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Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.
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Metabolismo Energético , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-33/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Inflamação/etiologia , Ativação de Macrófagos/genética , Mitocôndrias/genética , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Fagócitos , Transdução de SinaisRESUMO
Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.
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Proteínas do Sistema Complemento/imunologia , Fibroblastos/imunologia , Inflamação/imunologia , Membrana Sinovial/imunologia , Imunidade Adaptativa/imunologia , Animais , Artrite Reumatoide/imunologia , Linhagem Celular , Cães , Humanos , Mediadores da Inflamação/imunologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Ratos Wistar , Transdução de Sinais/imunologiaRESUMO
Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.
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Anti-Inflamatórios , Glucocorticoides , Inflamação , Macrófagos , Mitocôndrias , Succinatos , Animais , Feminino , Humanos , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Carboxiliases/metabolismo , Carboxiliases/antagonistas & inibidores , Ciclo do Ácido Cítrico/efeitos dos fármacos , Ciclo do Ácido Cítrico/genética , Citocinas/imunologia , Citocinas/metabolismo , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Hidroliases/deficiência , Hidroliases/genética , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Complexo Piruvato Desidrogenase/metabolismo , Receptores de Glucocorticoides/metabolismo , Succinatos/metabolismo , Ativação Enzimática/efeitos dos fármacosRESUMO
In systemic lupus erythematosus (SLE) loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage1. How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here, we set out to dissect layers and hierarchies of autoimmune kidney inflammation in order to identify tissue-specific cellular hubs that amplify auto-inflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blocking and genetic deficiency, we show that tissue-resident NKp46+ innate lymphoid cells (ILC) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signaling in a distinct subset of ILC1 instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46+ ILC promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody mNCR1.152) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data support that NKp46+ ILC1 promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1 thus constitutes a previously unrecognized, critical tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies.
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The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of ß-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.
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Artrite Reumatoide/imunologia , Autoanticorpos/metabolismo , Linfócitos B/imunologia , Tolerância Imunológica , Imunoglobulina G/metabolismo , Interleucina-23/metabolismo , Células Th17/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Glicosilação , Humanos , Interleucinas/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Sialiltransferases/genética , Sialiltransferases/metabolismo , Transdução de Sinais , beta-D-Galactosídeo alfa 2-6-Sialiltransferase , Interleucina 22RESUMO
BACKGROUND: Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS: We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded. RESULTS: The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization. CONCLUSIONS: In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).
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Antígenos CD19 , Imunoterapia Adotiva , Lúpus Eritematoso Sistêmico , Agonistas Mieloablativos , Miosite , Escleroderma Sistêmico , Humanos , Antígenos CD19/administração & dosagem , Síndrome da Liberação de Citocina/etiologia , Seguimentos , Lúpus Eritematoso Sistêmico/terapia , Miosite/terapia , Escleroderma Sistêmico/terapia , Agonistas Mieloablativos/administração & dosagem , Ciclofosfamida/administração & dosagem , Infecções/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. METHODS: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). FINDINGS: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. INTERPRETATION: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. FUNDING: Innovative Medicine Initiative.
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Antirreumáticos , Artrite Reumatoide , Adulto , Masculino , Humanos , Feminino , Adolescente , Abatacepte/efeitos adversos , Antirreumáticos/efeitos adversos , Resultado do Tratamento , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Artralgia/induzido quimicamenteRESUMO
Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX3CR1+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX3CR1- mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX3CR1+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.
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Articulações/citologia , Macrófagos/citologia , Macrófagos/fisiologia , Membrana Sinovial/citologia , Sinoviócitos/citologia , Sinoviócitos/fisiologia , Junções Íntimas/fisiologia , Animais , Artrite/imunologia , Artrite/patologia , Receptor 1 de Quimiocina CX3C/análise , Receptor 1 de Quimiocina CX3C/metabolismo , Rastreamento de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação/imunologia , Inflamação/patologia , Articulações/patologia , Macrófagos/classificação , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Componente Principal , RNA-Seq , Análise de Célula Única , Sinoviócitos/classificação , Sinoviócitos/metabolismo , Transcriptoma/genéticaRESUMO
B cells have a pivotal function in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. In autoimmune disease, B cells orchestrate antigen presentation, cytokine production and autoantibody production, the latter via their differentiation into antibody-secreting plasmablasts and plasma cells. This article addresses the current therapeutic strategies to deplete B cells in order to ameliorate or potentially even cure autoimmune disease. It addresses the main target antigens in the B-cell lineage that are used for therapeutic approaches. Furthermore, it summarises the current evidence for successful treatment of autoimmune disease with monoclonal antibodies targeting B cells and the limitations and challenges of these approaches. Finally, the concept of deep B-cell depletion and immunological reset by chimeric antigen receptor T cells is discussed, as well as the lessons from this approach for better understanding the role of B cells in autoimmune disease.
