RESUMEN
INTRODUCTION: An altered immune tolerance disturbed by immune checkpoint inhibitors (ICIs) may contribute to new-onset polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). This systematic literature review (SLR) examines the characteristics of PMR and GCA-like syndromes following anticancer treatment with ICIs, summarizing their demographic, clinical and treatment-related features to provide insights whether they differ from the idiopathic forms. METHODS: The SLR was conducted in Medline and EMBASE databases from inception to July 2024, and in the EULAR/ACR abstract database (2021-2023). ICI-induced PMR and GCA syndromes were compared to the primary forms of the diseases using data from studies that included both groups as comparators. For manuscripts lacking direct comparisons, we summarized the main findings and discussed the differences using systematic reviews or large observational studies on the primary forms. RESULTS: From 1237 screened abstracts, 46 met the inclusion criteria, involving 358 patients (314 with ICI-PMR and 44 with ICI-GCA). ICI-PMR had an estimated pooled prevalence of 0.1% [95% CI: 0.07%, 0.14%] among ICI recipients and 15.9% [95% CI: 12.6%, 19.9%] among patients experiencing rheumatic immune-related adverse events. Patients with ICI-PMR had a male-to-female ratio of 1.7:1 and a mean age of 71 ± 4 years. Most cases were associated with PD1/PDL1 blockers (87%). Clinical features included inflammatory pain in the girdles (100%), though pelvic girdle involvement was under-reported in some cases (3/28 studies). Peripheral arthritis was present in 35% of patients. Laboratory tests showed normal or slightly elevated inflammatory markers in 26% of cases. Glucocorticoids (GCs) led to symptom improvement in 84% of cases although 20% required immunosuppressive treatment and 14% experienced relapses. ICI-GCA had a prevalence of 0.06% among ICI recipients, with equal gender distribution and a mean age of 71 ± 5 years. Most patients received anti-PD1/PDL1 blockers (57%). Clinical manifestations included cephalic symptoms (75%), permanent visual loss (23%) and symptoms related to large-vessel involvement (54%). High-dose GCs were effective, with 96% achieving remission, though 17% experienced relapses. CONCLUSIONS: ICI-induced PMR and GCA may have distinct clinical profiles compared to idiopathic forms, with potentially milder symptoms and better treatment responses. Further studies are needed to confirm these findings and better understand the long-term outcomes and pathophysiology of these conditions.
Asunto(s)
Arteritis de Células Gigantes , Inhibidores de Puntos de Control Inmunológico , Polimialgia Reumática , Polimialgia Reumática/inducido químicamente , Polimialgia Reumática/tratamiento farmacológico , Polimialgia Reumática/inmunología , Humanos , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/inmunología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Femenino , AncianoRESUMEN
INTRODUCTION: The objective of this systematic review was to provide an overview of current developments and potentially available therapeutic options for polymyalgia rheumatic (PMR) and giant cell arteritis (GCA), in the coming years. METHODS: We conducted a systematic review of 17 national and international clinical trial databases for all disease-modifying anti-rheumatic drugs (DMARDs) for PMR and GCA that are already marketed, in clinical development or withdrawn. The search was performed on January 2024, with the keywords "polymyalgia rheumatica" and "giant cell arteritis". For each molecule, we only considered the study at the most advanced stage of clinical development. RESULTS: For PMR, a total of 15 DMARDs were identified: 2 conventional synthetic DMARDs (csDMARDs), 11 biologic DMARDs (bDMARDs) and 2 targeted synthetic DMARDs (tsDMARDs). For GCA, 18 DMARDs were identified: 2 csDMARDs, 14 bDMARDs and 2 tsDMARDs. Currently, there are only 2 approved corticosteroid-sparing therapies in these diseases, which both target the IL-6 signaling pathway, namely tocilizumab in GCA and sarilumab in PMR. Most of the molecules in current development are repurposed from from other conditions and clinical research in PMR/GCA seems to be mostly driven by the potential to repurpose existing treatments rather than by translational research. CONCLUSION: This systematic review identified 23 DMARDs evaluated for PMR and GCA: 3 csDMARDs, 17 bDMARDs and 3 tsDMARDs. Several promising treatments are likely to be marketed in the coming years.
