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OBJECTIVES: To evaluate the long-term impact of immunosuppressive therapeutic agents on antibody response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with autoimmune rheumatic diseases (AIRD) in order to propose a strategy for annual vaccination. METHODS: This prospective multicentre cohort study evaluated the humoral response to second and third BNT162b2 and/or mRNA-1273 vaccines in 382 Japanese AIRD patients classified into 12 different medication groups and in 326 healthy controls (HCs). The third vaccination was administered six months after the second vaccination. Antibody titres were measured using the Elecsys Anti-SARS-CoV-2 S assay. RESULTS: The seroconversion rate and antibody titres were lower in AIRD patients than in HCs 3-6 weeks after the second vaccination and 3-6 weeks after the third vaccination. Seroconversion rates were <90% after the third vaccination in patients receiving mycophenolate mofetil and rituximab. Antibody levels after the third vaccination were significantly lower in the groups prescribed TNF inhibitor with or without methotrexate, abatacept and rituximab or cyclophosphamide than those of HCs in a multivariate analysis adjusting for age, sex, and glucocorticoid dosage. The third vaccination induced an adequate humoral response in patients treated with sulfasalazine, bucillamine, methotrexate monotherapy, iguratimod, interleukin-6 inhibitors or calcineurin inhibitors including tacrolimus. CONCLUSIONS: Repeated vaccinations in many immunosuppressed patients produced antibody responses similar to those observed in HCs. In contrast, annual vaccination in patients receiving TNF inhibitors, abatacept, mycophenolate mofetil and rituximab may require caution.
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COVID-19 , Enfermedades Reumáticas , Humanos , Vacunas contra la COVID-19 , Rituximab , Abatacept , Vacuna BNT162 , Estudios de Cohortes , Metotrexato/uso terapéutico , Ácido Micofenólico , Estudios Prospectivos , COVID-19/prevención & control , SARS-CoV-2 , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Enfermedades Reumáticas/tratamiento farmacológico , Vacunación , AnticuerposRESUMEN
T follicular regulatory (Tfr) cells are a subset of CD4+ T cells that express CXCR5 and migrate into germinal centers (GCs). They regulate GC reactions by communicating with T follicular helper (Tfh) and B cells. TNF inhibitors are used in inflammatory diseases; however, the generation of autoantibodies or anti-drug Abs sometimes causes problems. Because TNFR2 signaling is important for suppressive functions of regulatory T cells, we investigated the role of TNFR2 on human Tfr cells. Tfr cells stimulated with MR2-1 (an anti-TNFR2 agonistic Ab) were analyzed for cell proliferation, Foxp3 expression, and surface molecules. Tfh/B cell proliferation, IgM production, and differentiation in cocultures with MR2-1-stimulated Tfr cells were examined. Tfr cells express a high level of TNFR2. MR2-1 stimulation altered the gene expression profile of Tfr cells. Cell proliferation and Foxp3 expression of Tfr cells were enhanced by MR2-1. MR2-1-stimulated Tfr cells expressed ICOS and Programmed cell death protein 1 and significantly suppressed Tfh/B cell proliferation, IgM production, and B cell differentiation. TNFR2-stimulated Tfr cells retained the migration function according to the CXCL13 gradient. In conclusion, we showed that TNFR2-stiumulated Tfr cells can regulate Tfh and B cells. Aberrant antibody production during TNF inhibitor treatment might be, at least in part, associated with TNFR2 signaling inhibition in Tfr cells. In addition, expansion and maturation of Tfr cells via TNFR2 stimulation in vitro may be useful for a cell-based therapy in inflammatory and autoimmune diseases to control GC reactions.