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Due to optimised treatment strategies and the availability of new therapies during the last decades, formerly devastating chronic inflammatory diseases such as rheumatoid arthritis or systemic sclerosis (SSc) have become less menacing. However, in many patients, even state-of-the-art treatment cannot induce remission. Moreover, the risk for flares strongly increases once anti-inflammatory therapy is tapered or withdrawn, suggesting that underlying pathological processes remain active even in the absence of overt inflammation. It has become evident that tissues have the ability to remember past encounters with pathogens, wounds and other irritants, and to react more strongly and/or persistently to the next occurrence. This priming of the tissue bears a paramount role in defence from microbes, but on the other hand drives inflammatory pathologies (the Dr Jekyll and Mr Hyde aspect of tissue adaptation). Emerging evidence suggests that long-lived tissue-resident cells, such as fibroblasts, macrophages, long-lived plasma cells and tissue-resident memory T cells, determine inflammatory tissue priming in an interplay with infiltrating immune cells of lymphoid and myeloid origin, and with systemically acting factors such as cytokines, extracellular vesicles and antibodies. Here, we review the current state of science on inflammatory tissue priming, focusing on tissue-resident and tissue-occupying cells in arthritis and SSc, and reflect on the most promising treatment options targeting the maladapted tissue response during these diseases.
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OBJECTIVES: Osteoclasts (OCs) are myeloid-derived multinucleated cells uniquely able to degrade bone. However, the exact nature of their myeloid precursors is not yet defined. METHODS: CD11c-diphtheria toxin receptor (CD11cDTR) transgenic mice were treated with diphtheria toxin (DT) or phosphate buffered saline (PBS) during serum transfer arthritis (STA) and human tumour necrosis factor transgenic (hTNFtg) arthritis and scored clinically and histologically. We measured cytokines in synovitis by quantitative polymerase chain reaction (qPCR). We performed ovariectomy in CD11cDTR mice treated with PBS or DT. We analysed CD11cDTR, CD11c-Cre/CX3CR1-STOP-DTR and Zbtb46-DTR-treated mice with DT using histomorphometry and OC of CD11c and Zbtb46 fate reporter mice by fluorescent imaging. We sorted murine and human OC precursors and stimulated them with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) to generate OCs. RESULTS: Targeting CD11c+ cells in vivo in models of inflammatory arthritis (STA and hTNFtg) ameliorates arthritis by reducing inflammatory bone destruction and OC generation. Targeting CD11c-expressing cells in unchallenged mice removes all OCs in their long bones. OCs do not seem to be derived from CD11c+ cells expressing CX3CR1+, but from Zbtb46+conventional dendritic cells (cDCs) as all OCs in Zbtb46-Tomato fate reporter mice are Tomato+. In line, administration of DT in Zbtb46-DTR mice depletes all OCs in long bones. Finally, human CD1c-expressing cDCs readily differentiated into bone resorbing OCs. CONCLUSION: Taken together, we identify DCs as important OC precursors in bone homeostasis and inflammation, which might open new avenues for therapeutic interventions in OC-mediated diseases.
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Artrite , Osteoclastos , Feminino , Camundongos , Humanos , Animais , Citocinas/metabolismo , Diferenciação Celular , Artrite/metabolismo , Células Dendríticas/metabolismo , Ligante RANK/metabolismoRESUMO
OBJECTIVES: Bone remodelling is a highly dynamic process dependent on the precise coordination of osteoblasts and haematopoietic-cell derived osteoclasts. Changes in core metabolic pathways during osteoclastogenesis, however, are largely unexplored and it is unknown whether and how these processes are involved in bone homeostasis. METHODS: We metabolically and transcriptionally profiled cells during osteoclast and osteoblast generation. Individual gene expression was characterised by quantitative PCR and western blot. Osteoblast function was assessed by Alizarin red staining. immunoresponsive gene 1 (Irg1)-deficient mice were used in various inflammatory or non-inflammatory models of bone loss. Tissue gene expression was analysed by RNA in situ hybridisation. RESULTS: We show that during differentiation preosteoclasts rearrange their tricarboxylic acid cycle, a process crucially depending on both glucose and glutamine. This rearrangement is characterised by the induction of Irg1 and production of itaconate, which accumulates intracellularly and extracellularly. While the IRG1-itaconate axis is dispensable for osteoclast generation in vitro and in vivo, we demonstrate that itaconate stimulates osteoblasts by accelerating osteogenic differentiation in both human and murine cells. This enhanced osteogenic differentiation is accompanied by reduced proliferation and altered metabolism. Additionally, supplementation of itaconate increases bone formation by boosting osteoblast activity in mice. Conversely, Irg1-deficient mice exhibit decreased bone mass and have reduced osteoproliferative lesions in experimental arthritis. CONCLUSION: In summary, we identify itaconate, generated as a result of the metabolic rewiring during osteoclast differentiation, as a previously unrecognised regulator of osteoblasts.