Asunto(s)
Arteritis de Células Gigantes , Polimialgia Reumática , Humanos , Polimialgia Reumática/tratamiento farmacológico , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/inmunología , Ensayos Clínicos como Asunto , Antirreumáticos/uso terapéutico , Agentes Inmunomoduladores/uso terapéuticoRESUMEN
OBJECTIVES: Giant cell arteritis (GCA) is a common vasculitis affecting patients aged 50 and older. GCA leads to chronic inflammation of large/medium-sized vessel walls with complications such as permanent vision loss and risk of stroke and aortic aneurysms. Early diagnosis is crucial and relies on temporal artery biopsy (TAB) and ultrasound imaging of temporal and axillary arteries. However, these methods have limitations. Serum biomarkers as autoantibodies have been reported but with inconclusive data for their use in the clinical setting. Additionally, C-reactive protein and erythrocyte sedimentation rate are non-specific and limited in reflecting disease activity, particularly in patients treated with IL-6 inhibitors. This study aimed to identify serum autoantibodies as new diagnostic biomarkers for GCA using a human protein array. METHODS: One commercial and one proprietary human protein array were used for antibody profiling of sera from patients with GCA (n=55), Takayasu (TAK n=7), and Healthy Controls (HC n=28). The identified candidate autoantigens were purified and tested for specific autoantibodies by ELISA. RESULTS: Antibodies against two proteins, VSIG10L (V-Set and Immunoglobulin Domain Containing 10 Like) and DCBLD1 (discoidin), were identified and found to be associated with GCA, with an overall prevalence of 43-57%, respectively, and high specificity as individual antibodies. A control series of TAK sera tested negative. CONCLUSIONS: Detecting GCA-specific autoantibodies may offer a new, non-invasive tool for improving our diagnostic power in GCA. Even though cell-mediated immune responses are crucial for GCA pathogenesis, this finding opens the way for investigating the additional role of humoral immune responses in the disease.
Asunto(s)
Autoanticuerpos , Autoantígenos , Biomarcadores , Arteritis de Células Gigantes , Humanos , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/sangre , Arteritis de Células Gigantes/diagnóstico , Autoanticuerpos/sangre , Biomarcadores/sangre , Autoantígenos/inmunología , Femenino , Anciano , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Arteritis de Takayasu/inmunología , Arteritis de Takayasu/sangre , Arteritis de Takayasu/diagnóstico , Valor Predictivo de las Pruebas , Análisis por Matrices de Proteínas , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
Large-vessel vasculitides (LVV) comprise a group of chronic inflammatory diseases of the aorta and its major branches. The most common forms of LVV are giant cell arteritis (GCA) and Takayasu arteritis (TAK). Both GCA and TAK are characterized by granulomatous inflammation of the vessel wall accompanied by a maladaptive immune and vascular response that promotes vascular damage and remodeling. The inflammatory process in LVV starts in the adventitia where fibroblasts constitute the dominant cell population. Fibroblasts are traditionally recognized for synthesizing and renewing the extracellular matrix thereby being major players in maintenance of normal tissue architecture and in tissue repair. More recently, fibroblasts have emerged as a highly plastic cell population exerting various functions, including the regulation of local immune processes and organization of immune cells at the site of inflammation through production of cytokines, chemokines and growth factors as well as cell-cell interaction. In this review, we summarize and discuss the current knowledge on fibroblasts in LVV. Furthermore, we identify key questions that need to be addressed to fully understand the role of fibroblasts in the pathogenesis of LVV.
Asunto(s)
Fibroblastos , Arteritis de Células Gigantes , Arteritis de Takayasu , Humanos , Fibroblastos/inmunología , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/terapia , Arteritis de Takayasu/inmunología , Arteritis de Takayasu/terapia , Animales , Citocinas/metabolismo , Citocinas/inmunologíaRESUMEN
BACKGROUND: Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4+ T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4+ T cells will yield new insights into its pathogenesis. METHODS: Transcriptome analysis was conducted on CD4+ T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14+ monocytes. RESULTS: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4+ T cells in GCA. Specifically, CD4+ T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4+ T cells and monocytes that could have pathogenic relevance in GCA. CONCLUSIONS: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis.
Asunto(s)
Linfocitos T CD4-Positivos , Perfilación de la Expresión Génica , Arteritis de Células Gigantes , Monocitos , Transducción de Señal , Transcriptoma , Humanos , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/genética , Monocitos/inmunología , Monocitos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Femenino , Masculino , Anciano , Metilación de ADN , Persona de Mediana Edad , Anciano de 80 o más Años , Epigénesis Genética , Comunicación Celular/inmunología , Regulación de la Expresión GénicaRESUMEN
Giant cell arteritis (GCA) is a prototypic autoimmune disease with a highly selective tissue tropism for medium and large arteries. Extravascular GCA manifests with intense systemic inflammation and polymyalgia rheumatica; vascular GCA results in vessel wall damage and stenosis, causing tissue ischemia. Typical granulomatous infiltrates in affected arteries are composed of CD4+ T cells and hyperactivated macrophages, signifying the involvement of the innate and adaptive immune system. Lesional CD4+ T cells undergo antigen-dependent clonal expansion, but antigen-nonspecific pathways ultimately control the intensity and duration of pathogenic immunity. Patient-derived CD4+ T cells receive strong co-stimulatory signals through the NOTCH1 receptor and the CD28/CD80-CD86 pathway. In parallel, co-inhibitory signals, designed to dampen overshooting T cell immunity, are defective, leaving CD4+ T cells unopposed and capable of supporting long-lasting and inappropriate immune responses. Based on recent data, two inhibitory checkpoints are defective in GCA: the Programmed death-1 (PD-1)/Programmed cell death ligand 1 (PD-L1) checkpoint and the CD96/CD155 checkpoint, giving rise to the "lost inhibition concept". Subcellular and molecular analysis has demonstrated trapping of the checkpoint ligands in the endoplasmic reticulum, creating PD-L1low CD155low antigen-presenting cells. Uninhibited CD4+ T cells expand, release copious amounts of the cytokine Interleukin (IL)-9, and differentiate into long-lived effector memory cells. These data place GCA and cancer on opposite ends of the co-inhibition spectrum, with cancer patients developing immune paralysis due to excessive inhibitory checkpoints and GCA patients developing autoimmunity due to nonfunctional inhibitory checkpoints.
