RESUMEN
Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3+/IL6+ fibroblasts (high FAP internalization) to pro-resolving CD200+DKK3+ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200+DKK3+ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3+/IL6+ fibroblasts colocalize with inflammatory immune cells. CD200+DKK3+ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200-CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.
Asunto(s)
Artritis , Inmunidad Innata , Humanos , Metaloproteinasa 3 de la Matriz , Interleucina-6/metabolismo , Linfocitos/metabolismo , Inflamación/metabolismo , Fibroblastos/metabolismoRESUMEN
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.
Asunto(s)
Proteínas del Sistema Complemento/inmunología , Fibroblastos/inmunología , Inflamación/inmunología , Membrana Sinovial/inmunología , Inmunidad Adaptativa/inmunología , Animales , Artritis Reumatoide/inmunología , Línea Celular , Perros , Humanos , Mediadores de Inflamación/inmunología , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Ratas Wistar , Transducción de Señal/inmunologíaRESUMEN
Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.
Asunto(s)
Inmunidad Innata , Linfocitos/inmunología , Adolescente , Adulto , Animales , Biomarcadores , Niño , Modelos Animales de Enfermedad , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Janus Quinasa 3/deficiencia , Recuento de Linfocitos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Linfocitos/metabolismo , Linfopenia/sangre , Linfopenia/etiología , Ratones , Ratones Noqueados , Fenotipo , Inmunodeficiencia Combinada Grave/sangre , Inmunodeficiencia Combinada Grave/inmunología , Inmunodeficiencia Combinada Grave/metabolismo , Inmunodeficiencia Combinada Grave/terapia , Piel/inmunología , Piel/patologíaRESUMEN
BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that can serve as a model to study vascular changes in response to inflammation, autoimmunity, and fibrotic remodeling. Although microvascular changes are the earliest histopathologic manifestation of SSc, the vascular pathophysiology remains poorly understood. METHODS: We applied spatial proteomic approaches to deconvolute the heterogeneity of vascular cells at the single-cell level in situ and characterize cellular alterations of the vascular niches of patients with SSc. Skin biopsies of patients with SSc and control individuals were analyzed by imaging mass cytometry, yielding a total of 90 755 cells including 2987 endothelial cells and 4096 immune cells. RESULTS: We identified 7 different subpopulations of blood vascular endothelial cells (VECs), 2 subpopulations of lymphatic endothelial cells, and 3 subpopulations of pericytes. A novel population of CD34+;αSMA+ (α-smooth muscle actin);CD31+ VECs was more common in SSc, whereas endothelial precursor cells were decreased. Co-detection by indexing and tyramide signal amplification confirmed these findings. The microenvironment of CD34+;αSMA+;CD31+ VECs was enriched for immune cells and myofibroblasts, and CD34+;αSMA+;CD31+ VECs expressed markers of endothelial-to-mesenchymal transition. The density of CD34+;αSMA+;CD31+ VECs was associated with clinical progression of fibrosis in SSc. CONCLUSIONS: Using spatial proteomics, we unraveled the heterogeneity of vascular cells in control individuals and patients with SSc. We identified CD34+;αSMA+;CD31+ VECs as a novel endothelial cell population that is increased in patients with SSc, expresses markers for endothelial-to-mesenchymal transition, and is located in close proximity to immune cells and myofibroblasts. CD34+;αSMA+;CD31+ VEC counts were associated with clinical outcomes of progressive fibrotic remodeling, thus providing a novel cellular correlate for the crosstalk of vasculopathy and fibrosis.
Asunto(s)
Células Progenitoras Endoteliales , Esclerodermia Sistémica , Humanos , Proteómica , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/patología , Fibrosis , Miofibroblastos/patologíaRESUMEN
Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.
