RESUMEN
BACKGROUND: Choosing the right intensity of medical care is a huge challenge particularly in long-term geriatric care. The Nascher score was developed to assess future medical care needs. The aim of this study was to determine whether the Nascher score and a revised version can predict future medical needs. METHODS: In this retrospective cohort study, 396 residents in long-term care hospitals, who were admitted over a period of two years and followed up to two and a half yeare, were analysed. Outcome parameters were: (1) number of medication changes, (2) number of ward doctor documentations and (3) number of acute illnesses treated with antibiotics, and mortality risk. Based on the first results, an alternative scoring of the Nascher score with 12 instead of 26 items was developed, called the revised Nascher score. RESULTS: The Nascher score significantly correlated with the number of medication changes, the number of ward doctor documentations, and the number of acute ilnesses treated with antibiotics with Spearman correlation coefficients of 0.30, 0.26, and 0.15, respectively. The revised Nascher score showed a higher correlation with correlation coefficients of 0.36, 0.26, and 0.21, respectively. Residents with a Nascher score in the highest quartile had a significantly higher mortality risk than residents in the lowest quartile (hazard ratio, HR 2.97, 95% confidence interval, CI 1.80-4.34). The corresponding values for the revised Nascher score were HR 3.03, 95% CI 2.03-4.54 in the highest and HR 1.80, 95% CI 1.24-2.60 in the middle quartiles. CONCLUSION: The Nascher score and even more so the revised Nascher score are well suited to predicting the various parameters of future medical needs and mortality risk.
RESUMEN
Memory B cells (mBCs) are characterized by their long-term stability, fast reactivation, and capability to rapidly differentiate into antibody-secreting cells (ASCs). However, the role of T cells in the differentiation of mBCs, in contrast to naive B cells, remains to be delineated. We study the role of T cells in mBC responses, using CD40L stimulation and autologous T-B co-cultures. Our results showed that increased CD40L levels led to a selective increased proliferation of IgM+ mBC, which did not class-switched, resulting in higher frequencies of IgM+ ASCs and a lower frequency of IgG+ ASCs. The IgG+/IgA+ mBCs were unaffected. We further compared the transcription of immune-related genes in IgM+ and IgG+ pre-plasmablasts cultured at high (500 ng/mL) and low (50 ng/mL) CD40L levels. In response to increased CD40L levels, both populations exhibited a core response to genes related to activation (TRAF1, AKT3, CD69, and CD80). However, they differed in genes related to cytokine/chemokine/homing interactions (CCL3/4/17, LTA, NKX2-3, BCL2 and IL21R) and cell-cell interactions (HLADR, CD40, and ICOSL), which were largely confined to IgG+ cells. Our findings revealed that in co-cultures with a high T-ratio, the response was similar to that found in cultures with high CD40L levels. These results suggest that IgG+ mBCs have a greater capacity for proliferation and T cell interaction, and weaker migration capabilities, leading to a preference for an IgG response over IgM in the short term. This adaptable response could fine-tune the memory repertoire with different functions of IgG versus IgM mBCs.
