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1.
Eur Respir J ; 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38485150

RESUMO

There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH). As immunity has been involved in the development and progression of vascular lesions in PAH, we review the potential contribution of B cells in its pathogenesis and evaluate the relevance of B cell-targeted therapies. Circulating B cell homeostasis is altered in PAH patients, with total B-cell lymphopenia, abnormal subset distribution (expansion of naïve and antibody-secreting cells, reduction of memory B cells) and chronic activation. B cells are recruited to the lungs through local chemokine secretion, and activated by several mechanisms: 1) interaction with lung vascular auto-antigens through cognate B cell receptors; 2) co-stimulatory signals provided by T follicular helper (Tfh) cells (IL-21), T helper 2 (Th2) cells and mast cells (IL-4, IL-6 and IL-13); and 3) increased survival signals provided by B cell activating factor (BAFF) pathways. This activity results in the formation of germinal centres within perivascular tertiary lymphoid organs and in the local production of pathogenic autoantibodies that target the pulmonary vasculature and vascular stabilization factors (including angiotensin-II/endothelin-1 receptors and bone morphogenetic protein receptors). B cells also mediate their effects through enhanced production of pro-inflammatory cytokines, reduced anti-inflammatory properties by regulatory B cells, IgG-induced complement activation, and IgE-induced mast cell activation. Precision-medicine approaches targeting B cell immunity are a promising direction for select PAH conditions, as suggested by the efficacy of anti-CD20 therapy in experimental models and a trial of rituximab in systemic sclerosis-associated PAH.

2.
Neurotherapeutics ; 20(6): 1707-1722, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37882961

RESUMO

Few studies have investigated sustained B-cell depletion after long-term intravenous (IV) anti-CD20 B-cell depleting therapy (BCDT) in multiple sclerosis (MS) with respect to strict and/or minimal disease activity. The main objective of this study was to investigate how sustained B-cell depletion after BCDT influences clinical and radiological stability as defined by "no evidence of disease activity" (NEDA-3) and "minimal evidence of disease activity" (MEDA) status in MS patients at 12 and 18 months. Furthermore, we assessed the frequency of serious adverse events (SAE), and the influence of prior lymphocytopenia-inducing treatment (LIT) on lymphocyte subset counts and gammaglobulins in MS patients receiving long-term BCDT. We performed a retrospective, prospectively collected, study in a cohort of 192 MS patients of all clinical phenotypes treated by BCDT between January 2014 and September 2021. Overall, 84.2% and 96.9% of patients attained NEDA-3 and MEDA status at 18 months, respectively. Sustained CD19+ depletion was observed in 85.8% of patients at 18 months. No significant difference was observed when comparing patients achieving either NEDA-3 or MEDA at 18 months and sustained B-cell depletion. Compared to baseline levels, IgM and IgG levels on BCDT significantly decreased at 6 months and 30 months, respectively. Patients receiving LIT prior to BCDT showed significant CD4+ lymphocytopenia and lower IgG levels compared to non-LIT patients. Grade 3 or above SAEs were rare. As nearly all patients achieved MEDA at 18 months, we suggest tailoring IV BCDT after 18 months given the occurrence of lymphocytopenia, hypogammaglobulinemia, and SAE after this time point.


Assuntos
Linfopenia , Esclerose Múltipla , Humanos , Rituximab/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Estudos Retrospectivos , Anticorpos Monoclonais Murinos , Depleção Linfocítica/métodos , Imunoglobulina G
3.
Sci Rep ; 13(1): 15102, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37700078