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Linfocitos B/inmunología , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Células T Auxiliares Foliculares/inmunología , Linfocitos T Reguladores/inmunología , Enfermedades Autoinmunes/terapia , Linfocitos B/citología , Antígeno B7-H1/metabolismo , Diferenciación Celular/inmunología , Movimiento Celular/inmunología , Proliferación Celular , Quimiocina CXCL13/metabolismo , Factores de Transcripción Forkhead/biosíntesis , Perfilación de la Expresión Génica , Centro Germinal/citología , Humanos , Inmunoglobulina M/biosíntesis , Proteína Coestimuladora de Linfocitos T Inducibles/biosíntesis , Activación de Linfocitos/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/antagonistas & inhibidores , Transducción de Señal/inmunología , Factores de Necrosis Tumoral/metabolismoRESUMEN
This study aimed to clarify the efficacy and safety of treatment escalation by initiating therapeutic agents in serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE). We retrospectively evaluated SACQ patients with SLE for ≥ 180 days, with the introduction of a therapeutic agent for SLE defined as exposure. The efficacy endpoints included the time to flare and time to remission, whereas the safety endpoint was the incidence of adverse events. The efficacy endpoints were assessed via Cox proportional hazards model with time-dependent covariates, which included exposure, serological activity, and prednisolone dose. Among 109 SACQ patients, 24 were initiated on the following therapeutic agents for SLE: hydroxychloroquine (10 patients), belimumab (6 patients), and immunosuppressive agents (8 patients). A total of 37 patients experienced a flare (8 and 29 patients during exposure and nonexposure periods, respectively). The time to flare was comparable between the exposure and control groups. Among 68 patients who were not in remission at the start of observation, 27 patients achieved remission (5 and 22 patients during exposure and nonexposure periods, respectively). Although both groups had a similar time to remission, the exposure group treated with belimumab had a significantly higher rate of remission than the control group. The adverse events were more frequent during the exposure period than during the nonexposure period. Thus, this study did not reveal a clear influence of treatment escalation on flare prevention and remission achievement.
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OBJECTIVES: This study aimed to describe the treatment selection for systemic lupus erythematosus (SLE) using data from the Kyushu Collagen Disease Network for SLE (KCDN-SLE) registry, a multicenter prospective registry in Japan. METHODS: This study used data from patients registered between August 2022 and November 2023. Clinical characteristics, purpose of agent initiation, other candidate agents, and short-term efficacy and safety were evaluated. RESULTS: We analyzed 69 previously treated patients with SLE (mean age 43.7 years; 62 females, 7 males). Hydroxychloroquine, biological agents, and immunosuppressive agents were initiated during the maintenance phase in 12, 41, and 16 patients, respectively. In patients with active organ involvement, hydroxychloroquine and biological agents were widely used for initiation. In those who already achieved treatment goals, biological agents alone were predominantly selected. The SLE Disease Activity Index 2000 score and prednisolone dose declined significantly over a 6-month follow-up period. Among 48 patients with active disease, 22 achieved a lupus low disease activity state, but this had no evident association with the initiation of a biological agent. In total, 14 adverse events, predominantly infections, were observed. CONCLUSIONS: Biological agents were used preferentially, and the therapeutic agents were appropriately effective and mostly achieved the purpose of agent initiation.
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OBJECTIVES: Recently, the involvement of basophils and IgE-type autoantibodies in the pathogenesis of SLE has been elucidated using mouse models; however, few studies have been conducted in humans. In this study, the role of basophils and anti-double-stranded DNA (dsDNA) IgE in SLE was examined using human samples. METHODS: The correlation between disease activity and serum levels of anti-dsDNA IgE in SLE was evaluated using enzyme-linked immunosorbent assay. Cytokines produced by IgE-stimulated basophils from healthy subjects were assessed using RNA sequences. The interaction of basophils and B cells to promote B cell differentiation was investigated using a co-culture system. The ability of basophils from patients with SLE with anti-dsDNA IgE to create cytokines that may be involved in B cell differentiation in response to dsDNA was examined using real-time PCR. RESULTS: Anti-dsDNA IgE levels in the serum of patients with SLE correlated with disease activity. Healthy donor basophils produced IL-3, IL-4 and TGF-ß1 after anti-IgE stimulation. Co-culture of B cells with anti-IgE-stimulated basophils increased plasmablasts which were cancelled by neutralizing IL-4. After encountering the antigen, basophils released IL-4 more quickly than follicular helper T cells. Basophils isolated from patients with anti-dsDNA IgE promoted IL-4 expression by adding dsDNA. CONCLUSIONS: These results suggest that basophils contribute to the pathogenesis of SLE by promoting B cell differentiation via dsDNA-specific IgE in patients similar to the process described in mouse models.