Asunto(s)
Diferenciación Celular/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis/genética , Fibrosis/patología , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Animales , Secuencia de Bases , Epigénesis Genética , Femenino , Humanos , Inflamación/genética , Inflamación/patología , Masculino , Ratones , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Transactivadores/antagonistas & inhibidoresRESUMEN
BACKGROUND: The interleukin (IL)-1 receptor accessory protein (IL1RAP) is an essential coreceptor required for signalling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). METHODS: The expression of IL1RAP-associated signalling molecules was determined by data mining of publicly available RNA sequencing (RNAseq) data as well as by imaging mass cytometry. The efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complementary mouse models: sclerodermatous chronic graft-versus-host disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. RESULTS: SSc skin showed upregulation of IL1RAP and IL1RAP-related signalling molecules on mRNA and protein level compared with normal skin. IL-1, IL-33 and IL-36 all regulate distinct gene sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33 and IL-36 were completely blocked by treatment with an anti-IL1RAP antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-induced, bleomycin-induced and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. CONCLUSION: This study provides the first evidence for the therapeutic benefits of targeting IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase one clinical trial.
RESUMEN
OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of mortality in SSc. Novel biomarkers are crucial to improve outcomes in SSc-ILD. We aimed to compare the performance of potential serum biomarkers of SSc-ILD that reflect different pathogenic processes: KL-6 and SP-D (epithelial injury), CCL18 (type 2 immune response), YKL-40 (endothelial injury and matrix remodelling) and MMP-7 (ECM remodelling). METHODS: Baseline and follow-up serum samples from 225 SSc patients were analysed by ELISA. Progressive ILD was defined according to the 2022-ATS/ERS/JRS/ALAT guidelines. Linear mixed models and random forest models were used for statistical analyses. RESULTS: Serum levels of KL-6 [MD 35.67 (95% CI 22.44-48.89, P < 0.01)], SP-D [81.13 (28.46-133.79, P < 0.01)], CCL18 [17.07 (6.36-27.77, P < 0.01)], YKL-40 [22.81 (7.19-38.44, P < 0.01)] and MMP-7 [2.84 (0.88-4.80, P < 0.01)] were independently associated with the presence of SSc-ILD. A machine-learning model including all candidates classified patients with or without ILD with an accuracy of 85%. The combination of KL-6 and SP-D was associated with the presence [0.77 (0.53-1.00, P' <0.01)] and previous progression of SSc-ILD [OR 1.28 (1.01-1.61, P' =0.047)]. Higher baseline levels of KL-6 [OR 3.70 (1.52-9.03, P < 0.01)] or SP-D [OR 2.00 (1.06-3.78, P = 0.03)] increased the odds of future SSc-ILD progression, independent of other conventional risk factors, and the combination of KL-6 and SP-D [1.109 (0.665-1.554, P < 0.01)] showed improved performance compared with KL-6 and SP-D alone. CONCLUSION: All candidates performed well as diagnostic biomarkers for SSc-ILD. The combination of KL-6 and SP-D might serve as biomarker for the identification of SSc patients at risk of ILD progression.
Asunto(s)
Enfermedades Pulmonares Intersticiales , Esclerodermia Sistémica , Humanos , Metaloproteinasa 7 de la Matriz , Proteína 1 Similar a Quitinasa-3 , Proteína D Asociada a Surfactante Pulmonar , Esclerodermia Sistémica/diagnóstico , Mucina-1 , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/complicaciones , BiomarcadoresRESUMEN
OBJECTIVES: Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis. METHODS: The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing). RESULTS: Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-ß/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc. CONCLUSION: Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.
Asunto(s)
Alarminas , Piel , Animales , Humanos , Ratones , Anticuerpos Monoclonales/farmacología , Bleomicina/toxicidad , Modelos Animales de Enfermedad , Proteína de Unión al Calcio S100A4/genética , Piel/patología , FibrosisRESUMEN
Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids' biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.