RESUMO

Systemic sclerosis (SSc) is the most severe systemic autoimmune disease with currently no cure. Intravenous immunoglobulins (IVIg) are an attractive candidate in this disease to counteract inflammation and fibrosis but data are scarce and conflicting. This study, assessed the effects of IVIg in a murine HOCl-induced model of SSc. We showed that IVIg prevented skin inflammation and fibrosis, by mitigating the immune cell infiltration (p = 0.04), proinflammatory cytokines gene overexpression (IL1ß, p = 0.04; TNFα, p = 0.04; IL6, p = 0.05), skin and dermal thickening (p = 0.003 at d21 and p = 0.0003 at d42), the expression markers of fibrosis, such as αSMA (p = 0.031 for mRNA and p = 0.05 for protein), collagen (p = 0.05 for mRNA and p = 0.04 for protein, p = 0.05 for the hydroxyproline content) and fibronectin (p = 0.033 for mRNA). Moreover, IVIg prevented HOCl-induced alterations in splenic cell homeostasis. When administered in curative mode, despite their ability to reduce skin and dermal thickness (p < 0.0001 and p = 0.0002), IVIg showed partial or more mixed effects on skin inflammation and established fibrosis. These data favor further clinical trials in SSc patients on the potential efficiency of early and/or repeated IVIg administration.


Assuntos
Dermatite , Escleroderma Sistêmico , Dermatopatias , Humanos , Animais , Camundongos , Imunoglobulinas Intravenosas/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/tratamento farmacológico , Inflamação , Fibrose , Modelos Teóricos
4.
Clin Exp Rheumatol ; 41(9): 1875-1881, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37279145

RESUMO

OBJECTIVES: To evaluate whether inflammatory and complement biomarkers are associated with specific characteristics of antiphospholipid syndrome (APS). METHODS: Serum levels of interleukin (IL)-1ß (IL-1ß), IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, interferon-α (IFN)-α, IFN-γ, vascular endothelial growth factor (VEGF), intercellular adhesion molecule 1 (ICAM-1), E-selectin, and vascular cell adhesion molecule (VCAM)-1, and plasma levels of soluble C5b-9 (sC5b-9), C3a, C4a, Bb fragment were measured in unselected APS patients. Twenty-five healthy blood donors were included as controls. RESULTS: Between January 2020 and April 2021, 98 APS patients were included outside acute thrombosis (median time from the last APS manifestation: 60 (23;132) months). Levels of IL6, VCAM-1, sC5b-9, C3a, C4a, and Bb were significantly increased in APS patients compared to controls. A cluster analysis allowed to divide patients into two clusters: "inflammatory" (higher levels of IL-6 and VCAM-1) and "complement". In APS, elevated IL-6 was associated with hypertension, diabetes, BMI, and hypertriglyceridaemia. 85% of our APS patients had elevated levels of at least one complement biomarker. Elevated Bb (34%) was associated with aPL positivities, especially with triple aPL positivity (50% vs. 18%, p<0.001). 7/8 patients with history of catastrophic APS had elevated levels of complement biomarkers. CONCLUSIONS: Our findings suggested that APS patients outside acute thrombosis might be divided into two clusters: "inflammatory" and "complement". Elevated IL-6 was associated with cardiovascular risk factors and metabolic parameters, whereas Bb fragments, a marker of alternative pathway complement activation, was strongly associated with aPL profile at highest risk of severe disease.


Assuntos
Síndrome Antifosfolipídica , Trombose , Humanos , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/diagnóstico , Molécula 1 de Adesão de Célula Vascular/metabolismo , Interleucina-6 , Fator A de Crescimento do Endotélio Vascular , Ativação do Complemento , Trombose/etiologia , Trombose/complicações , Proteínas do Sistema Complemento , Biomarcadores
5.
Biomedicines ; 11(6)2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-37371599

RESUMO

Severe COVID-19 infections are at high risk of causing thromboembolic events (TEEs). However, the usual exams may be unavailable or unreliable in predicting the risk of TEEs at admission or during hospitalization. We performed a retrospective analysis of two centers (n = 124 patients) including severe COVID-19 patients to determine the specific risk factors of TEEs in SARS-CoV-2 infection at admission and during stays at the intensive care unit (ICU). We used stepwise regression to create two composite scores in order to predict TEEs in the first 48 h (H0-H48) and during the first 15 days (D1-D15) in ICU. We then evaluated the performance of our scores in our cohort. During the period H0-H48, patients with a TEE diagnosis had higher D-Dimers and ferritin values at day 1 (D1) and day 3 (D3) and a greater drop in fibrinogen between D1 and D3 compared with patients without TEEs. Over the period D1-D15, patients with a diagnosis of a TEE showed a more marked drop in fibrinogen and had higher D-Dimers and lactate dehydrogenase (LDH) values at D1 and D3. Based on ROC analysis, the COVID-related acute lung and deep vein thrombosis (CALT) 1 score, calculated at D1, had a diagnostic performance for TEEs at H0-H48, estimated using an area under the curve (AUC) of 0.85 (CI95%: 0.76-0.93, p < 10-3). The CALT 2 score, calculated at D3, predicted the occurrence of TEEs over the period D1-D15 with an estimated AUC of 0.85 (CI95%: 0.77-0.93, p < 10-3). These two scores were used as the basis for the development of the CALT protocol, a tool to assist in the decision to use anticoagulation during severe SARS-CoV-2 infections. The CALT scores showed good performances in predicting the risk of TEEs in severe COVID-19 patients at admission and during ICU stays. They could, therefore, be used as a decision support protocol on whether or not to initiate therapeutic anticoagulation.