Asunto(s)
Arteritis de Células Gigantes , Humanos , Arteritis de Células Gigantes/inmunología , Linfocitos T CD4-Positivos/inmunología , Enfermedades Autoinmunes/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Antígeno B7-H1/inmunología , Proteínas de Punto de Control Inmunitario/inmunologíaRESUMEN
Giant cell arteritis (GCA), the most common systemic vasculitis, is characterised by aberrant interactions between infiltrating and resident cells of the vessel wall. Ageing and breach of tolerance are prerequisites for GCA development, resulting in dendritic and T-cell dysfunction. Inflammatory cytokines polarise T-cells, activate resident macrophages and synergistically enhance vascular inflammation, providing a loop of autoreactivity. These events originate in the adventitia, commonly regarded as the biological epicentre of the vessel wall, with additional recruitment of cells that infiltrate and migrate towards the intima. Thus, GCA-vessels exhibit infiltrates across the vascular layers, with various cytokines and growth factors amplifying the pathogenic process. These events activate ineffective repair mechanisms, where dysfunctional vascular smooth muscle cells and fibroblasts phenotypically shift along their lineage and colonise the intima. While high-dose glucocorticoids broadly suppress these inflammatory events, they cause well known deleterious effects. Despite the emerging targeted therapeutics, disease relapse remains common, affecting >50% of patients. This may reflect a discrepancy between systemic and local mediators of inflammation. Indeed, temporal arteries and aortas of GCA-patients can show immune-mediated abnormalities, despite the treatment induced clinical remission. The mechanisms of persistence of vascular disease in GCA remain elusive. Studies in other chronic inflammatory diseases point to the fibroblasts (and their lineage cells including myofibroblasts) as possible orchestrators or even effectors of disease chronicity through interactions with immune cells. Here, we critically review the contribution of immune and stromal cells to GCA pathogenesis and analyse the molecular mechanisms by which these would underpin the persistence of vascular disease.
Asunto(s)
Arteritis de Células Gigantes , Células del Estroma , Arteritis de Células Gigantes/patología , Arteritis de Células Gigantes/inmunología , Humanos , Células del Estroma/patología , Células del Estroma/inmunología , Fibroblastos/patología , Fibroblastos/inmunologíaRESUMEN
INTRODUCTION: The IL-12-IFNγ-Th1 and the IL-6-IL-23-Th17 axes are considered the dominant pathogenic pathways in Giant Cell Arteritis (GCA). Both pathways signal via activation of the downstream JAK/STAT proteins. We hypothesized that phosphorylated STAT (pSTAT) signatures in circulating immune cells may aid to stratify GCA-patients for personalized treatment. METHODS: To investigate pSTAT expression, PBMCs from treatment-naive GCA-patients (n = 18), infection controls (INF, n = 11) and age-matched healthy controls (HC, n = 15) were stimulated in vitro with IL-6, IL-2, IL-10, IFN-γ, M-CSF or GM-CSF, and stained with CD3, CD4, CD19, CD45RO, pSTAT1, pSTAT3, pSTAT5 antibodies, and analyzed by flow cytometry. Serum IL-6, sIL-6-receptor and gp130 were measured by Luminex. The change in percentages of pSTAT3+CD4+T-cells was evaluated at diagnosis and at 3 months and 1-year of follow-up. Kaplan-Meier analyses was used to asses prognostic accuracy. RESULTS: Analysis of IL-6 stimulated immune cell subsets revealed a significant decrease in percentages of pSTAT3+CD4+T-cells of GCA-patients and INF-controls compared to HCs. Following patient stratification according to high (median>1.5 pg/mL) and low (median<1.5 pg/mL) IL-6 levels, we observed a reduction in the pSTAT3 response in GCA-patients with high serum IL-6. Percentages of pSTAT3+CD4+T-cells in patients with high serum IL-6 levels at diagnosis normalized after glucocorticoid (GC) treatment. Importantly, we found that patients with low percentages of pSTAT3+CD4+T-cells at baseline require longer GC-treatment. CONCLUSION: Overall, in GCA, the percentages of in vitro IL-6-induced pSTAT3+CD4+T-cells likely reflect prior in vivo exposure to high IL-6 and may serve as a prognostic marker for GC-treatment duration and may assist improving personalized treatment options in the future.