Asunto(s)
Ligando de CD40 , Inmunoglobulina G , Inmunoglobulina M , Células B de Memoria , Linfocitos T , Ligando de CD40/metabolismo , Ligando de CD40/inmunología , Humanos , Inmunoglobulina M/inmunología , Inmunoglobulina M/metabolismo , Inmunoglobulina G/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células B de Memoria/inmunología , Células B de Memoria/metabolismo , Comunicación Celular/inmunología , Técnicas de Cocultivo , Memoria Inmunológica , Activación de Linfocitos/inmunología , Células Cultivadas , Diferenciación Celular/inmunología , Proliferación CelularRESUMEN
BACKGROUND: Difficulties in activities of daily living (ADL) and instrumental activities of daily living (IADL) in older adults are associated with diminished quality of life and increased demand for long-term care. The present study examined the prevalence of disability among individuals aged 65 years and older in Austria, using data from the Austrian Health Interview Surveys (ATHIS). METHODS: The ATHIS 2014 and 2019 surveys were used (Nâ¯= 5853) for the analysis. Binary logistic regression was performed to measure the association between disability in at least one ADL or IADL limitation and independent variables adjusted for sociodemographic, health-related behavior and survey year. RESULTS: The prevalence of ADL or IADL limitations increased in both sexes during the 5year follow-up period. For ADL limitations, the prevalence rose from 12.8% to 17.9% in men (pâ¯< 0.001) and from 19.2% to 25.7% in women (pâ¯< 0.001). The IADL limitations increased from 18.9% to 35.1% in men (pâ¯< 0.001) and from 38.2% to 50.8% in women (pâ¯< 0.001). Women reported significantly higher odds for ADL (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 0.93-1.26) and IADL limitations (OR: 1.74, 95% CI: 1.53-1.98). In both sexes, participants aged 80 years and older reported higher odds for ADL (OR: 4.37, 95% CI:3.77-5.07) and IADL limitations (OR: 4.43, 95% CI: 3.86-5.09) compared to the younger group. Participants with at least one chronic disease reported higher odds for ADL (OR: 4.00, 95% CI: 3.41-4.70) and IADL limitations (OR: 4.37, 95% CI: 3.85-4.96). Primary education, single status, being born in non-EU/EFTA countries, and residing in Vienna were associated with higher odds of ADL and IADL limitations. CONCLUSION: Gender, age, education, country of birth, residence, partnership status, number of chronic diseases, noncompliance with physical activity, and nutrition recommendations had a strong association with increased vulnerability to disability. Public health policy must address these factors for disability prevention strategies.
RESUMEN
Introduction: The transplantation of highly sensitized patients remains a major obstacle. Immunized patients wait longer for a transplant if not prioritized, and if transplanted, their transplant outcome is worse. Case Presentation: We report a successful AB0- and HLA-incompatible living donor kidney transplantation in a 35-year-old female patient with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The patient had a positive T- and B-cell complement-dependent cytotoxicity (CDC) crossmatch and previous graft loss due to renal vein thrombosis. We treated the patient with intravenous immunoglobulins, rituximab, horse anti-thymocyte globulin, daratumumab, and imlifidase, besides standard immunosuppression. All IgG antibodies were sensitive to imlifidase treatment. Besides donor-specific HLA antibodies, anti-dsDNA antibodies and antiphospholipid antibodies were cleaved. The patient initially had delayed graft function. Two kidney biopsies (day 7 and day 14) revealed acute tubular necrosis without signs of HLA antibody-mediated rejection. On posttransplant day 30, hemodialysis was stopped, and creatinine levels declined over the next weeks to a baseline creatinine of about 1.7 mg/dL after 12 months. Conclusion: In this case, a novel multimodal treatment strategy including daratumumab and imlifidase enabled successful kidney transplantation for a highly immunized patient with antiphospholipid antibodies.
RESUMEN
Systemic sclerosis, a severe inflammatory autoimmune disease, shares a common thread with cancer through the underlying mechanism of inflammation. This inflammatory milieu not only drives the immune dysregulation characteristic of autoimmune diseases but also plays a pivotal role in the pathogenesis of cancer. Among the cellular components involved, B cells have emerged as key players in hematologic tumor and autoimmune disease, contributing to immune dysregulation and persistent tissue fibrosis in systemic sclerosis, as well as tumor progression and immune evasion in cancer. Consequently, novel therapeutic strategies targeting B cells hold promise in both conditions. Recent exploration of CD19 CAR T cells in severe systemic sclerosis patients has shown great potential, but also introduced possible risks and drawbacks associated with viral vectors, prolonged CAR T cell persistence, lengthy production timelines, high costs, and the necessity of conditioning patients with organotoxic and fertility-damaging chemotherapy. Given these challenges, alternative CD19-depleting approaches are of high interest for managing severe systemic autoimmune diseases. Here, we present the pioneering use of blinatumomab, a bispecific anti-CD3/anti-CD19 T cell engager in a patient with progressive, severe systemic sclerosis, offering a promising alternative for such challenging cases.