7.
Clin Infect Dis ; 76(5): 800-808, 2023 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-36285530

RESUMO

BACKGROUND: Primary immunodeficiencies (PIDs) in adults are mainly revealed by recurrent and/or severe bacterial infections. The objective of this study was to evaluate a systematic research strategy of PIDs in adults with unexplained bacterial infections, with a special focus on specific polysaccharide antibody deficiency (SPAD). METHODS: In this prospective multicenter study, inclusion criteria were recurrent benign upper and lower respiratory tract infections (RTIs) for at least two years (group 1), at least one upper or lower RTI requiring hospitalization (group 2), and/or at least one invasive infection documented with encapsulated bacteria (group 3). Main exclusion criteria were all local and general conditions that could explain infections. If no PID diagnosis was made, response to polysaccharide antigens was assessed using a pneumococcal polysaccharide vaccine. RESULTS: From March 2015 to March 2020, 118 patients were included (37 males, median age of 41 years): 73, 17, and 28 in groups 1, 2, and 3, respectively. Forty-seven PIDs were diagnosed, giving an estimated frequency of 39.8% (95% confidence interval [CI] [30.4, 48.8]). SPAD was the most frequent diagnosis by far (n = 37/47, 78.7%), and was made in 23, 5, and 9 patients from groups 1 to 3, respectively. All SPAD patients received conjugate vaccines and, according to their infectious history, were on surveillance or treated with preventive antibiotics (n = 6) and/or with immunoglobulins replacement therapy (n = 10), the latter being dramatically efficient in all cases. CONCLUSIONS: Considering its high prevalence among adults with unexplained recurrent and/or severe bacterial infections, SPAD should be screened in those patients. CLINICAL TRIALS REGISTRATION: NCT02972281.


Assuntos
Infecções Bacterianas , Síndromes de Imunodeficiência , Infecções Pneumocócicas , Doenças da Imunodeficiência Primária , Masculino , Humanos , Adulto , Estudos Prospectivos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/diagnóstico , Polissacarídeos , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/tratamento farmacológico , Doenças da Imunodeficiência Primária/tratamento farmacológico , Bactérias , Vacinas Pneumocócicas , Anticorpos Antibacterianos , Infecções Pneumocócicas/prevenção & controle
9.
Ann Rheum Dis ; 82(4): 546-555, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36572507

RESUMO

OBJECTIVES: To discover new and detect known antisynthetase autoantibodies (ASAs) through protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS). METHODS: IP-MS was performed using sera of individuals showing features of antisynthetase syndrome (ASyS) without (n=5) and with (n=12) previously detected ASAs, and healthy controls (n=4). New candidate aminoacyl-tRNA-synthetase (ARS) autoantigens identified through unbiased IP-MS were confirmed by IP-western blot. A targeted IP-MS assay for various ASA specificities was developed and validated with sera of patients with known ASAs (n=16), disease controls (n=20) and healthy controls (n=25). The targeted IP-MS assay was applied in an additional cohort of patients with multiple ASyS features or isolated myositis without previously detected ASAs (n=26). RESULTS: Autoantibodies to cytoplasmic cysteinyl-tRNA-synthetase (CARS1) were identified by IP-MS and confirmed by western blot as a new ASA specificity, named anti-Ly, in the serum of a patient with ASyS features. Rare ASAs, such as anti-OJ, anti-Zo and anti-KS, and common ASAs could also be identified by IP-MS. A targeted IP-MS approach for ASA detection was developed and validated. Application of this method in an additional cohort identified an additional patient with anti-OJ autoantibodies that were missed by line and dot immunoassays. DISCUSSION: CARS1 is the dominant cognate ARS autoantigen of the newly discovered anti-Ly ASA specificity. Rare and common ASA specificities could be detected by both unbiased and targeted IP-MS. Unbiased and targeted IP-MS are promising methods for discovery and detection of autoantibodies, especially autoantibodies that target complex autoantigens.