Asunto(s)
Fibrosis Pulmonar , Humanos , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Análisis de Expresión Génica de una Sola Célula , Metabolismo de los Lípidos/genética , Células Endoteliales/metabolismo , Fosfolípidos/metabolismo , Colesterol/metabolismo , FosfatidilcolinasRESUMEN
BACKGROUND: The diagnosis of inflammatory rheumatic diseases (IRDs) is often delayed due to unspecific symptoms and a shortage of rheumatologists. Digital diagnostic decision support systems (DDSSs) have the potential to expedite diagnosis and help patients navigate the health care system more efficiently. OBJECTIVE: The aim of this study was to assess the diagnostic accuracy of a mobile artificial intelligence (AI)-based symptom checker (Ada) and a web-based self-referral tool (Rheport) regarding IRDs. METHODS: A prospective, multicenter, open-label, crossover randomized controlled trial was conducted with patients newly presenting to 3 rheumatology centers. Participants were randomly assigned to complete a symptom assessment using either Ada or Rheport. The primary outcome was the correct identification of IRDs by the DDSSs, defined as the presence of any IRD in the list of suggested diagnoses by Ada or achieving a prespecified threshold score with Rheport. The gold standard was the diagnosis made by rheumatologists. RESULTS: A total of 600 patients were included, among whom 214 (35.7%) were diagnosed with an IRD. Most frequent IRD was rheumatoid arthritis with 69 (11.5%) patients. Rheport's disease suggestion and Ada's top 1 (D1) and top 5 (D5) disease suggestions demonstrated overall diagnostic accuracies of 52%, 63%, and 58%, respectively, for IRDs. Rheport showed a sensitivity of 62% and a specificity of 47% for IRDs. Ada's D1 and D5 disease suggestions showed a sensitivity of 52% and 66%, respectively, and a specificity of 68% and 54%, respectively, concerning IRDs. Ada's diagnostic accuracy regarding individual diagnoses was heterogenous, and Ada performed considerably better in identifying rheumatoid arthritis in comparison to other diagnoses (D1: 42%; D5: 64%). The Cohen κ statistic of Rheport for agreement on any rheumatic disease diagnosis with Ada D1 was 0.15 (95% CI 0.08-0.18) and with Ada D5 was 0.08 (95% CI 0.00-0.16), indicating poor agreement for the presence of any rheumatic disease between the 2 DDSSs. CONCLUSIONS: To our knowledge, this is the largest comparative DDSS trial with actual use of DDSSs by patients. The diagnostic accuracies of both DDSSs for IRDs were not promising in this high-prevalence patient population. DDSSs may lead to a misuse of scarce health care resources. Our results underscore the need for stringent regulation and drastic improvements to ensure the safety and efficacy of DDSSs. TRIAL REGISTRATION: German Register of Clinical Trials DRKS00017642; https://drks.de/search/en/trial/DRKS00017642.
Asunto(s)
Inteligencia Artificial , Reumatología , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reumatología/métodos , Adulto , Estudios Cruzados , Enfermedades Reumáticas/diagnóstico , Internet , Anciano , Derivación y Consulta/estadística & datos numéricosRESUMEN
Fibroblast activation protein (FAP) is mainly found on the surface of activated fibroblasts but is not expressed on the surface of inactive fibroblasts. Selective FAP inhibitors (FAPI), which are coupled to a radioactive tracer, can be used to quantify profibrotic and proinflammatory fibroblasts in patients using FAPI positron emission tomography (PET) computed tomography (CT). Following initial applications in neoplastic diseases, FAPI-PET/CT is also increasingly being applied in rheumatological diseases. The first studies have shown that in patients with systemic sclerosis (SSc) FAPI accumulates in actively fibrotically remodeled pulmonary and myocardial areas, that a high FAPI accumulation is associated with the risk of short-term progression and that this accumulation in the lungs regresses after successful treatment. In cases of immunoglobulin 4 (IgG4)-associated diseases (IgG4 rheumatic disease, RD), the FAPI signal correlates with the histological accumulation of activated fibroblasts and a poorer response to treatment to inhibit inflammation. Fibroblasts in chronically inflamed tissue, such as patients with inflammatory joint diseases, vasculitis or myositis, also express FAP and can be quantified by FAPI-PET/CT. The treatment-induced change of the phenotype from a destructive IL-6+/MMP3+THY1+ fibroblast subtype to an inflammation inhibiting CD200+DKK3+ subtype can be mechanistically demonstrated using FAPI-PET/CT. These studies provide indications that FAPI-PET/CT enables quantification of the tissue response in patients with fibrosing and chronic inflammatory diseases and can be used for patient stratification; however, further studies are essential for validation of the use of FAPI-PET/CT as a molecular imaging marker.