Asunto(s)
Anticuerpos Biespecíficos , Antígenos CD19 , Esclerodermia Sistémica , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/inmunología , Antígenos CD19/inmunología , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Femenino , Complejo CD3/inmunología , Complejo CD3/metabolismo , Persona de Mediana Edad , Inmunoterapia Adoptiva/métodosRESUMEN
Bone marrow plasma cells (BMPC) are the correlate of humoral immunity, consistently releasing antibodies into the bloodstream. It remains unclear if BMPC reflect different activation environments or maturation of their precursors. Here we define human BMPC heterogeneity and track the recruitment of antibody-secreting cells (ASC) from SARS-CoV-2 vaccine immune reactions to the bone marrow (BM). Trajectories based on single-cell transcriptomes and repertoires of peripheral and BM ASC reveal sequential colonisation of BMPC compartments. In activated B cells, IL-21 suppresses CD19 expression, indicating that CD19low-BMPC are derived from follicular, while CD19high-BMPC originate from extrafollicular immune reactions. In primary immune reactions, both CD19low- and CD19high-BMPC compartments are populated. In secondary immune reactions, most BMPC are recruited to CD19high-BMPC compartments, reflecting their origin from extrafollicular reactivations of memory B cells. A pattern also observable in vaccinated-convalescent individuals and upon diphtheria/tetanus/pertussis recall-vaccination. Thus, BMPC diversity reflects the evolution of a given humoral immune response.
Asunto(s)
Antígenos CD19 , Médula Ósea , Interleucinas , Células Plasmáticas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células Productoras de Anticuerpos/inmunología , Antígenos CD19/inmunología , Antígenos CD19/metabolismo , Linfocitos B/inmunología , Médula Ósea/inmunología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/citología , COVID-19/inmunología , COVID-19/virología , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Inmunidad Humoral/inmunología , Interleucinas/inmunología , Interleucinas/metabolismo , Células Plasmáticas/inmunología , SARS-CoV-2/inmunología , Análisis de la Célula Individual , VacunaciónRESUMEN
OBJECTIVES: Autoreactive B cells and interferon (IFN) signature are hallmarks of primary sjögren's syndrome (pSS), but how IFN signaling pathways influence autoantibody production and clinical manifestations remain unclear. More detailed studies hold promise for improved diagnostic methodologies and personalized treatment. METHODS: We analyzed peripheral blood T and B cell subsets from 34 pSS patients and 38 healthy donors (HDs) at baseline and upon stimulation regarding their expression levels of type I and II IFN signaling molecules (STAT1/2, IRF1, IRF9). Additionally, we investigated how the levels of these molecules correlated with serological and clinical characteristics and performed ROC analysis. RESULTS: Patients showed elevated IFN pathway molecules, including STAT1, STAT2 and IRF9 among most T and B cell subsets. We found a reduced ratio of phosphorylated STAT1 and STAT2 in patients in comparison to HDs, although B cells from patients were highly responsive by increased phosphorylation upon IFN stimulation. Correlation matrices showed further interrelations between STAT1, IRF1 and IRF9 in pSS. Levels of STAT1 and IRF9 in T and B cells correlated with the IFN type I marker Siglec-1 (CD169) on monocytes. High levels of STAT1 and IRF9 within pSS B cells were significantly associated with hypergammaglobulinemia as well as anti-SSA/anti-SSB autoantibodies. Elevated STAT1 levels were found in patients with extraglandular disease and could serve as a biomarker for this subgroup (p < 0.01). Notably, IRF9 levels in T and B cells correlated with EULAR Sjögren's syndrome disease activity index (ESSDAI). CONCLUSION: Here, we provide evidence that in active pSS patients, enhanced IFN signaling incl. unphosphorylated STAT1 and STAT2 with IRFs entertain chronic T and B cell activation. Furthermore, increased STAT1 levels candidate as biomarker of extraglandular disease, while IRF9 levels can serve as biomarker for disease activity.