Asunto(s)
Linfocitos T CD4-Positivos , Arteritis de Células Gigantes , Interleucina-6 , Transducción de Señal , Humanos , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/metabolismo , Interleucina-6/metabolismo , Interleucina-6/sangre , Femenino , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Masculino , Anciano , Quinasas Janus/metabolismo , Persona de Mediana Edad , Fosforilación , Factor de Transcripción STAT3/metabolismo , Anciano de 80 o más Años , Factores de Transcripción STAT/metabolismo , Receptores de Interleucina-6/metabolismo , Biomarcadores , Receptor gp130 de Citocinas/metabolismoRESUMEN
Objective: Proteome analyses in patients with newly diagnosed, untreated giant cell arteritis (GCA) have not been reported previously, nor are changes of protein expression upon treatment with glucocorticoids (GC) and/or tocilizumab (TCZ) known. The GUSTO trial allows to address these questions, provides the opportunity to learn about the differential effects of GC and TCZ on proteomics and may help to identify serum proteins to monitor disease activity. Methods: Serum samples obtained from 16 patients with new-onset GCA at different time points (day 0, 3, 10, and week 4, 24, 52) during the GUSTO trial (NCT03745586) were examined for 1436 differentially expressed proteins (DEPs) based on proximity extension assay technology. The patients received 500 mg methylprednisolone intravenously for 3 consecutive days followed by TCZ monotherapy. Results: When comparing day 0 (before the first GC infusion) with week 52 (lasting remission), 434 DEPs (213↑, 221↓) were identified. In response to treatment, the majority of changes occurred within 10 days. GC inversely regulated 25 proteins compared to remission. No difference was observed between weeks 24 and 52 during established remission and ongoing TCZ treatment. Expression of CCL7, MMP12, and CXCL9 was not regulated by IL6. Conclusion: Disease-regulated serum proteins improved within 10 days and were normalized within 24 weeks, showing a kinetic corresponding to the gradual achievement of clinical remission. The proteins inversely regulated by GC and TCZ shed light on the differential effects of the two drugs. CCL7, CXCL9, and MMP12 are biomarkers that reflect disease activity despite normalized C-reactive protein levels.
Asunto(s)
Arteritis de Células Gigantes , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/metabolismo , Humanos , Proteómica , Glucocorticoides/uso terapéuticoRESUMEN
Blood vessels are indispensable for host survival and are protected from inappropriate inflammation by immune privilege. This protection is lost in patients with autoimmune vasculitides, a heterogeneous group of diseases causing damage to arteries, arterioles, and capillaries. Vasculitis leads to vascular wall destruction and/or luminal occlusion, resulting in hemorrhage and tissue ischemia. Failure in the quantity and quality of immunosuppressive regulatory T cells (Treg) has been implicated in the breakdown of the vascular immune privilege. Emerging data suggest that Treg deficiencies are disease-specific, affecting distinct pathways in distinct vasculitides. Mechanistic studies have identified faulty CD8+ Tregs in Giant Cell Arteritis (GCA), a vasculitis of the aorta and the large aortic branch vessels. Specifically, aberrant signaling through the NOTCH4 receptor expressed on CD8+ Treg cells leads to rerouting of intracellular vesicle trafficking and failure in the release of immunosuppressive exosomes, ultimately boosting inflammatory attack to medium and large arteries. In Kawasaki's disease, a medium vessel vasculitis targeting the coronary arteries, aberrant expression of miR-155 and dysregulated STAT5 signaling have been implicated in undermining CD4+ Treg function. Explorations of mechanisms leading to insufficient immunosuppression and uncontrolled vascular inflammation hold the promise to discover novel therapeutic interventions that could potentially restore the immune privilege of blood vessels and pave the way for urgently needed innovations in vasculitis management.
Asunto(s)
Arteritis de Células Gigantes , Granulomatosis con Poliangitis , Síndrome Mucocutáneo Linfonodular , Poliarteritis Nudosa , Linfocitos T Reguladores/patología , Arterias/patología , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/patología , Granulomatosis con Poliangitis/inmunología , Granulomatosis con Poliangitis/patología , Humanos , Inflamación , Síndrome Mucocutáneo Linfonodular/inmunología , Síndrome Mucocutáneo Linfonodular/patología , Poliarteritis Nudosa/inmunología , Poliarteritis Nudosa/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
OBJECTIVES: Giant cell arteritis (GCA) is the most common primary vasculitis, preferentially affecting the aorta and its large-calibre branches. An imbalance between proinflammatory CD4+ T helper cell subsets and regulatory T cells (Tregs) is thought to be involved in the pathogenesis of GCA and Treg dysfunction has been associated with active disease. Our work aims to explore the aetiology of Treg dysfunction and the way it is affected by remission-inducing immunomodulatory regimens. METHODS: A total of 41 GCA patients were classified into active disease (n=14) and disease in remission (n=27). GCA patients' and healthy blood donors' (HD) Tregs were sorted and subjected to transcriptome and phenotypic analysis. RESULTS: Transcriptome analysis revealed 27 genes, which were differentially regulated between GCA-derived and HD-derived Tregs. Among those, we identified transcription factors, glycolytic enzymes and IL-2 signalling mediators. We confirmed the downregulation of forkhead box P3 (FOXP3) and interferon regulatory factor 4 (IRF4) at protein level and identified the ineffective induction of glycoprotein A repetitions predominant (GARP) and CD25 as well as the reduced T cell receptor (TCR)-induced calcium influx as correlates of Treg dysfunction in GCA. Inhibition of glycolysis in HD-derived Tregs recapitulated most identified dysfunctions of GCA Tregs, suggesting the central pathogenic role of the downregulation of the glycolytic enzymes. Separate analysis of the subgroup of tocilizumab-treated patients identified the recovery of the TCR-induced calcium influx and the Treg suppressive function to associate with disease remission. CONCLUSIONS: Our findings suggest that low glycolysis and calcium signalling account for Treg dysfunction and inflammation in GCA.