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Basófilos , Lupus Eritematoso Sistémico , Ratones , Animales , Humanos , Basófilos/metabolismo , Interleucina-4 , Citocinas/metabolismo , ADN , Inmunoglobulina E , Diferenciación CelularRESUMEN
OBJECTIVES: We aim to clarify the efficacy and safety of switching immunosuppressive drugs and to identify the predictive factors for treatment failure after switching in patients with systemic lupus erythematosus (SLE). METHODS: We retrospectively evaluated patients with SLE who switched immunosuppressive drugs for any reason in our hospital between 2015 and 2020. The efficacy endpoints were the change in SLE Disease Activity Index 2000 score, prednisolone dose, and disease status over 12 months, as well as treatment continuation rates. The safety endpoint was the frequency of adverse events over 1 year before and after switching. Cox hazard regression analyses were used to identify the predictive factors for treatment failure. RESULTS: Thirty-nine patients (age, 41.5 ± 12.6 years; 35 women and 4 men) were analysed. The SLE Disease Activity Index score and prednisolone dose were significantly reduced after switching, with few disease exacerbations over 12 months. The 1- and 2-year continuation rates were 71.4% and 62.3%, respectively. The frequency of adverse events was similar in the year before and after switching the drug. Drug switching due to inadequate efficacy was a predictive factor of less likely treatment failure. CONCLUSIONS: Immunosuppressive drug switching led to reduced disease activity and decreased glucocorticoid dose without disease exacerbations and severe adverse events.
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Inmunosupresores , Lupus Eritematoso Sistémico , Masculino , Humanos , Femenino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Factores de Tiempo , Inmunosupresores/efectos adversos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Prednisolona/efectos adversos , Progresión de la EnfermedadRESUMEN
OBJECTIVES: To evaluate the impact of medication on antibody response to severe acute respiratory syndrome coronavirus-2 mRNA vaccines in Japanese patients with rheumatic diseases. METHODS: This prospective multicentre cohort study evaluated the humoral response in 12 different medication groups. Antibody levels before the first vaccination and 3-6 weeks after the second vaccination were measured using the Elecsys Anti-SARS-CoV-2 S assay. Statistical analysis included comparing antibody titres among the different medication groups using the Kruskal-Wallis test followed by the Bonferroni-Dunn test and multiple linear regression analysis. RESULTS: 295 patients were analysed. The seroconversion rate was 92.2% and the median antibody titre was 255 U/ml (interquartile range, 34.1-685) after the second mRNA vaccination. Antibody levels were significantly lower in the groups treated with Tumour necrosis factor inhibitor with methotrexate, abatacept, mycophenolate mofetil (MMF), MMF or mizoribine combined with calcineurin inhibitor, and rituximab or cyclophosphamide compared with those treated with sulfasalazine and/or bucillamine or calcineurin inhibitor (p < 0.01). The correlation between antibody titre and treatment was significant after adjusting for age, gender, and glucocorticoid dose (p < 0.01). CONCLUSIONS: Additional early vaccination is required in patients treated with Tumour necrosis factor inhibitor and methotrexate, abatacept, MMF, MMF or mizoribine combined with calcineurin inhibitor and rituximab or cyclophosphamide.
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COVID-19 , Enfermedades Reumáticas , Humanos , Inmunosupresores/uso terapéutico , Rituximab , Metotrexato/uso terapéutico , Abatacept , Inhibidores de la Calcineurina , Japón , Formación de Anticuerpos , Vacunas contra la COVID-19/uso terapéutico , Estudios Prospectivos , Estudios de Cohortes , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , COVID-19/prevención & control , SARS-CoV-2 , Ácido Micofenólico/uso terapéutico , Ciclofosfamida , Enfermedades Reumáticas/tratamiento farmacológicoRESUMEN
OBJECTIVES: Emerging evidence has shown the importance of inflammasome activation in the progression of autoimmune diseases. In this study, we aimed to identify the main cell types activating inflammasome in autoimmune diseases and to clarify the intracellular pathway of inflammasome activation in systemic lupus erythematosus (SLE). METHODS: Active caspase-1 in each subset of human peripheral blood cells from healthy controls (n=18), SLE (n=51), and other rheumatic diseases (n=36) were fluorescently probed with FLICA™-caspase-1 followed by flow cytometric analysis. The correlation of caspase-1 activation in monocytes and clinical parameters in SLE patients were evaluated. In-vitro experiments were performed to identify the pathway involved in caspase-1 activation induced by SLE serum in monocytes. RESULTS: Active caspase-1 in monocytes was upregulated in SLE patients. Cluster of differentiation 14 (CD14)-positive and CD16-positive monocytes showed considerable activation of caspase-1 compared with the other subsets of monocytes. Serum titres of anti-double stranded DNA antibodies were positively correlated with active caspase-1 in monocytes, and serum complement component 3 and platelet count were negatively correlated with active caspase-1 in monocytes. The SLE serum-induced activation of caspase-1 and IL-1ß secretion were down-regulated by inhibition of NLR family pyrin domain containing 3 (NLRP3), cyclic GMP-AMP synthase (cGAS), or stimulator of interferon genes (STING). CONCLUSIONS: These findings suggest that targeting inflammasome by regulating cGAS/STING and NLRP3 are potential therapeutic strategies for SLE.