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INTRODUCTION: The role of uric acid (UA) on bone metabolism is controversially discussed. Higher UA levels have been associated with higher T-scores and a reduced incidence of fractures in postmenopausal women. However, in the context of rheumatoid arthritis (RA), the role of UA remains unclear. This pilot study aimed to investigate the association of UA levels with bone mineral density in RA female and male patients. METHODS: This pilot study analyzed patients with RA to explore preliminary associations. We utilized data from the Rh-GIOP cohort, a prospective monocentric observational study focusing on bone health in chronic rheumatic diseases. To assess the association between UA levels and the lowest T-scores measured at the lumbar spine, hip, or femur, we used linear regression with adjustment for various confounders. An interaction term was included to evaluate differential associations in pre- and postmenopausal women. RESULTS: Data on dual X-ray absorptiometry (DXA) measurements and serum UA levels were analyzed in a total of 206 patients. Among the 167 women 16 were premenopausal (age 40 ± 8 years) and 149 postmenopausal (age 65 ± 10 years). As expected, postmenopausal had lower T-scores than premenopausal patients (-1.53 ± 1.01 versus - 0.41 ± 1.29, respectively). No association of UA levels with T-scores was found when analyzing the whole cohort (Slope ß: -0.04; p = 0.45). However, a significant negative correlation of UA with T-scores in premenopausal (Slope ß: -0.98; p = 0.014), but not postmenopausal (Slope ß: -0.04; p > 0.05) women was found. CONCLUSION: Uric acid appears to be negatively associated with bone mineral density in premenopausal but not in postmenopausal women with RA. Thus, the impact of UA on bone health seems to depend on the hormonal status of women. Further investigations are required to validate these results in a larger cohort of patients and to investigate the underlying mechanisms.
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OBJECTIVE: To explore the metabolic characteristics of arthritis and enthesitis using multispectral opto-acoustic tomography (MSOT), a technology using near-infrared multispectral laser to stimulate tissues and detect the emitted acoustic energy, enabling non-invasive quantification of tissue components in vivo based on differential absorbance at multiple wavelengths. METHODS: We performed a cross-sectional study in patients with RA or PsA and healthy controls (HCs). Participants underwent clinical, ultrasonographic and MSOT examination of MCP and wrist joints as well as the entheses of the common extensor tendon at the lateral humeral epicondyles and of the patellar, quadriceps and Achilles tendon. MSOT-measured haemoglobin (Hb), oxygen saturation, collagen and lipid levels were quantified and scaled mean differences between affected and unaffected joints and entheses were calculated as defined by clinical examination or ultrasonography using linear mixed effects models. RESULTS: We obtained 1535 MSOT and 982 ultrasonography scans from 87 participants (34 PsA, 17 RA, 36 HCs). Entheseal tenderness was not associated with significant metabolic changes, whereas enthesitis-related sonographic changes were associated with increased total Hb, oxygen saturation and collagen content. In contrast, the presence of arthritis-related clinical and sonographic findings showed increased Hb levels, reduced oxygen saturation and reduced collagen content. Synovial hypertrophy was associated with increased lipid content in the joints. CONCLUSION: MSOT allows determination of distinct metabolic differences between arthritis and enthesitis in a non-invasive setting in humans in vivo.