Asunto(s)
Factores de Transcripción Forkhead/genética , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/genética , Factores Reguladores del Interferón/genética , Linfocitos T Reguladores/fisiología , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Calcio/metabolismo , Señalización del Calcio/genética , Estudios de Casos y Controles , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Arteritis de Células Gigantes/inmunología , Glucólisis/genética , Humanos , Agentes Inmunomoduladores/uso terapéutico , Subunidad alfa del Receptor de Interleucina-2/genética , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , FenotipoRESUMEN
OBJECTIVE: Inflammatory thoracic aortic aneurysms (TAAs) are very rare aortic conditions. Resection and replacement of the inflammatory aorta is the first-line treatment, and thoracic endovascular aortic repair (TEVAR) has recently been reported as a less invasive alternative even for this aortic cohort. In the present study, we reviewed our experience with inflammatory TAAs and assessed the preoperative management, surgical procedures, and outcomes. METHODS: From 2006 to 2019, 21 surgeries were performed for inflammatory TAAs in 17 of 2583 patients (0.7%) who had undergone cardiovascular surgery at our institution. The etiologies were Takayasu's arteritis in 13 patients, giant cell arteritis in 2, antineutrophil cytoplasmic antibody-associated vasculitis in 1, and unknown in 1. The mean follow-up period was 66.2 ± 50.2 months (range, 19-186 months). RESULTS: Three patients had undergone multiple surgeries. The aorta was replaced in 14 patients (ascending aorta in 9, aortic arch in 4, and thoracoabdominal aorta in 1). Three isolated TEVARs were performed in two patients and single-stage hybrid aortic repair (ascending aorta and partial arch replacement combined with zone 0 TEVAR) in four patients for extended arch and descending thoracic aortic aneurysms. Stent grafts were deployed on the native aorta in five of the seven TEVARs. The perioperative inflammation was well-controlled with prednisolone (mean dose, 7.4 ± 9.4 mg) in all patients except for one who had required two surgeries under inflammation-uncontrolled situations. No aorta-related complications, including anastomotic aneurysms and TEVAR-related aortic dissection, developed during the follow-up period, and the 5-year freedom from all-cause death was 92.9%. CONCLUSIONS: The mid-term outcomes of surgery for inflammatory TAAs were acceptable. Although replacement remains the standard procedure for inflammatory TAAs, TEVAR is a less invasive acceptable alternative when the inflammation is properly managed.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Aneurisma de la Aorta Torácica/cirugía , Procedimientos Endovasculares/métodos , Arteritis de Células Gigantes/complicaciones , Arteritis de Takayasu/complicaciones , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/inmunología , Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/inmunología , Angiografía por Tomografía Computarizada , Procedimientos Endovasculares/instrumentación , Femenino , Estudios de Seguimiento , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/terapia , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Arteritis de Takayasu/inmunología , Arteritis de Takayasu/terapia , Adulto JovenRESUMEN
OBJECTIVE: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis. METHODS: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel. RESULTS: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions. CONCLUSION: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.