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Caspasa 1 , Interferones , Lupus Eritematoso Sistémico , Monocitos , Proteína con Dominio Pirina 3 de la Familia NLR , Estudios de Casos y Controles , Caspasa 1/metabolismo , Humanos , Inflamasomas/metabolismo , Interferones/genética , Interferones/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
DNase 1-like 3 (DNase1L3), which belongs to DNase1 family, was originally identified as one of apoptosis- and necrosis-related endonucleases that fragmentate intranucleosomal DNA. A loss-of-function mutation has been reported in murine models of systemic lupus erythematosus (SLE) and in familial SLE patients. These reports suggest DNase1L3 plays an important role in the prevention of developing SLE; however, expression and function of DNase1L3 in human immune systems have been largely unclarified. As previous reports showed DNase1L3 is expressed in hematopoietic organs, we first analyzed expression levels of DNase1L3 in each subset of human peripheral blood cells by quantitative real-time PCR. Plasmacytoid dendritic cells showed the highest expression levels of DNase1L3 mRNA among peripheral blood cells. IL-4 enhanced DNase1L3 expression in monocytes, monocyte-derived dendritic cells, and monocyte-derived macrophages (MDMs), but not in T cells, B cells, or plasmacytoid dendritic cells. Together with IL-4, all-trans retinoic acid and apoptotic cells efficiently upregulated expression of DNalse1L3 in MDMs. As a result of intracellular signaling analysis, Jak1-IRS2-ERK/PI3K pathway was essential for IL-4-induced DNase1L3 expression. IL-4-treated monocyte-derived dendritic cells and MDMs secreted active DNase1L3 protein that could degrade liposome-DNA complexes, which were resistant to DNase1. Our results indicate DNase1L3 is secreted by innate immune cells and may play a critical role in the tissue homeostasis and on prevention of developing autoimmunity by degrading self-DNA.
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Endodesoxirribonucleasas/biosíntesis , Homeostasis , Células Mieloides/enzimología , Células Cultivadas , ADN/inmunología , ADN/metabolismo , Endodesoxirribonucleasas/genética , HumanosRESUMEN
OBJECTIVES: We aimed to reveal the effectiveness of hydroxychloroquine (HCQ) compared with tacrolimus (TAC), an immunosuppressive agent, in patients with systemic lupus erythematosus (SLE) with persistent activity on standard treatment. METHODS: We retrospectively compared the efficacy and safety of the treatment between 18 patients receiving HCQ and 27 patients receiving TAC. None of the patients were in the lupus low disease activity state (LLDAS) at the beginning of this study. The efficacy end points were the cumulative incidence of LLDAS attainment without additional immunosuppressive agents, drug continuation rate, and treatment failure-free survival. The safety end point was the frequency of adverse events. RESULTS: Eight (44.4%) patients in the HCQ group and 10 (37.0%) patients in the TAC group achieved LLDAS during the follow-up period; thus, the cumulative incidences of LLDAS attainment of the two treatments were nearly identical. The drug continuation and treatment failure-free survival rates were also not different between the two groups. The frequency of adverse events showed no clear differences between the two groups. CONCLUSIONS: The efficacy and safety of an add-on treatment with HCQ are similar to those with TAC. Patients with persistently active SLE can benefit from HCQ in efforts to achieve at least low disease activity.
