylase family members Tet2 and Tet3 in B cells led to hyperactivation of B and T cells, autoantibody production and lupus-like disease in mice. Mechanistically, in the absence of Tet2 and Tet3, downregulation of CD86, which normally occurs following chronic exposure of self-reactive B cells to self-antigen, did not take place. The importance of dysregulated CD86 expression in Tet2- and Tet3-deficient B cells was further demonstrated by the restriction, albeit not complete, on aberrant T and B cell activation following anti-CD86 blockade. Tet2- and Tet3-deficient B cells had decreased accumulation of histone deacetylase 1 (HDAC1) and HDAC2 at the Cd86 locus. Thus, our findings suggest that Tet2- and Tet3-mediated chromatin modification participates in repression of CD86 on chronically stimulated self-reactive B cells, which contributes, at least in part, to preventing autoimmunity.
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Autoimunidade/imunologia , Linfócitos B/imunologia , Antígeno B7-2/imunologia , Proteínas de Ligação a DNA/imunologia , Dioxigenases/imunologia , Proteínas Proto-Oncogênicas/imunologia , Animais , Doenças Autoimunes/imunologia , Epigênese Genética/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
The receptor activator of nuclear factor κB ligand (RANKL) is an important factor for osteoclastogenesis and contributes to the pathology of rheumatoid arthritis (RA); thus, the anti-RANKL antibody (Ab) has been expected to protect joint destruction in RA patients. IL-8 also has osteoclastogenic activity; however, the role of IL-8 in the bone pathology of RA as well as the relation between IL-8 and RANKL remain unclear. In the present study, clinical observation revealed serum IL-8 levels of 611 pg ml-1 in RA patients with anti-RANKL Ab and 266 pg ml-1 in the same patients without anti-RANKL Ab. In vitro assay showed that anti-RANKL Ab induced production of IL-8 from pre-osteoclast-like cells (OCLs), and IL-8 promoted the formation of OCLs from peripheral monocytes even without RANKL activity. We further showed that treatment with FK506 (tacrolimus) possibly inhibits the increase in IL-8 levels in RA patients with anti-RANKL Ab, and in vitro assay confirmed that FK506 suppressed IL-8 production in pre-OCLs. These results suggest that inhibition of RANKL induces the change in osteoclastogenesis-promoting factor from RANKL to IL-8, and FK506 may be a valuable combination drug to support the use of anti-RANKL Ab in treatment of RA.
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Artrite Reumatoide/imunologia , Denosumab/imunologia , Denosumab/farmacologia , Interleucina-8/imunologia , Osteogênese/imunologia , Ligante RANK/antagonistas & inibidores , Ligante RANK/imunologia , Artrite Reumatoide/tratamento farmacológico , Células Cultivadas , Denosumab/uso terapêutico , Feminino , Humanos , Interleucina-8/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Systemic sclerosis (SSc) is a connective tissue disease, the pathogenesis of which is thought to involve interleukin-6 (IL-6), an inflammatory cytokine. This is based on findings of its concentration in patient serum, the results of an IL-6 suppression experiment in an animal model, and the results of a pilot study using IL-6 receptor antibody. However, it appears that a number of factors are involved in the pathology of SSc depending on the state of disease progression. In addition, the degree of involvement of IL-6 differs depending on the difference of organs within particular severe symptoms. Based on the findings from measurements of patient serum, the influence of IL-6 on the pathogenesis of SSc is greater in patients at a relatively early phase of the disease and in patients with lung lesions. Interleukin-13 (IL-13) is one of pro-fibrotic factors, and it is afraid that SSc patients with higher IL-13 have already lost the influence of IL-6. Therefore, although a clinical trial using the anti-IL-6 receptor antibody tocilizumab is underway, it is important to recognize the state of SSc patients prior to selecting treatment.
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Anticorpos Monoclonais Humanizados/farmacologia , Interleucina-6 , Escleroderma Sistêmico , Animais , Progressão da Doença , Humanos , Fatores Imunológicos/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Gravidade do Paciente , Seleção de Pacientes , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/terapiaRESUMO
OBJECTIVES: To evaluate the anti-interleukin (IL)-6 receptor antibody tocilizumab (TCZ) as a treatment of systemic sclerosis (SSc), a randomised parallel group study was conducted, and compared their results and baseline cytokine/chemokine profiles. METHODS: Patients were assigned to a TCZ add-on group (TCZ group, n = 7) and a conventional therapy group (Conv group, n = 6). TCZ (8 mg/kg/month) for 6 months, and the modified Rodnan total skin score (mRSS) were used to compare the efficacy. The association of medical history, baseline pulmonary function tests, blood cell counts, serum C-reactive protein (CRP) and 26 cytokines/chemokines and decrease in mRSS were analysed. RESULTS: The mean change in mRSS was larger in the TCZ group (6.3) than in the Conv group (3.4), but the difference was not statistically significant because of high variance in the TCZ group. Patients with shorter disease histories and higher CRP had larger decreases in mRSS, and the decrease in mRSS was negatively correlated with IL-13 and C-C motif chemokine ligand (CCL)5. CONCLUSION: Although significant between-group differences were not observed, some patients had a decrease in mRSS. Short disease duration, high CRP, low IL-13 and low CCL5 may represent an SSc endotype responsive to TCZ therapy.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Citocinas/sangue , Escleroderma Sistêmico/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Proteína C-Reativa/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/sangueRESUMO
OBJECTIVE: Despite the importance of type I interferon (IFN-I) in systemic lupus erythematosus (SLE) pathogenesis, the mechanisms of IFN-I production have not been fully elucidated. Recognition of nucleic acids by DNA sensors induces IFN-I and interferon-stimulated genes (ISGs), but the involvement of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) and stimulator of interferon genes (STING) in SLE remains unclear. We studied the role of the cGAS-STING pathway in the IFN-I-producing cascade driven by SLE serum. METHODS: We collected sera from patients with SLE (n=64), patients with other autoimmune diseases (n=31) and healthy controls (n=35), and assayed them using a cell-based reporter system that enables highly sensitive detection of IFN-I and ISG-inducing activity. We used Toll-like receptor-specific reporter cells and reporter cells harbouring knockouts of cGAS, STING and IFNAR2 to evaluate signalling pathway-dependent ISG induction. RESULTS: IFN-I bioactivity and ISG-inducing activities of serum were higher in patients with SLE than in patients with other autoimmune diseases or healthy controls. ISG-inducing activity of SLE sera was significantly reduced in STING-knockout reporter cells, and STING-dependent ISG-inducing activity correlated with disease activity. Double-stranded DNA levels were elevated in SLE. Apoptosis-derived membrane vesicles (AdMVs) from SLE sera had high ISG-inducing activity, which was diminished in cGAS-knockout or STING-knockout reporter cells. CONCLUSIONS: AdMVs in SLE serum induce IFN-I production through activation of the cGAS-STING pathway. Thus, blockade of the cGAS-STING axis represents a promising therapeutic target for SLE. Moreover, our cell-based reporter system may be useful for stratifying patients with SLE with high ISG-inducing activity.