Asunto(s)
Arteritis de Células Gigantes/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Inmunosupresores/uso terapéutico , Reumatología/normas , Arteritis de Takayasu/tratamiento farmacológico , Toma de Decisiones Clínicas , Consenso , Técnicas de Apoyo para la Decisión , Quimioterapia Combinada , Medicina Basada en la Evidencia/normas , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/inmunología , Glucocorticoides/efectos adversos , Humanos , Inmunosupresores/efectos adversos , Arteritis de Takayasu/diagnóstico , Arteritis de Takayasu/inmunología , Resultado del TratamientoRESUMEN
OBJECTIVE: B-cells are present in the inflamed arteries of giant cell arteritis (GCA) patients and a disturbed B-cell homeostasis is reported in peripheral blood of both GCA and the overlapping disease polymyalgia rheumatica (PMR). In this study, we aimed to investigate chemokine-chemokine receptor axes governing the migration of B-cells in GCA and PMR. METHODS: We performed Luminex screening assay for serum levels of B-cell related chemokines in treatment-naïve GCA (n = 41), PMR (n = 31) and age- and sex matched healthy controls (HC, n = 34). Expression of chemokine receptors on circulating B-cell subsets were investigated by flow cytometry. Immunohistochemistry was performed on GCA temporal artery (n = 14) and aorta (n = 10) and on atherosclerosis aorta (n = 10) tissue. RESULTS: The chemokines CXCL9 and CXCL13 were significantly increased in the circulation of treatment-naïve GCA and PMR patients. CXCL13 increased even further after three months of glucocorticoid treatment. At baseline CXCL13 correlated with disease activity markers. Peripheral CXCR3+ and CXCR5+ switched memory B-cells were significantly reduced in both patient groups and correlated inversely with their complementary chemokines CXCL9 and CXCL13. At the arterial lesions in GCA, CXCR3+ and CXCR5+ B-cells were observed in areas with high CXCL9 and CXCL13 expression. CONCLUSION: Changes in systemic and local chemokine and chemokine receptor pathways related to B-cell migration were observed in GCA and PMR mainly in the CXCL9-CXCR3 and CXCL13-CXCR5 axes. These changes can contribute to homing and organization of B-cells in the vessel wall and provide further evidence for an active involvement of B-cells in GCA and PMR.
Asunto(s)
Linfocitos B/fisiología , Quimiocinas/fisiología , Arteritis de Células Gigantes/inmunología , Polimialgia Reumática/inmunología , Anciano , Anciano de 80 o más Años , Movimiento Celular , Quimiocina CXCL13/sangre , Quimiocina CXCL13/fisiología , Quimiocina CXCL9/sangre , Quimiocina CXCL9/fisiología , Femenino , Arteritis de Células Gigantes/etiología , Humanos , Masculino , Persona de Mediana Edad , Polimialgia Reumática/etiología , Receptores CXCR3/sangre , Receptores CXCR3/fisiología , Receptores CXCR5/sangre , Receptores CXCR5/fisiologíaRESUMEN
This study aimed to assess the implication of mucosal-associated invariant T (MAIT) cells in GCA. Blood samples were obtained from 34 GCA patients (before and after 3 months of treatment with glucocorticoids (GC) alone) and compared with 20 controls aged >50 years. MAIT cells, defined by a CD3+CD4-TCRγδ-TCRVα7.2+CD161+ phenotype, were analyzed by flow cytometry. After sorting, we assessed the ability of MAIT cells to proliferate and produce cytokines after stimulation with anti CD3/CD28 microbeads or IL-12 and IL-18. MAIT were stained in temporal artery biopsies (TAB) by confocal microscopy. MAIT cells were found in the arterial wall of positive TABs but was absent in negative TAB. MAIT frequency among total αß-T cells was similar in the blood of patients and controls (0.52 vs. 0.57%; P = 0.43) and not modified after GC treatment (P = 0.82). Expression of IFN-γ was increased in MAIT cells from GCA patients compared to controls (44.49 vs. 32.9%; P = 0.029), and not modified after 3 months of GC therapy (P = 0.82). When they were stimulated with IL-12 and IL-18, MAIT from GCA patients produced very high levels of IFN-γ and displayed a stronger proliferation compared with MAIT from controls (proliferation index 3.39 vs. 1.4; P = 0.032). In GCA, the functional characteristics of MAIT cells are modified toward a pro-inflammatory phenotype and a stronger proliferation capability in response to IL-12 and IL-18, suggesting that MAIT might play a role in GCA pathogenesis. Our results support the use of treatments targeting IL-12/IL-18 to inhibit the IFN-γ pathway in GCA.