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Antirreumáticos , Lupus Eritematoso Sistémico , Antirreumáticos/efectos adversos , Humanos , Hidroxicloroquina/efectos adversos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Estudios Retrospectivos , Tacrolimus/efectos adversosRESUMEN
Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Trastornos Linfoproliferativos/tratamiento farmacológico , Metotrexato/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Quinasas Janus/antagonistas & inhibidores , Estimación de Kaplan-Meier , Linfoma no Hodgkin/mortalidad , Trastornos Linfoproliferativos/inducido químicamente , Trastornos Linfoproliferativos/mortalidad , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Prednisona/administración & dosificación , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Rituximab/administración & dosificación , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Vinblastina/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
Efficacy of B-cell depletion therapy highlights the antibody-independent effector functions of B cells in rheumatoid arthritis (RA). Given type 1 helper T (Th1) cells abundant in synovial fluid (SF) of RA, we have determined whether Th1 cells could generate novel effector B cells. Microarray and qPCR analysis identified CXCL9/10 transcripts as highly expressed genes upon BCR/CD40/IFN-γ stimulation. Activated Th1 cells promoted the generation of CXCL9/10-producing T-bet+ B cells. Expression of CXCL9/10 was most pronounced in CXCR3+ switched memory B cells. Compared with peripheral blood, SFRA enriched highly activated Th1 cells that coexisted with abundant CXCL9/10-producing T-bet+ B cells. Intriguingly, anti-IFN-γ antibody and JAK inhibitors significantly abrogated the generation of CXCL9/10-producing T-bet+ B cells. B cell derived CXCL9/10 significantly facilitated the migration of CD4+ T cells. These findings suggest that Th1 cells generate the novel CXCL9/10-producing T-bet+ effector B cells that could be an ideal pathogenic B cell target for RA therapy.
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Artritis Reumatoide/patología , Subgrupos de Linfocitos B/inmunología , Células TH1/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/inmunología , Subgrupos de Linfocitos B/metabolismo , Quimiocina CXCL10/inmunología , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/inmunología , Quimiocina CXCL9/metabolismo , Quimiocina CXCL9/fisiología , Femenino , Expresión Génica , Humanos , Interferón gamma/metabolismo , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Células TH1/metabolismoRESUMEN
OBJECTIVE: The number of pregnant and delivery cases in systemic lupus erythematosus (SLE) patients are increasing due to the advances in therapies. However, there are many problems such as the exacerbation of SLE during pregnancy and the risk of fetal complications. We investigated the impact of both pregnancy on lupus and lupus on pregnancy in Japanese patients. METHODS: We retrospectively analyzed 64 pregnancies in 39 cases of lupus patients at Kyushu University Hospital, Japan, from October 2002 to July 2018 and then assessed the clinical profiles and maternal and fetal outcomes. RESULTS: In terms of the impact of pregnancy on SLE, 29.7% of patients had lupus flare during pregnancy. Multivariate analysis showed that flare rates were significantly higher in patients who discontinued the immunosuppressants when pregnancy was detected or before pregnancy. Pregnancy results were 25.0% for preterm birth, 39.1% for low birth weight infants, and 31.3% for small-for-gestational-age infants. Regarding the effect of SLE on fetal death, the rates of stillbirth were significantly higher in cases whose C3 value at 12 weeks of gestation was lower than before conception. Preterm birth was associated with disease duration and lupus flare during pregnancy. CONCLUSIONS: Discontinuation of immunosuppressive drugs was a predictive factor for lupus flare during pregnancy. Further, the decrease of C3 levels at 12 weeks of gestation from baseline was a predictive factor for fetal loss. It is essential for lupus pregnant patients to prevent flares, even with the use of immunosuppressive medications.
