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1.
Artigo em Inglês | MEDLINE | ID: mdl-38323660

RESUMO

OBJECTIVES: We investigated the potential of serum proteins to distinguish clinical and molecular subtypes in patients with giant cell arteritis (GCA). METHODS: Proximity extension assays were used to analyse 1463 proteins in serum samples from patients with new-onset GCA (n = 16) and after achieving remission (n = 13). Unsupervised and supervised cluster analyses were performed. RESULTS: Unsupervised cluster analysis identified three distinct clusters based on the protein signature. Compared with cluster 2, patients of cluster 1 had less polymyalgia rheumatica symptoms, increased levels of macrophage migration inhibitory factor (MIF) and pronounced NF-kB, STAT5 and interleukin-1 signalling. The changes in serum proteins upon remission differed between cluster 1 and 2.Patients with cranial GCA were characterised by altered endothelial and Th17 signalling whereas patients not responding to treatment within the GUSTO-trial showed increased Th1 and diminished B cell signalling. Patients with anterior ischemic optic neuropathy displayed higher levels of CHI3L1 (YKL40), MMP12 and reduced levels of TIMP3. CONCLUSIONS: Protein profiling identifies patient clusters in GCA with distinct proteomic features and therefore likely different pathophysiology. These unique proteomic footprints might lead to more targeted treatments in future.

2.
Front Immunol ; 14: 1165758, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37287970

RESUMO

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.


Assuntos
Arterite de Células Gigantes , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/metabolismo , Humanos , Proteômica , Glucocorticoides/uso terapêutico
3.
Semin Immunopathol ; 44(3): 281-301, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35141865

RESUMO

Two vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are recognized as autoimmune and autoinflammatory diseases that manifest exclusively within the aorta and its large branches. In both entities, the age of the affected host is a critical risk factor. TAK manifests during the 2nd-4th decade of life, occurring while the immune system is at its height of performance. GCA is a disease of older individuals, with infrequent cases during the 6th decade and peak incidence during the 8th decade of life. In both vasculitides, macrophages and T cells infiltrate into the adventitia and media of affected vessels, induce granulomatous inflammation, cause vessel wall destruction, and reprogram vascular cells to drive adventitial and neointimal expansion. In GCA, abnormal immunity originates in an aged immune system and evolves within the aged vascular microenvironment. One hallmark of the aging immune system is the preferential loss of CD8+ T cell function. Accordingly, in GCA but not in TAK, CD8+ effector T cells play a negligible role and anti-inflammatory CD8+ T regulatory cells are selectively impaired. Here, we review current evidence of how the process of immunosenescence impacts the risk for GCA and how fundamental differences in the age of the immune system translate into differences in the granulomatous immunopathology of TAK versus GCA.


Assuntos
Imunossenescência , Vasculite , Idoso , Envelhecimento , Humanos , Macrófagos , Fatores de Risco
4.
Clin Dermatol ; 39(2): 261-270, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272020

RESUMO

Neutrophilic dermatoses (NDs) are a group of reactive, noninfectious autoinflammatory diseases characterized by (1) infiltration of the epidermis, dermis, and or/hypodermis by neutrophils; (2) their association with distinct diseases (eg, hematologic malignancy and chronic inflammatory diseases); (3) potential extracutaneous involvement; and (4) response to anti-inflammatory drugs, such as corticosteroids, dapsone, colchicine, and novel biologic therapies, such as the anti-interleukin-1 blockade. Although distinct NDs have been described, transitional forms with overlapping features are often identified. These justify a simplified classification of NDs with three major forms: superficial (epidermal or pustular) NDs, dermal (en plaques) NDs, and deep NDs. We review selected or novel variants of NDs, including subcorneal pustular dermatosis, the group of immunoglobulin A neutrophilic dermatoses, amicrobial pustular dermatosis of the folds, and neutrophilic urticarial dermatosis, as well as atypical forms of Sweet syndrome and pyoderma gangrenosum closely mimicking severe infectious diseases. Knowledge of these variants is essential for proper diagnosis, adequate management, and avoidance of a dangerous escalation of therapy, such as unnecessary immunosuppression or extensive surgery.