Asunto(s)
Arteritis de Células Gigantes/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Anciano , Biopsia , Estudios de Casos y Controles , Proliferación Celular , Células Cultivadas , Femenino , Arteritis de Células Gigantes/sangre , Arteritis de Células Gigantes/patología , Voluntarios Sanos , Humanos , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Interleucina-18/metabolismo , Masculino , Persona de Mediana Edad , Células T Invariantes Asociadas a Mucosa/metabolismo , Cultivo Primario de Células , Estudios Prospectivos , Transducción de Señal/inmunología , Arterias Temporales/patología , Técnicas de Cultivo de TejidosRESUMEN
Background: Neutrophil extracellular traps (NETs) have been implicated in host immune responses. Attempts have been made to examine how NETs affect the pathogenesis of complications such as autoimmune and vascular disorders. Aim: This study aimed to explore the relationship between NETs and vasculitis. Material and Methods: The current study entailed the searching of PsycINFO, PubMed, Web of Science, and CINAHL for articles related to the research topic. The search terms and phrases included "vasculitis," "NETs," "neutrophil extracellular traps," "NETosis," and "pathogenesis." The search was limited to articles published between 2009 and 2019. Results: Researchers have shown that NETs contribute to the pathogenesis of vasculitis through different mechanisms and processes, including renal failure and vascular damage. The protective effects of NETs have also been highlighted. Discussion: Overall, some scholars have shown the effectiveness of using DNase I and the PAD4 inhibitor Cl-amidine to treat vasculitis by restricting NET formation. However, observations have been noted in only animal experimental models. Conclusion: Neutrophil hyperactivity and its role in vasculitis are not yet fully understood. More studies aiming to determine the accurate function of NETs in vasculitis pathogenesis, particularly in humans, should be undertaken. Intensive research on NETs and vasculitis can increase the knowledge of medical practitioners and contribute to the development of new treatment methods to enhance patient outcomes in the future.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Trampas Extracelulares/inmunología , Arteritis de Células Gigantes/inmunología , Neutrófilos/inmunología , Arteritis de Takayasu/inmunología , Animales , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Apoptosis , Desoxirribonucleasa I/farmacología , Desoxirribonucleasa I/uso terapéutico , Modelos Animales de Enfermedad , Trampas Extracelulares/efectos de los fármacos , Arteritis de Células Gigantes/sangre , Arteritis de Células Gigantes/tratamiento farmacológico , Humanos , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Ornitina/análogos & derivados , Ornitina/farmacología , Ornitina/uso terapéutico , Arginina Deiminasa Proteína-Tipo 4/antagonistas & inhibidores , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Muerte Celular Regulada/efectos de los fármacos , Muerte Celular Regulada/inmunología , Arteritis de Takayasu/sangre , Arteritis de Takayasu/tratamiento farmacológicoRESUMEN
Giant cell arteritis (GCA) is a granulomatous systemic vasculitis of large- and medium-sized arteries that affects the elderly. In recent years, advances in diagnostic imaging have revealed a greater degree of large vessel involvement than previously recognized, distinguishing classical cranial- from large vessel (LV)- GCA. GCA often co-occurs with the poorly understood inflammatory arthritis/bursitis condition polymyalgia rheumatica (PMR) and has overlapping features with other non-infectious granulomatous vasculitides that affect the aorta, namely Takayasu Arteritis (TAK) and the more recently described clinically isolated aortitis (CIA). Here, we review the literature focused on the immunopathology of GCA on the background of the three settings in which comparisons are informative: LV and cranial variants of GCA; PMR and GCA; the three granulomatous vasculitides (GCA, TAK, and CIA). We discuss overlapping and unique features between these conditions across clinical presentation, epidemiology, imaging, and conventional histology. We propose a model of GCA where abnormally activated circulating cells, especially monocytes and CD4+ T cells, enter arteries after an unknown stimulus and cooperate to destroy it and review the evidence for how this mechanistically occurs in active disease and improves with treatment.
Asunto(s)
Aorta/patología , Arteritis de Células Gigantes/patología , Arteritis de Takayasu/patología , Arterias Temporales/patología , Animales , Aorta/inmunología , Aorta/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Arteritis de Células Gigantes/epidemiología , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Arteritis de Takayasu/epidemiología , Arteritis de Takayasu/inmunología , Arteritis de Takayasu/metabolismo , Arterias Temporales/inmunología , Arterias Temporales/metabolismoRESUMEN
OBJECTIVE: Our aim was to compare transcriptome and phenotype profiles of CD4+ T cells and CD19+ B cells in patients with Takayasu arteritis (TAK), patients with giant cell arteritis (GCA), and healthy donors. METHODS: Gene expression analyses, flow cytometry immunophenotyping, T cell receptor (TCR) gene sequencing, and functional assessments of cells from peripheral blood and arterial lesions from TAK patients, GCA patients, and healthy donors were performed. RESULTS: Among the most significantly dysregulated genes in CD4+ T cells of TAK patients compared to GCA patients (n = 720 genes) and in CD4+ T cells of TAK patients compared to healthy donors (n = 1,447 genes), we identified a follicular helper T (Tfh) cell signature, which included CXCR5, CCR6, and CCL20 genes, that was transcriptionally up-regulated in TAK patients. Phenotypically, there was an increase in CD4+CXCR5+CCR6+CXCR3- Tfh17 cells in TAK patients that was associated with a significant enrichment of CD19+ B cell activation. Functionally, Tfh cells helped B cells to proliferate, differentiate into memory cells, and secrete IgG antibodies. Maturation of B cells was inhibited by JAK inhibitors. Locally, in areas of arterial inflammation, we found a higher proportion of tertiary lymphoid structures comprised CD4+, CXCR5+, programmed death 1+, and CD20+ cells in TAK patients compared to GCA patients. CD4+CXCR5+ T cells in the aortas of TAK patients had an oligoclonal α/ß TCR repertoire. CONCLUSION: We established the presence of a specific Tfh cell signature in both circulating and aorta-infiltrating CD4+ T cells from TAK patients. The cooperation of Tfh cells and B cells might be critical in the occurrence of vascular inflammation in patients with TAK.