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Artrite Psoriásica , Entesopatia , Humanos , Artrite Psoriásica/diagnóstico por imagem , Estudos Transversais , Inflamação/diagnóstico por imagem , Ultrassonografia , Entesopatia/diagnóstico por imagem , Tomografia Computadorizada por Raios X , LipídeosRESUMO
Patient-reported outcomes (PRO) represent a cornerstone in the management of patients with rheumatoid arthritis (RA). However, PRO are currently recorded mainly on paper and only during on-site appointments. Electronic PRO (ePRO) enable continuous remote monitoring and could improve shared decision-making (SDM) and implementation of a treat-to-target (T2T) approach. This study aims to investigate patient and physician experiences, perceived drawbacks and benefits of using an ePRO web-app (ABATON RA) to digitally support SDM and T2T. A qualitative study embedded in a multicenter randomized controlled trial (RCT) consisting of interviews with RA patients and physicians that were subsequently analyzed using deductive-inductive qualitative content analysis. Between August 2021 and May 2022, interviews with ten RA patients and five physicians were completed. Three key themes emerged in the analysis: (i) App user experiences; (ii) perceived drawbacks of app-supported rheumatology care; and (iii) perceived benefits of app-supported rheumatology care. Continuous ePRO collection and a high level of standardization strained some RA patients. Certain ePRO seemed outdated and were hard to understand. Patients and physicians appreciated having an improved overview of disease activity, capturing disease flares and continuous remote monitoring. Paper- and time-saving were associated with using ePRO. Physicians feared to become too focused on ePRO data, stressed the lack of ePRO monitoring reimbursement and app interoperability. For RA patients and physicians, benefits seemed to outweigh observed drawbacks of the digitally supported SDM using ePRO. The software was easy to use and could lead to a better understanding of the individual disease course, resource allocation and treatment of rheumatoid arthritis.
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Artrite Reumatoide , Reumatologia , Humanos , Pesquisa Qualitativa , Medidas de Resultados Relatados pelo Paciente , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológicoRESUMO
COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood. Comparing the immunological phenotype in healthy donors and patients with mild versus severe COVID-19 shows that in COVID-19 patients, NK-/B-cell activation and proliferation are enhanced independent of severity. As an important precondition for effective antibody responses, T-follicular helper cells and antibody secreting cells are increased both in patients with mild and severe SARS-CoV-2 infection. Beyond this, T cells in COVID-19 patients exhibit a stronger activation profile with differentiation toward effector cell phenotypes. Importantly, when looking at the rates of pulmonary complications in COVID-19 patients, the chemokine receptor CCR4 is higher expressed by both CD4 and CD8 T cells of patients with severe COVID-19. This raises the hypothesis that CCR4 upregulation on T cells in the pathogenesis of COVID-19 promotes stronger T-cell attraction to the lungs leading to increased immune activation with presumably higher pulmonary toxicity. Our study contributes significantly to the understanding of the immunological changes during COVID-19, as new therapeutic agents, preferentially targeting the immune system, are highly warranted.
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Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Pulmão/imunologia , Ativação Linfocitária , Receptores CCR4/imunologia , SARS-CoV-2/imunologia , Regulação para Cima/imunologia , Adulto , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: To test whether patients with immune-mediated inflammatory disease (IMIDs), who did not respond to two doses of the SARS-CoV-2 vaccine, develop protective immunity, if a third vaccine dose is administered. METHODS: Patients with IMID who failed to seroconvert after two doses of SARS-CoV-2 vaccine were subjected to a third vaccination with either mRNA or vector-based vaccines. Anti-SARS-CoV-2 IgG, neutralising activity and T cell responses were assessed at baseline and 3 weeks after revaccination and also evaluated seprarately in rituximab (RTX) and non-RTX exposed patients. RESULTS: 66 non-responders were recruited, 33 treated with RTX, and 33 non-exposed to RTX. Overall, 49.2% patients seroconverted and 50.0% developed neutralising antibody activity. Seroconversion (78.8% vs 18.2%) and neutralising activity (80.0% vs 21.9%) was higher in non-RTX than RTX-treated patients with IMID, respectively. Humoral vaccination responses were not different among patients showing positive (59.3%) or negative (49.7%) T cell responses at baseline. Patients remaining on mRNA-based vaccines showed similar vaccination responses compared with those switching to vector-based vaccines. CONCLUSIONS: Overall, these data strongly argue in favor of a third vaccination in patients with IMID lacking response to standard vaccination irrespective of their B cell status.
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COVID-19 , SARS-CoV-2 , Vacinas contra COVID-19 , Humanos , Imunização Secundária , RNA Mensageiro , RituximabRESUMO
OBJECTIVES: To evaluate whether neural networks can distinguish between seropositive RA, seronegative RA, and PsA based on inflammatory patterns from hand MRIs and to test how psoriasis patients with subclinical inflammation fit into such patterns. METHODS: ResNet neural networks were utilized to compare seropositive RA vs PsA, seronegative RA vs PsA, and seropositive vs seronegative RA with respect to hand MRI data. Results from T1 coronal, T2 coronal, T1 coronal and axial fat-suppressed contrast-enhanced (CE), and T2 fat-suppressed axial sequences were used. The performance of such trained networks was analysed by the area under the receiver operating characteristics curve (AUROC) with and without presentation of demographic and clinical parameters. Additionally, the trained networks were applied to psoriasis patients without clinical arthritis. RESULTS: MRI scans from 649 patients (135 seronegative RA, 190 seropositive RA, 177 PsA, 147 psoriasis) were fed into ResNet neural networks. The AUROC was 75% for seropositive RA vs PsA, 74% for seronegative RA vs PsA, and 67% for seropositive vs seronegative RA. All MRI sequences were relevant for classification, however, when deleting contrast agent-based sequences the loss of performance was only marginal. The addition of demographic and clinical data to the networks did not provide significant improvements for classification. Psoriasis patients were mostly assigned to PsA by the neural networks, suggesting that a PsA-like MRI pattern may be present early in the course of psoriatic disease. CONCLUSION: Neural networks can be successfully trained to distinguish MRI inflammation related to seropositive RA, seronegative RA, and PsA.