Asunto(s)
Biomarcadores , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón , Factor de Transcripción STAT1 , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/metabolismo , Factor de Transcripción STAT1/metabolismo , Femenino , Fosforilación , Persona de Mediana Edad , Masculino , Subunidad gamma del Factor 3 de Genes Estimulados por el Interferón/metabolismo , Anciano , Adulto , Linfocitos B/inmunología , Linfocitos B/metabolismo , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Transducción de Señal , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Lectina 1 Similar a Ig de Unión al Ácido Siálico/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Monitoring survey methods, as well as movement recommendations, evolves over time. These changes can make trend observations over time difficult. The aim of this study was to examine the differences between 2 computer-assisted survey administration methods and the effect of the omission of the 10-minute minimum bout requirement in physical activity (PA) questions on PA outcomes. METHODS: We used data from the second Austrian PA Surveillance System for 2998 adults (18-64 y), applying computer-assisted personal interviewing and computer-assisted web interviewing. Within the computer-assisted web interviewing sample only, we added PA questions without the 10-minute requirement. Quantile and logistic regressions were applied. RESULTS: Between computer-assisted web interviewing and computer-assisted personal interviewing, within the computer-assisted personal interviewing sample, we found lower PA estimates in the leisure domain and work and household domain, but not in the travel domain, and no significant difference in the proportion of people meeting the PA recommendations. In all 3 PA domains, the median minutes did not differ when assessed with or without the 10-minute requirement. However, the percentage participation in the travel domain and work and household domain performing >0 minutes per week PA was higher when there was no 10-minute requirement. The proportion of people meeting the Austrian aerobic recommendation for adults when computed with or without the 10-minute requirement did not differ. CONCLUSION: Our findings suggest that the omission of the 10-minute requirement does not seem to result in marked differences in PA estimates or the proportion of adults meeting the recommendations.
Asunto(s)
Ejercicio Físico , Humanos , Austria , Adulto , Masculino , Femenino , Persona de Mediana Edad , Adolescente , Adulto Joven , Factores de Tiempo , Encuestas y Cuestionarios , Entrevistas como Asunto , Actividad Motora , Actividades RecreativasRESUMEN
UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.
Asunto(s)
Lupus Eritematoso Sistémico , Receptor Toll-Like 7 , Ratones , Animales , Humanos , Receptor Toll-Like 7/genética , Autoinmunidad/genética , Receptor Toll-Like 9/metabolismo , Receptor Toll-Like 8 , Receptor Toll-Like 3/metabolismo , Lupus Eritematoso Sistémico/genética , Proteínas de Transporte de MembranaRESUMEN
The climate crisis is developing into a life-changing event on a global level. Health promotion with the aim to increase the health status of individuals, independent of the present health status, has been developed on a scientific basis at least for the last eight decades. There are some basic principles which are prerequisites for both health promotion and climate protection. Those principles include (1) sustainability, (2) orientation on determinants, and (3) requirement of individual as well as community approaches. People are generally aiming to protect their lifestyle habits (e.g., traveling and consumer habits) and personal property (e.g., car and house) with easy solutions and as little effort as possible, and this can affect both health and climate. To reduce the emission of greenhouse gases and to protect our environment, changes towards a sustainable lifestyle have to be embedded into everybody's mind. Examples for domains that need to be addressed in health promotion as well as in climate protection include (health and climate) literacy, physical activity and active mobility, and nutrition and dietary habits. If health promotion fails to tackle those domains, this will continue to drive the climate crisis. And climate change, in turn, will affect health. On the other hand, developing and promoting health resources in the domains mentioned could help to mitigate the health-damaging effects of climate change. Success in the joint efforts to promote health and protect the climate would improve the One Health approach, the health of people and the environment.
Asunto(s)
Promoción de la Salud , Estilo de Vida , Humanos , Políticas , Cambio Climático , Ejercicio FísicoRESUMEN
Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.