Assuntos
Doenças Pulmonares Intersticiais , Miosite , Humanos , Autoanticorpos , Autoantígenos , RNA de Transferência
10.
Front Immunol ; 13: 954007, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967377

RESUMO

Introduction: Soluble markers of B cell activation are interesting diagnostic and prognostic tools in autoimmune diseases. Data in systemic sclerosis (SSc) are scarce and few studies focused on their association with disease characteristics. Methods: 1. Serum levels of 14 B cell biomarkers (ß2-microglobulin, rheumatoid factor (RF), immunoglobulins (Ig) G, IgA, IgM, BAFF, APRIL, soluble (s)TACI, sBCMA sCD21, sCD23, sCD25, sCD27, CXCL13) were measured in SSc patients and healthy controls (HC). 2. Associations between these biomarkers and SSc characteristics were assessed. 3. The pathophysiological relevance of identified associations was explored by studying protein production in B cell culture supernatant. Results: In a discovery panel of 80 SSc patients encompassing the broad spectrum of disease manifestations, we observed a higher frequency of RF positivity, and increased levels of ß2-microglobulin, IgG and CXCL13 compared with HC. We found significant associations between several biomarkers and SSc characteristics related to disease phenotype, activity and severity. Especially, serum IgG levels were associated with pulmonary hypertension (PH); ß2-microglobulin with Nt-pro-BNP and DLCO; and BAFF with peak tricuspid regurgitation velocity (TRV). In a validation cohort of limited cutaneous SSc patients without extensive ILD, we observed lower serum IgG levels, and higher ß2-microglobulin, sBCMA, sCD23 and sCD27 levels in patients with pulmonary arterial hypertension (PAH). BAFF levels strongly correlated with Nt-pro-BNP levels, FVC/DLCO ratio and peak TRV in SSc-PAH patients. Cultured SSc B cells showed increased production of various angiogenic factors (angiogenin, angiopoietin-1, VEGFR-1, PDGF-AA, MMP-8, TIMP-1, L-selectin) and decreased production of angiopoietin-2 compared to HC. Conclusion: Soluble markers of B cell activation could be relevant tools to assess organ involvements, activity and severity in SSc. Their associations with PAH could plead for a role of B cell activation in the pathogenesis of pulmonary microangiopathy. B cells may contribute to SSc vasculopathy through production of angiogenic mediators.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Escleroderma Sistêmico , Biomarcadores , Hipertensão Pulmonar Primária Familiar , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Imunoglobulina G , Fator Reumatoide
11.
Front Immunol ; 13: 930970, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35837382

RESUMO

Systemic sclerosis (SSc) is a connective tissue disease characterized by extensive fibrosis of the skin and internal organs, associated with vasculopathy and autoimmune features. Antinuclear antibodies (ANA) are found in almost all SSc patients and constitute strong diagnosis and prognosis biomarkers. However, it remains unclear whether ANA are simple bystanders or if they can have a role in the pathophysiology of the disease. One might think that the nuclear nature of their targets prevents any accessibility to autoantibodies. Nevertheless, recent data suggest that ANA could be pathogenic or at least contribute to the perennation of the disease. We review here first the indirect clues of the contribution of ANA to SSc: they are associated to the disease subtypes, they may precede disease onset, their titer correlates with disease activity and severity, there is an association between molecular subsets, and some patients can respond to B-cell targeting therapy. Then, we describe in a second part the mechanisms of ANA production in SSc from individual genetic background to post-transcriptional modifications of neoantigens. Finally, we elaborate on the potential mechanisms of pathogenicity: ANA could be pathogenic through immune-complex-mediated mechanisms; other processes potentially involve molecular mimicry and ANA penetration into the target cell, with a focus on anti-topoisomerase-I antibodies, which are the most probable candidate to play a role in the pathophysiology of SSc. Finally, we outline some technical and conceptual ways to improve our understanding in this field.