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Lupus Eritematoso Sistémico , Complicaciones del Embarazo , Nacimiento Prematuro , Femenino , Humanos , Inmunosupresores/efectos adversos , Recién Nacido , Japón/epidemiología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/epidemiología , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/epidemiología , Resultado del Embarazo , Nacimiento Prematuro/epidemiología , Estudios Retrospectivos , Brote de los SíntomasRESUMEN
BACKGROUND: Follicular helper CD4+ T (Tfh) cells have a critical role in IgG4 production by B cells in IgG4-related disease (IgG4-RD). Recent studies including ours showed that SLAMF7+CD4+ T cells are an important pathological driver of IgG4-RD. In this study, we have sought to elucidate a relationship between helper CD4+ T (Th), particularly Tfh, cells and SLAMF7+ CD4+ T cells in IgG4-RD. RESULTS: The patients with IgG4-RD enrolled in this study were aged 66 ± 12 years and their titers of serum IgG4 were 372 ± 336 mg/dl. Th1 cells, activated circulating Tfh1 (cTfh1), and activated cTfh2 cells increased in IgG4-RD. SLAMF7 was mainly expressed on Th1 and cTfh1, but not cTfh2, cells in the patients. SLAMF7+ cTfh1 cells were PD-1/CD28 double-positive, whereas SLAMF7+ Th1 cells were CD28 negative. Positive correlations were noted between serum IgG4 levels and the number of activated cTfh2 cells and SLAMF7+ cTfh1 cells, but not SLAMF7+ Th1 cells. Intriguingly, among cTfh1 cells, activated SLAMF7+ cTfh1 cells were high producers of IL-10 along with IL-21. Blimp-1, but not Bcl-6, mRNA was expressed at high levels in activated SLAMF7+ cTfh1 cells. In addition to CD4+ T cells, the frequency of SLAMF7+ fraction was higher in memory B cells than naïve B cells in patients with IgG4RD. Finally, upon stimulation via B-cell receptor and CD40, Tfh1-associated cytokines, IL-21 and IFN-γ, most significantly induced SLAMF7 expression in memory B cells. CONCLUSIONS: Together, these results suggest that circulating SLAMF7+ Tfh1 cells, along with Tfh2 cells, play a pathologic role in IgG4 production in IgG4-RD.
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Inmunoglobulina G/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Células T Auxiliares Foliculares/metabolismo , Anciano , Linfocitos B/metabolismo , Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Antígenos CD40/metabolismo , Células Cultivadas , Femenino , Humanos , Interleucina-10/metabolismo , Interleucinas/metabolismo , Masculino , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Células TH1/metabolismoRESUMEN
We aimed to identify predictors of inadequate response to glucocorticoid (GC) treatment in patients with polymyalgia rheumatica (PMR). We retrospectively studied 32 patients as a derivation cohort and 24 patients as a validation cohort. The patients were divided into two groups according to the response to GC treatment: GC-responders and GC-inadequate responders (GC-IRs). We compared laboratory data and bilateral shoulder ultrasound findings between the groups. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff value of candidate predictors of treatment response; the predictors were examined using multivariate logistic analysis. Gray-scale ultrasound findings of long head of the biceps (LHB) tenosynovitis and subacromial/subdeltoid (SAD) bursitis were scored semiquantitatively (0-3). A total gray-scale score (TGSS) was calculated as the sum of the gray-scale scores. In the derivation cohort, serum lactate dehydrogenase (LDH) levels and TGSS were significantly higher in GC-IRs than in GC-responders. On ROC analysis, the cutoff values of serum LDH levels ≥ 175 IU/ml and TGSS ≥ 5 were found to be the candidate predictors. Multivariate logistic analysis revealed an independent association of both the predictors with inadequate response to GC treatment. In the validation cohort, patients with one or both predictors exhibited a higher incidence of inadequate response to GC treatment. These findings indicate that the severities of LHB tenosynovitis and SAD bursitis evaluated using ultrasound and serum LDH levels are independent predictors of inadequate response to GC treatment in patients with PMR. Treatment adjustment based on prediction model may allow precise treatment of patients with PMR.
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Bursitis/diagnóstico por imagen , Glucocorticoides/uso terapéutico , L-Lactato Deshidrogenasa/sangre , Polimialgia Reumática/tratamiento farmacológico , Articulación del Hombro/diagnóstico por imagen , Tenosinovitis/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Logísticos , Masculino , Polimialgia Reumática/sangre , Polimialgia Reumática/diagnóstico por imagen , Pronóstico , Hombro/diagnóstico por imagen , Resultado del Tratamiento , UltrasonografíaRESUMEN
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8(+) T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8(+) T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8(+) T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8(+) T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226(high)CD8(+) T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226(+)CD8(+) T cells produced higher amount of various cytokines than CD226(-) ones, and CD226(high)CD8(+) T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8(+) T cells against HUVECs. Finally, the neutralization of CD226 in CD8(+) T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8(+) T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc.