Asunto(s)
Endopeptidasas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Enfermedades Reumáticas , Humanos , Enfermedades Reumáticas/diagnóstico por imagen , Proteínas de la Membrana/metabolismo , Gelatinasas/metabolismo , Serina Endopeptidasas/metabolismo , Radiofármacos , Fibroblastos/patología , Resultado del Tratamiento , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: To estimate the prevalence of long-term exposure to glucocorticoids (GCs) and to identify factors associated with, and variations in prescribing practices over time and across recruiting countries. METHODS: We included patients with SSc having a visit recorded in the EUSTAR database from January 2013 onward. We analysed the prevalence and the main features of GCs users, their exposure to GCs over time, and their GCs dosages. Multivariable linear regression was used to analyse the factors identified as associated with GCs intake duration. Time trends, and variations in GCs utilization across recruiting countries were explored. Missing data were imputed using multiple imputation with chained equations. RESULTS: The 9819 patients included were mostly females (85%), the majority had lcSSc (73%), and the median age was 58 years. At baseline, 34% of patients (n = 2769/8109) (48% dcSSc vs 29% lcSSc) were on GCs, and the median dose was 7.5 mg/day. GCs users were more frequently males and anti-Scl70 positive, and more commonly had dcSSc and more severe disease. On average, GCs users spent 25% of their follow-up time (median 33.2 months) on GCs, with no significant between-subsets difference. Notably, 33% (n = 971/2959) and 22% (n = 647/2959) of patients followed up for >1 year had received GCs for >6 and >12 months, respectively. Multivariable analysis showed that patient and disease characteristics poorly explained the variability in GCs exposure (adjusted-R2 = 0.06, P < 0.001). GCs utilization varied within and across countries, and gradually decreased over time (36% in 2013 vs 23% in 2018). CONCLUSIONS: GCs are widely and long-term prescribed in SSc, with significant between-countries and within-country differences. A gradual decrease in their utilization has been observed.
Asunto(s)
Glucocorticoides , Esclerodermia Sistémica , Masculino , Femenino , Humanos , Persona de Mediana Edad , Glucocorticoides/uso terapéutico , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/complicaciones , Bases de Datos Factuales , Recolección de DatosRESUMEN
Chronic graft-versus-host disease (cGVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGVHD remain poorly understood, and targeted therapies for clinical use are not well established. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGVHD (sclGVHD). WNT signaling was activated in human sclGVHD with increased nuclear accumulation of the transcription factor ß-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1α agonist pyrvinium, or the LRP6 inhibitor salinomycin abrogated the activation of WNT signaling and protected against experimental cGVHD, without a significant impact on graft-versus-leukemia effect (GVL). Treatment with G007-LK, pyrvinium, or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d) â BALB/c (H-2d) and LP/J (H-2b) â C57BL/6 (H-2b) models of sclGVHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect inflammation-dependent effects in sclGVHD. Our findings may have direct translational potential, because pyrvinium is in clinical use, and tankyrase inhibitors are in clinical trials for other indications.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Piranos/farmacología , Compuestos de Pirvinio/farmacología , Esclerodermia Sistémica/prevención & control , Sulfonas/farmacología , Triazoles/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Antibacterianos/farmacología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/patología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Persona de Mediana Edad , Esclerodermia Sistémica/etiología , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patologíaRESUMEN
PURPOSE: Myocardial fibrosis (MF) is a factor of poor prognosis in systemic sclerosis (SSc). Direct in-vivo visualization of fibroblast activation as early readout of MF has not been feasible to date. Here, we characterize 68Gallium-labeled-Fibroblast-Activation-Inhibitor-04 ([68Ga]Ga-FAPI-04)-PET-CT as a diagnostic tool in SSc-related MF. METHODS: In this proof-of-concept trial, six SSc patients with and eight without MF of the EUSTAR cohort Erlangen underwent [68Ga]Ga-FAPI-04-PET-CT and cardiac MRI (cMRI) and clinical and serologic investigations just before baseline and during follow-up between January 2020 and December 2020. Myocardial biopsy was performed as clinically indicated. RESULTS: [68Ga]Ga-FAPI-04 tracer uptake was increased