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Artrite Psoriásica , Artrite Reumatoide , Psoríase , Humanos , Artrite Psoriásica/diagnóstico por imagem , Artrite Reumatoide/diagnóstico por imagem , Psoríase/diagnóstico por imagem , Inflamação , Imageamento por Ressonância Magnética , Redes Neurais de ComputaçãoRESUMO
BACKGROUND: The goal of the study was to investigate patients' with systemic rheumatic diseases and healthcare professionals' experiences and preferences regarding self-sampling of capillary blood in rheumatology care. METHODS: Patients performed a supervised and consecutive unsupervised capillary blood self-collection using an upper arm based device. Subsequently, patients (n = 15) and their attending health care professionals (n = 5) participated in an explorative, qualitative study using problem-centered, telephone interviews. Interview data were analyzed using structured qualitative content analysis. RESULTS: Interviewed patients reported easy application and high usability. Patients and health care professionals alike reported time and cost savings, increased independence and flexibility, improved monitoring and reduction of risk of infection during Covid-19 as benefits. Reported drawbacks include limited blood volume, limited usability in case of functional restrictions, and environmental concerns. Older, immobile patients with long journeys to traditional blood collection sites and young patients with little time to spare for traditional blood collection appointments could be user groups, likely to benefit from self-sampling services. CONCLUSIONS: At-home blood self-sampling could effectively complement current rheumatology telehealth care. Appropriateness and value of this service needs to be carefully discussed with patients on an individual basis. TRIAL REGISTRATION: WHO International Clinical Trials Registry: DRKS00024925. Registered on 15/04/2021.
Assuntos
COVID-19 , Reumatologia , Humanos , Pesquisa Qualitativa , Pessoal de Saúde , Coleta de Amostras SanguíneasRESUMO
OBJECTIVE: A steadily increasing demand and decreasing number of rheumatologists push current rheumatology care to its limits. Long travel times and poor accessibility of rheumatologists present particular challenges for patients. Need-adapted, digitally supported, patient-centered and flexible models of care could contribute to maintaining high-quality patient care. This qualitative study was embedded in a randomized controlled trial (TELERA) investigating a new model of care consisting of the use of a medical app for ePRO (electronic patient-reported outcomes), a self-administered CRP (C-reactive protein) test, and joint self-examination in rheumatoid arthritis (RA) patients. The qualitative study aimed to explore experiences of RA patients and rheumatology staff regarding (1) current care and (2) the new care model. METHODS: The study included qualitative interviews with RA patients (n = 15), a focus group with patient representatives (n = 1), rheumatology nurses (n = 2), ambulatory rheumatologists (n = 2) and hospital-based rheumatologists (n = 3). Data was analyzed by qualitative content analysis. RESULTS: Participants described current follow-up care as burdensome. Patients in remission have to travel long distances. Despite pre-scheduled visits physicians lack questionnaire results and laboratory results to make informed shared decisions during face-to-face visits. Patients reported that using all study components (medical app for ePRO, self-performed CRP test and joint self-examination) was easy and helped them to better assess their disease condition. Parts of the validated questionnaire used in the trial (routine assessment of patient index data 3; RAPID3) seemed outdated or not clear enough for many patients. Patients wanted to be automatically contacted in case of abnormalities or at least have an app feature to request a call-back or chat. Financial and psychological barriers were identified among rheumatologists preventing them to stop automatically scheduling new appointments for patients in remission. Rheumatology nurses pointed to the potential lack of personal contact, which may limit the holistic care of RA-patients. CONCLUSION: The new care model enables more patient autonomy, allowing patients more control and flexibility at the same time. All components were well accepted and easy to carry out for patients. To ensure success, the model needs to be more responsive and allow seamless integration of education material. TRIAL REGISTRATION: The study was prospectively registered on 2021/04/09 at the German Registry for Clinical Trials (DRKS00024928).