Assuntos
Dermatite , Pioderma Gangrenoso , Dermatopatias Vesiculobolhosas , Síndrome de Sweet , Anti-Inflamatórios/uso terapêutico , Humanos , Neutrófilos , Pioderma Gangrenoso/diagnóstico , Pioderma Gangrenoso/tratamento farmacológico , Dermatopatias Vesiculobolhosas/diagnóstico , Dermatopatias Vesiculobolhosas/tratamento farmacológico , Síndrome de Sweet/diagnóstico , Síndrome de Sweet/tratamento farmacológico
5.
PLoS One ; 16(6): e0250025, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34143786

RESUMO

OBJECTIVE: Takayasu arteritis (TAK) is a rare immune-mediated vasculitis of the aorta and its branches. Aims were to calculate prevalence and incidence in Switzerland, to assess disease activity and performance of MR-Angiography (MRA). METHODS: 31 patients were recorded in a database, 27 were followed prospectively up to 3 years. Prevalence was calculated based on data of the national statistical bureau. Disease activity was defined using the revised EULAR criteria. MRA depicted stenotic changes and aortic wall enhancement. RESULTS: A disease prevalence of 14.5/1.000.000 inhabitants and an incidence of 0.3/1.000.000 per year was calculated. Aortic wall enhancement was found in 10 patients while in clinical and serological remission. EULAR criteria missed 5 patients with disease activity with isolated elevations of ESR/CRP. Arterial stenosis did not change over time in 5 cases, it improved in 2 and increased in 7. At follow-up 16 patients were treated with tocilizumab, 11/16 in monotherapy, 5 patients were treatment-free, 25/27 stayed in remission. CONCLUSION: In addition to prevalence and incidence, our data show that MRA qualifies to detect subclinical disease activity, but, on the other hand, that EULAR criteria may miss disease activity in case of isolated elevation of ESR/CRP.


Assuntos
Angiografia por Ressonância Magnética/métodos , Arterite de Takayasu/epidemiologia , Arterite de Takayasu/patologia , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Prospectivos , Suíça/epidemiologia , Arterite de Takayasu/diagnóstico por imagem , Adulto Jovem
6.
Rheumatology (Oxford) ; 57(10): 1795-1801, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29961816

RESUMO

Objective: Tocilizumab is effective in inducing and maintaining remission of GCA. Despite clinical and serological control of disease, magnetic resonance angiography may show persistence of inflammatory signals of unknown significance in arterial walls. Thus, there is an unmet need for tools to detect subclinical disease activity. Methods: Immune-inflammatory markers were measured in prospectively collected sera of the first randomized, double-blind, placebo-controlled trial investigating the use of tocilizumab in GCA. As a comparison, immune-inflammatory markers were also measured in sera from age- and sex-matched healthy volunteers. The biomarkers were quantified using luminex technology. Results: Of all the parameters determined, only MMP-3, pentraxin-3 and sTNFR2 were significantly elevated, while ICAM-1 and CD163 were significantly decreased during the early stages of the study, at time points of full clinical remission under treatment with tocilizumab plus glucocorticoids. In contrast, tocilizumab monotherapy towards the end of the study resulted in an almost complete normalization of immune-inflammatory molecules, as defined by the healthy controls. MMP-3 levels showed a weak association with magnetic resonance signal intensity; none of the biomarkers predicted relapse occurring within 6 months after study end. Conclusion: The data documented a subclinical disease activity in GCA that was more pronounced during the early stages of treatment and almost disappeared towards the study end. They indicated that tocilizumab treatment of at least 52 weeks is necessary in order to reset a broad range of immune-inflammatory pathways. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01450137.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Arterite de Células Gigantes/sangue , Glucocorticoides/uso terapêutico , Quimioterapia de Indução/métodos , Monitorização Imunológica/métodos , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Biomarcadores/sangue , Proteína C-Reativa/análise , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/patologia , Humanos , Molécula 1 de Adesão Intercelular/sangue , Masculino , Metaloproteinase 3 da Matriz/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores de Superfície Celular/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Componente Amiloide P Sérico/análise , Resultado do Tratamento
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