in SSc-related MF with higher uptake in SSc patients with arrhythmias, elevated serum-NT-pro-BNP, and increased late gadolinium enhancement (LGE) in cMRI. Histologically, myocardial biopsies from cMRI- and [68Ga]Ga-FAPI-04-positive regions confirmed the accumulation of FAP+ fibroblasts surrounded by collagen deposits. We observed similar but not equal spatial distributions of [68Ga]Ga-FAPI-04 uptake and quantitative cMRI-based techniques. Using sequential [68Ga]Ga-FAPI-04-PET-CTs, we observed dynamic changes of [68Ga]Ga-FAPI-04 uptake associated with changes in the activity of SSc-related MF, while cMRI parameters remained stable after regression of molecular activity and rather indicated tissue damage. CONCLUSIONS: We present first in-human evidence that [68Ga]Ga-FAPI-04 uptake visualizes fibroblast activation in SSc-related MF and may be a diagnostic option to monitor cardiac fibroblast activity in situ.
Asunto(s)
Radioisótopos de Galio , Esclerodermia Sistémica , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Medios de Contraste , Gadolinio , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico por imagen , FibrosisRESUMEN
The population-based prevalence of psoriatic arthritis (PsA) is still unclear and not well described globally. The aim of this study was to conduct a population-based prevalence projection and provide long-term future estimations of PsA patients in Germany until 2050, using the illness-death model and based on historical data. We analyzed the national statutory health insurance data of 65 million population in the German Institute for Medical Documentation and Information between January 2009 and December 2012. We constructed an estimation of the PsA burden among the German population using the relevant epidemiological parameters to project the numbers of patients with PsA in Germany until 2050 under five possible scenarios by varying the incidence and mortality. The overall conservatively estimated prevalence of PsA in Germany in 2019 was 0.31% (95% CI 0.28-0.36%). Women contribute a higher prevalence than men in all five scenarios. In the assumed scenarios with increased incidence, the prevalence of PsA at 60 years of age could rise from 1% in 2019 to more than 3% in 2050 for both genders, with the increase particularly pronounced for women, reaching around 3.5%. However, in the assumed scenarios with decreasing incidence, the prevalence curve may flatten and begin a decreasing trend from 2035 to 2050 for both genders, achieving a prevalence of less than 1% in 2050. Our research is to generate assumed population-based data on PsA in Germany that can serve as a reference for public health stakeholders to prepare an optional intervention. We would expect worryingly high numbers in the coming decades if preventive strategies are not implemented. In the long term, it will be necessary to implement preventive strategies to identify predictors and treat psoriasis symptoms early in order to delay or even prevent the transition of psoriasis to PsA.
Asunto(s)
Artritis Psoriásica , Psoriasis , Femenino , Humanos , Masculino , Artritis Psoriásica/epidemiología , Alemania/epidemiología , Salud Pública , Seguro de SaludRESUMEN
Early and effective discrimination (triage) of patients with inflammatory rheumatic diseases (IRD) and other diseases (non-IRD) is essential for successful treatment and preventing damage. The aim of this study was to investigate diagnostic delays and pre-diagnosis treatment in patients newly presenting to rheumatology outpatient clinics. A total of 600 patients newly presenting to one university hospital and two non-academic centers were included. Time from onset of symptoms to rheumatology consultation "total delay" as well as medical treatment before consultation were recorded. Median time from symptom onset to rheumatologist appointment (total delay) was 30 weeks. Median time to online search, first physician appointment request and first physician appointment was 2, 4 and 5 weeks, respectively. Total delay was significantly shorter for IRD patients compared to non-IRD patients, 26 vs 35 weeks (p = 0.007). Only 17.7% of all patients and 22.9% of IRD patients had a delay of less than 12 weeks. Total delay was significantly lower in patients seen in non-academic centers compared to the university center, 20 vs 50 weeks (p < 0.0001). 32.2% of IRD patients received medical treatment that eased their symptoms prior to the rheumatology appointment. These findings highlight the persistent diagnostic delays in rheumatology; however, they also suggest that current triage strategies effectively lead to earlier appointments for IRD patients. Improvement of triage methods and pre-diagnosis treatment could decrease overall burden of disease in IRD patients.