Asunto(s)
Inmunosupresores , Ácido Micofenólico , Humanos , Ácido Micofenólico/uso terapéutico , Abatacept , Inmunosupresores/efectos adversos , Tacrolimus/uso terapéutico , Inhibidores de la Calcineurina/efectos adversos , Terapia de Inmunosupresión , Sirolimus/farmacología , Rechazo de Injerto/prevención & controlRESUMEN
OBJECTIVES: To evaluate the safety and efficacy of remibrutinib in patients with moderate-to-severe Sjögren's syndrome (SjS) in a phase 2 randomised, double-blind trial (NCT04035668; LOUiSSE (LOU064 in Sjögren's Syndrome) study). METHODS: Eligible patients fulfilling 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for SjS, positive for anti-Ro/Sjögren's syndrome-related antigen A antibodies, with moderate-to-severe disease activity (EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (based on weighted score) ≥ 5, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥ 5) received remibrutinib (100 mg) either one or two times a day, or placebo for the 24-week study treatment period. The primary endpoint was change from baseline in ESSDAI at week 24. Key secondary endpoints included change from baseline in ESSDAI over time, change from baseline in ESSPRI over time and safety of remibrutinib in SjS. Key exploratory endpoints included changes to the salivary flow rate, soluble biomarkers, blood transcriptomic and serum proteomic profiles. RESULTS: Remibrutinib significantly improved ESSDAI score in patients with SjS over 24 weeks compared with placebo (ΔESSDAI -2.86, p=0.003). No treatment effect was observed in ESSPRI score (ΔESSPRI 0.17, p=0.663). There was a trend towards improvement of unstimulated salivary flow with remibrutinib compared with placebo over 24 weeks. Remibrutinib had a favourable safety profile in patients with SjS over 24 weeks. Remibrutinib induced significant changes in gene expression in blood, and serum protein abundance compared with placebo. CONCLUSIONS: These data show preliminary efficacy and favourable safety of remibrutinib in a phase 2 trial for SjS.
Asunto(s)
Pirimidinas , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/tratamiento farmacológico , Síndrome de Sjögren/complicaciones , Proteómica , Anticuerpos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.
Asunto(s)
Azatioprina , Lupus Eritematoso Sistémico , Humanos , Azatioprina/uso terapéutico , Tacrolimus/uso terapéutico , Rituximab/uso terapéutico , Metotrexato/uso terapéutico , Lupus Eritematoso Sistémico/complicaciones , Inmunosupresores/uso terapéutico , Ciclofosfamida/uso terapéutico , Hidroxicloroquina/uso terapéutico , Glucocorticoides/uso terapéutico , Inhibidores Enzimáticos/uso terapéuticoRESUMEN
BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints and produces pain, swelling, and stiffness. It has a lifetime prevalence of up to 1% worldwide. An extract of Tripterygium wilfordii Hook F (TwHF), a member of the Celastraceae herbal family widely available in south China, has been used for treatment of RA since 1960s. METHODS: The current consensus practice guidance (CPG) aims to offer guidance on the application of TwHF in the clinical management of active RA. The CPG followed World Health Organisation (WHO)'s recommended process, carried out three systematic reviews to synthesize data from 19 randomised controlled trials (RCT) involving 1795 participants. We utilized Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to evaluate certainty of evidence and derive recommendations. We rigorously followed The Appraisal of Guidelines for Research and Evaluation II (AGREE II) as conduct guides to minimise bias and promote transparency. RESULTS: There was no obvious difference between TwHF monotherapy and methotrexate (MTX) monotherapy on ACR20 (RCT = 2, N = 390, RR = 1.06, 95%CI 0.90-1.26, moderate certainty), ACR50 (RCT = 3, N = 419, RR = 1.03, 95%CI 0.80-1.34, moderate certainty), ACR70 (RCT = 2, N = 390, RR = 1.12, 95%CI 0.69-1.79, low certainty). TwHF monotherapy may be better than salicylazosulfapyridine monotherapy on ACR20 and the effect may be similar on ACR50 and ACR70. Seven RCTs compared MTX combined with TwHF versus MTX monotherapy, and the meta-analysis results favoured combination therapy group on ACR20 (RCT = 3, N = 470, RR = 1.44, 95%CI 1.28-1.62, moderate certainty), ACR50 (RCT = 4, N = 500, RR = 1.88, 95%CI 1.56-2.28, moderate certainty) and ACR70 (RCT = 2, N = 390, RR = 2.12, 95%CI 1.40-3.19, low certainty). We found no obvious difference between groups on critical safety outcomes, including infection (RCT = 3, N = 493, RR = 1.37, 95%CI 0.84-2.23), liver dysfunction (RCT = 5, N = 643, RR = 1.14, 95%CI 0.71-1.85), renal damage (RCT = 3, N = 450, RR = 2.20, 95%CI 0.50-9.72). CONCLUSION: Upon full review of the evidence, the guidance panel reached consensus on recommendations for the use of TwHF in people with active RA, either as monotherapy or as combination therapy with MTX.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Humanos , Antirreumáticos/uso terapéutico , Tripterygium , Consenso , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/uso terapéutico , Enfermedad CrónicaRESUMEN
Systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) share clinical as well as pathogenic similarities. Although previous studies suggest various abnormalities in different immune cell compartments, dedicated cell-type specific transcriptomic signatures are often masked by patient heterogeneity. Here, we performed transcriptional profiling of isolated CD4, CD8, CD16 and CD19 lymphocytes from pSS and SLE patients upon T cell stimulation, in addition to a steady-state condition directly after blood drawing, in total comprising 581 sequencing samples. T cell stimulation, which induced a pronounced inflammatory response in all four cell types, gave rise to substantial re-modulation of lymphocyte subsets in the two autoimmune diseases compared to healthy controls, far exceeding the transcriptomic differences detected at steady-state. In particular, we detected cell-type and disease-specific down-regulation of a range of pro-inflammatory cytokine and chemokine pathways. Such differences between SLE and pSS patients are instrumental for selective immune targeting by future therapies.
Asunto(s)
Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/genética , Síndrome de Sjögren/metabolismo , Linfocitos T/metabolismo , Regulación hacia Abajo/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismoRESUMEN
The commensal microflora provides a repertoire of antigens that illicit mucosal antibodies. In some cases, these antibodies can cross-react with host proteins, inducing autoimmunity, or with other microbial antigens. We demonstrate that the oral microbiota can induce salivary anti-SARS-CoV-2 Spike IgG antibodies via molecular mimicry. Anti-Spike IgG antibodies in the saliva correlated with enhanced abundance of Streptococcus salivarius 1 month after anti-SARS-CoV-2 vaccination. Several human commensal bacteria, including S. salivarius, were recognized by SARS-CoV-2-neutralizing monoclonal antibodies and induced cross-reactive anti-Spike antibodies in mice, facilitating SARS-CoV-2 clearance. A specific S. salivarius protein, RSSL-01370, contains regions with homology to the Spike receptor-binding domain, and immunization of mice with RSSL-01370 elicited anti-Spike IgG antibodies in the serum. Additionally, oral S. salivarius supplementation enhanced salivary anti-Spike antibodies in vaccinated individuals. Altogether, these data show that distinct species of the human microbiota can express molecular mimics of SARS-CoV-2 Spike protein, potentially enhancing protective immunity.
Asunto(s)
COVID-19 , Microbiota , Humanos , Animales , Ratones , Glicoproteína de la Espiga del Coronavirus , Formación de Anticuerpos , Imitación Molecular , SARS-CoV-2 , Anticuerpos Monoclonales , Anticuerpos Antivirales , Inmunoglobulina A Secretora , Inmunoglobulina G , Anticuerpos NeutralizantesRESUMEN
OBJECTIVES: To assess the safety of the oral Janus kinase inhibitor baricitinib in adult patients with systemic lupus erythematosus (SLE) receiving stable background therapy. Topics of special interest included infections and cardiovascular and thromboembolic events. METHODS: This analysis included integrated safety data from three randomised, placebo-controlled studies (one phase 2 and two phase 3) and one long-term extension study. Data are reported in three data sets: placebo-controlled, extended exposure and all-baricitinib. Outcomes include treatment-emergent adverse events (AEs), AEs of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IRs) were calculated. RESULTS: A total of 1655 patients received baricitinib for up to 3.5 years (median duration 473 days). With baricitinib 4 mg, baricitinib 2 mg and placebo, respectively, 50.8%, 50.7% and 49.0% of patients reported at least one infection and 4.4%, 3.4% and 1.9% of patients had a serious infection. The most common treatment-emergent infections included urinary tract infection, COVID-19, upper respiratory tract infection and nasopharyngitis. Herpes zoster was more common with baricitinib 4 mg (4.7%) vs baricitinib 2 mg (2.7%) and placebo (2.8%). Among baricitinib-4 mg, 2 mg and placebo-treated patients, respectively, 4 (IR=0.9), 1 (IR=0.2) and 0 experienced at least one positively adjudicated major adverse cardiovascular event, and 0, 3 (IR=0.6) and 2 (IR=0.4) reported at least one positively adjudicated venous thromboembolism. CONCLUSIONS: The results of this integrated safety analysis in patients with SLE are not substantially different to the established safety profile of baricitinib. No increased venous thromboembolism was found.