Asunto(s)
Linfocitos B/inmunología , Arteritis de Células Gigantes/inmunología , Células T Auxiliares Foliculares/inmunología , Arteritis de Takayasu/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD19/metabolismo , Antígenos CD20/metabolismo , Aorta , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Femenino , Perfilación de la Expresión Génica , Arteritis de Células Gigantes/genética , Humanos , Inmunoglobulina G/metabolismo , Memoria Inmunológica , Inmunofenotipificación , Inhibidores de las Cinasas Janus/farmacología , Masculino , Persona de Mediana Edad , Nitrilos , Receptor de Muerte Celular Programada 1/metabolismo , Pirazoles/farmacología , Pirimidinas , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores CXCR5/metabolismo , Células T Auxiliares Foliculares/efectos de los fármacos , Células T Auxiliares Foliculares/metabolismo , Arteritis de Takayasu/genética , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/metabolismo , Estructuras Linfoides Terciarias/patología , TranscriptomaRESUMEN
Objectives: The aim of this study was to quantitatively assess distinct immune cell subsets comprising inflammatory infiltrate in temporal artery biopsies (TABs) from patients with giant cell arteritis (GCA), and to link the obtained histopathological data with expression profiles of immune-related microRNAs (miRNAs). Methods: The study included 68 formalin-fixed, paraffin-embedded TABs from treatment-naïve patients, including 30 histologically positive GCA and 16 negative GCA TABs, and 22 control non-GCA TABs. Quantitative assessment of histological parameters was performed using histopathological and immunohistochemical techniques. miRNA expression analysis was performed by quantitative real-time PCR. Results: Intense transmural mononuclear inflammatory infiltrates in TAB-positive GCA arteries were predominantly composed of CD3+, CD4+ and CD8+ T lymphocytes, and CD68+ macrophages, accompanied by a strong nuclear overexpression of the nuclear factor of activated T cells, cytoplasmic 1 (NFATC) in the lymphocyte infiltrate fraction. Furthermore, TAB-positive GCA arteries were characterized by significant overexpression of nine pro-inflammatory miRNAs (miR-132-3p/-142-3p/-142-5p/-155-5p/-210-3p/-212-3p/-326/-342-5p/-511-5p) and a significant under-expression of six regulatory immune-related miRNAs (miR-30a-5p/-30b-5p/-30c-5p/-30d-5p/-30e-5p/-124-3p), whose expression levels significantly associated with most evaluated histopathological parameters. Notably, we revealed miR-132-3p/-142-3p/-142-5p/-155-5p/-212-3p/-511-5p as major promoters of arterial inflammation and miR-30a-5p/-30c-5p/-30d-5p as putative regulators of NFATC signaling in TAB-positive GCA arteries. Conclusion: Overall, we demonstrated that an altered arterial tissue-specific pro-inflammatory miRNA signature favors enhanced T cell-driven inflammation and macrophage activity in TAB-positive GCA arteries. Moreover, dysregulation of several immune-related miRNAs seems to contribute crucially to GCA pathogenesis, through impairing their regulatory activity towards T cell-mediated immune responses driven by the calcineurin (CaN)/NFAT signaling pathway, indicating their therapeutic, diagnostic and prognostic potential.
Asunto(s)
Arteritis de Células Gigantes/genética , Macrófagos/metabolismo , MicroARNs/genética , Linfocitos T/metabolismo , Arterias Temporales/metabolismo , Transcriptoma , Anciano , Anciano de 80 o más Años , Biopsia , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/patología , Humanos , Macrófagos/inmunología , Masculino , MicroARNs/inmunología , MicroARNs/metabolismo , Persona de Mediana Edad , Fenotipo , Linfocitos T/inmunología , Arterias Temporales/inmunología , Arterias Temporales/patologíaRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of ustekinumab (UST) in giant cell arteritis (GCA). METHODS: We conducted a prospective, open-label trial of UST in patients with active new-onset or relapsing GCA. Active disease was defined as the presence of GCA symptoms and elevation of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level within 6 weeks of baseline. All patients received a 24-week prednisone taper and subcutaneous UST 90 mg at baseline and at weeks 4, 12, 20, 28, 36, and 44. The primary endpoint, prednisone-free remission, was defined as the absence of relapse through week 52 and normalization of the ESR and CRP level. Relapse was defined as the recurrence of GCA symptoms requiring treatment intensification. A sensitivity analysis excluding ESR/CRP level normalization from the prednisone-free remission definition was performed. RESULTS: The study enrolled 13 patients (target sample size 20). Enrollment was closed prematurely after 7 of the initial 10 patients relapsed. Five patients (39%) had new-onset disease. The initial prednisone doses were 20 mg (1 patient), 40 mg (9 patients), and 60 mg (3 patients). All patients entered disease remission within 4 weeks of baseline. Only 3 (23%) achieved the primary endpoint. Of the 10 patients (77%) who failed to achieve the primary endpoint, 7 relapsed after a mean period of 23 weeks. The remaining 3 patients met the alternative definition of prednisone-free remission that did not require ESR/CRP level normalization. One serious adverse event occurred. CONCLUSION: UST combined with 24 weeks of prednisone was associated with a high rate of treatment failure in this prospective GCA trial.