Asunto(s)
Enfermedades Reumáticas , Reumatología , Humanos , Diagnóstico Tardío , Enfermedades Reumáticas/diagnóstico , Reumatólogos , Derivación y ConsultaRESUMEN
SSc is a chronic autoimmune rheumatic disease that involves numerous organs and presents major management challenges. The histopathologic hallmarks of SSc include vasculopathy, fibrosis and autoimmune phenomena involving both innate and adaptive immune systems. Purinergic signalling is a pathway that may be implicated in the pathophysiology of several of these disease manifestations. Extracellular purines are potent signalling mediators, which have been shown to be dysregulated in SSc. As examples, purines can exacerbate vasculopathy and provoke platelet dysfunction; as well as contributing to immune dysregulation. Elements of purinergic signalling further promote organ and tissue fibrosis in several disease models. Here, we provide an overview of extracellular purine metabolism in purinergic signalling and link disorders of these to the molecular pathology of SSc. We also discuss targeting the purinergic signalling and explore the translational applications for new therapeutic options in SSc.
Asunto(s)
Esclerodermia Sistémica , Enfermedades Vasculares , Fibrosis , Humanos , Purinas/uso terapéutico , Transducción de SeñalRESUMEN
OBJECTIVE: Digital pitting scars (DPS) are frequent, but little studied in SSc to date. METHODS: An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to (i) examine DPS prevalence; (ii) examine whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene); and (iii) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with (i) functional impairment; (ii) structural microvascular disease; and (iii) mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia and mortality. RESULTS: A total of 9671 patients were included with reported DPS at any time point (n = 4924) or 'never' DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud's duration (both P ≤ 0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P ≤ 0.001) and joint synovitis (P = 0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (odds ratio) with DUs: 22.03 (19.51-24.87), active digital ischaemia: 6.30 (5.34-7.42) and death: 1.86 (1.48-2.36). CONCLUSION: DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimize the therapeutic strategy.
Asunto(s)
Cicatriz/etiología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/mortalidad , Úlcera Cutánea/etiología , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: Treatments for SSc-associated interstitial lung disease (SSc-ILD) differ in attributes, i.e. mode of administration, adverse events (AEs) and efficacy. As physicians and patients may perceive treatments differently, shared decision-making can be essential for optimal treatment provision. We therefore aimed to quantify patient preferences for different treatment attributes. METHODS: Seven SSc-ILD attributes were identified from mixed-methods research and clinician input: mode of administration, shortness of breath, skin tightness, cough, tiredness, risk of gastrointestinal AEs (GI-AEs) and risk of serious and non-serious infections. Patients with SSc-ILD completed an online discrete choice experiment (DCE) in which they were asked to repeatedly choose between two alternatives characterized by varying severity levels of the included attributes. The data were analysed using a multinomial logit model; relative attribute importance and maximum acceptable risk measures were calculated. RESULTS: Overall, 231 patients with SSc-ILD completed the DCE. Patients preferred twice-daily oral treatments and 6-12 monthly infusions. Patients' choices were mostly influenced by the risk of GI-AEs or infections. Improvement was more important in respiratory symptoms than in skin tightness. Concerning trade-offs, patients accepted different levels of increase in GI-AE risk: +21% if it reduced the infusions' frequency; +15% if changing to an oral treatment; up to +37% if it improved breathlessness; and up to +36% if it reduced the risk of infections. CONCLUSIONS: This is the first study to quantitatively elicit patients' preferences for treatment attributes in SSc-ILD. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in clinical practice.