Asunto(s)
COVID-19 , Lupus Eritematoso Sistémico , Tromboembolia Venosa , Adulto , Humanos , Tratamiento Farmacológico de COVID-19 , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológicoRESUMEN
Improved characterization of relevant pathogenic pathways in systemic lupus erythematosus (SLE) has been further delineated over the last decades. This led to the development of targeted treatments including belimumab and anifrolumab, which recently became available in clinics. Therapeutic targets in SLE encompass interferon (IFN) signaling, B-T costimulation including immune checkpoints, and increasing modalities of B lineage targeting, such as chimeric antigen receptor (CAR) T cells directed against CD19 or sequential anti-B cell targeting. Patient profiling based on characterization of underlying molecular abnormalities, often performed through comprehensive omics analyses, has recently been shown to better predict patients' treatment responses and also holds promise to unravel key molecular mechanisms driving SLE. SLE carries two key signatures, namely the IFN and B lineage/plasma cell signatures. Recent advances in SLE treatments clearly indicate that targeting innate and adaptive immunity is successful in such a complex autoimmune disease. Although those signatures may interact at the molecular level and provide the basis for the first selective treatments in SLE, it remains to be clarified whether these distinct treatments show different treatment responses among certain patient subsets. In fact, notwithstanding the remarkable amount of novel clues for innovative SLE treatment, harmonization of big data within tailored treatment strategies will be instrumental to better understand and treat this challenging autoimmune disorder. This review will provide an overview of recent improvements in SLE pathogenesis, related insights by analyses of big data and machine learning as well as technical improvements in conducting clinical trials with the ultimate goal that translational research results in improved patient outcomes.
RESUMEN
BACKGROUND: Status inequality is hypothesised to increase socioeconomic inequalities in health by creating an environment in which social cohesion erodes and social comparisons intensify. Such an environment may cause systemic chronic inflammation. Although these are often-used explanations in social epidemiology, empirical tests remain rare. METHODS: We analysed data from the West of Scotland Twenty-07 Study. Our sample consisted of 1977 participants in 499 small residential areas. Systemic chronic inflammation was measured by high-sensitivity C-reactive protein (hs-CRP; <10 mg/L). An area-level measurement of status inequality was created using census data and contextual-level social cohesion was measured applying ecometrics. We estimated linear multilevel models with cross-level interactions between socioeconomic position (SEP), status inequality, and social cohesion adjusted for age and gender. Our main analysis on postcode sector-level was re-estimated on three smaller spatial levels. RESULTS: The difference in hs-CRP between disadvantaged and advantaged SEPs (0.806 mg/L; p = 0.063; [95%CI: -0.044; 1.656]) was highest among participants living in areas where most residents were in advantaged SEPs. In these status distributions, high social cohesion was associated with a shallower socioeconomic gradient in hs-CRP and low social cohesion was associated with a steeper gradient. In areas with an equal mix of SEPs or most residents in disadvantaged SEPs, the estimated difference in hs-CRP between disadvantaged and advantaged SEPs was -0.039 mg/L (p = 0.898; [95%CI: 0.644; 0.566]) and -0.257 mg/L (p = 0.568; [95%CI: 1.139; 0.625]) respectively. In these status distributions, the gradient in hs-CRP appeared steeper when social cohesion was high and potentially reversed when social cohesion was low. Results were broadly consistent when using area-levels smaller than postcode sectors. CONCLUSIONS: Inequalities in hs-CRP were greatest among participants living in areas wherein a majority of residents were in advantaged SEPs and social cohesion was low. In other combinations of these contextual characteristics, inequalities in systemic chronic inflammation were not detectable or potentially even reversed.