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Antígenos de Diferenciación de Linfocitos T/genética , Linfocitos T CD8-positivos/metabolismo , Citotoxicidad Inmunológica/inmunología , Células Endoteliales de la Vena Umbilical Humana/patología , Esclerodermia Sistémica/patología , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Adhesión Celular/genética , Células Cultivadas , Técnicas de Cocultivo , Citocinas/biosíntesis , Citotoxicidad Inmunológica/genética , Femenino , Humanos , Interleucina-13/biosíntesis , Japón , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Esclerodermia Sistémica/inmunología , Activación Transcripcional/inmunologíaRESUMEN
OBJECTIVES: Understanding interpatient variation in CD4+T-cell responses is the bases for understanding the pathogenesis and management of rheumatoid arthritis (RA). We examined immune responses to SARS-CoV-2 vaccine in a cohort of patients with RA and determined factors associated with the responses. METHODS: Four hundred and thirty-one patients with RA having received two doses of BNT162b2, a messenger RNA-based vaccine for SARS-CoV-2, were included. Vaccine antigen-specific IgG was detected by ELISA, and antigen-specific CD4+T cells were detected by CD154 expression in response to antigenic stimulation. Expression of cytokines was concomitantly detected by intracellular staining. Associations among background variables, antigen-specific antibody production and the CD4+T-cell responses were analysed. Unsupervised hierarchical clustering was performed based on the profiles of antigen-specific cytokine production by CD4+T cells to stratify patients with RA. RESULTS: Multivariate analysis indicated that ageing negatively affects CD4+T-cell response as well as antibody production. No association was detected between the presence or the levels of rheumatoid factor/anti-cyclic citrullinated peptide antibody and anti-vaccine immune responses. Methotrexate and prednisolone reduced B cell but not T-cell responses. Conventional immunophenotyping by the expression of chemokine receptors was not associated with the actual CD4+T-cell response, except for T helper cells (Th1). Functional immunophenotyping based on the profiles of antigen-specific cytokine production of CD4+T cells stratified patients with RA into three clusters, among which Th1-dominant type less frequently underwent joint surgery. CONCLUSIONS: Clinical and immunological variables that are associated with antigen-specific CD4 T-cell responses in patients with RA were determined by analysing immune responses against SARS-CoV-2 vaccine.
Asunto(s)
Artritis Reumatoide , Linfocitos T CD4-Positivos , Humanos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Vacuna BNT162 , Vacunas contra la COVID-19 , Citocinas/metabolismoRESUMEN
OBJECTIVE: To evaluate trends in results of care and management for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). METHODS: We employed multicenter cohort data collected during 2011-2021, recruiting 43 patients with granulomatosis with polyangiitis (GPA) and 91 with microscopic polyangiitis (MPA). According to the median registration date of September 2015, patients have split into two groups: an early group and a late group (both of them, n = 67). To prevent bias, a propensity score according to numerous baseline characteristics variables was calculated; 50 matching members of each group were statistically extracted. Their treatments and clinical outcomes were examined at 6, 12, and 24 months after initial remission therapy. RESULTS: Statistics demonstrated that the baseline characteristics were similar. The late group used rituximab (RTX) more often for both remission induction and maintenance therapy, compared with the early group. The mean daily PSL doses of the late group were significantly lower than those of early group at each time point. The late group discontinued PSL 14.0% at 12 months and 23.3% at 24 months. Despite their intensive glucocorticoids (GC) tapering, the remission rates and the relapse rates were significantly fairer in the late group. The Vasculitis Damage Index (VDI) and VDI due to GC at each time point were lower in the late group, and those differences had become wider over time. CONCLUSION: Recent developments in AAV treatment have allowed efficient remission and prevention of relapses, which in turn enabled extensive GC tapering causing fewer sequelae.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Granulomatosis con Poliangitis , Poliangitis Microscópica , Humanos , Glucocorticoides/efectos adversos , Resultado del Tratamiento , Rituximab/uso terapéutico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Anticuerpos Anticitoplasma de Neutrófilos , Inducción de Remisión , Granulomatosis con Poliangitis/tratamiento farmacológicoRESUMEN
Systemic lupus erythematosus (SLE) is a disease of immune complex deposition; therefore, complement plays a vital role in the pathogenesis of SLE. In general, complement levels in blood and complement deposition in histological tests are used for the management of SLE. Thus, the evaluation of complement status can be useful in the diagnosis of SLE, assessment of disease activity, and prediction of treatment response and prognosis. In addition, novel complement biomarkers, such as split products and cell-bound complement activation products, are considered to be more sensitive than traditional complement markers, such as serum C3 and C4 levels and total complement activity (CH50), which become more widely used. In this review, we report the complement testing in the management of SLE over the last decade and summarize their utility.