Assuntos
Anticorpos Antinucleares , Escleroderma Sistêmico , Autoanticorpos , Fibrose , Humanos , Escleroderma Sistêmico/diagnóstico
12.
Sci Rep ; 12(1): 11748, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35817787

RESUMO

We provide an original multi-stage approach identifying a gene signature to assess murine fibroblast polarization. Prototypic polarizations (inflammatory/fibrotic) were induced by seeded mouse embryonic fibroblasts (MEFs) with TNFα or TGFß1, respectively. The transcriptomic and proteomic profiles were obtained by RNA microarray and LC-MS/MS. Gene Ontology and pathways analysis were performed among the differentially expressed genes (DEGs) and proteins (DEPs). Balb/c mice underwent daily intradermal injections of HOCl (or PBS) as an experimental murine model of inflammation-mediated fibrosis in a time-dependent manner. As results, 1456 and 2215 DEGs, and 289 and 233 DEPs were respectively found in MEFs in response to TNFα or TGFß1, respectively. Among the most significant pathways, we combined 26 representative genes to encompass the proinflammatory and profibrotic polarizations of fibroblasts. Based on principal component analysis, this signature deciphered baseline state, proinflammatory polarization, and profibrotic polarization as accurately as RNA microarray and LC-MS/MS did. Then, we assessed the gene signature on dermal fibroblasts isolated from the experimental murine model. We observed a proinflammatory polarization at day 7, and a mixture of a proinflammatory and profibrotic polarizations at day 42 in line with histological findings. Our approach provides a small-size and convenient gene signature to assess murine fibroblast polarization.


Assuntos
Fibroblastos , Fator de Necrose Tumoral alfa , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibrose , Camundongos , Camundongos Endogâmicos BALB C , Proteômica , RNA/metabolismo , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa/metabolismo
13.
Front Immunol ; 13: 904631, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844491

RESUMO

Autoantibodies (Aabs) are frequent in systemic sclerosis (SSc). Although recognized as potent biomarkers, their pathogenic role is debated. This study explored the effect of purified immunoglobulin G (IgG) from SSc patients on protein and mRNA expression of dermal fibroblasts (FBs) using an innovative multi-omics approach. Dermal FBs were cultured in the presence of sera or purified IgG from patients with diffuse cutaneous SSc (dcSSc), limited cutaneous SSc or healthy controls (HCs). The FB proteome and transcriptome were explored using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and microarray assays, respectively. Proteomic analysis identified 3,310 proteins. SSc sera and purified IgG induced singular protein profile patterns. These FB proteome changes depended on the Aab serotype, with a singular effect observed with purified IgG from anti-topoisomerase-I autoantibody (ATA) positive patients compared to HC or other SSc serotypes. IgG from ATA positive SSc patients induced enrichment in proteins involved in focal adhesion, cadherin binding, cytosolic part, or lytic vacuole. Multi-omics analysis was performed in two ways: first by restricting the analysis of the transcriptomic data to differentially expressed proteins; and secondly, by performing a global statistical analysis integrating proteomics and transcriptomics. Transcriptomic analysis distinguished 764 differentially expressed genes and revealed that IgG from dcSSc can induce extracellular matrix (ECM) remodeling changes in gene expression profiles in FB. Global statistical analysis integrating proteomics and transcriptomics confirmed that IgG from SSc can induce ECM remodeling and activate FB profiles. This effect depended on the serotype of the patient, suggesting that SSc Aab might play a pathogenic role in some SSc subsets.


Assuntos
Imunoglobulina G , Escleroderma Sistêmico , Autoanticorpos , Cromatografia Líquida , Fibroblastos/metabolismo , Humanos , Proteoma/metabolismo , Proteômica , Espectrometria de Massas em Tandem
14.
J Clin Immunol ; 42(7): 1461-1472, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35737255

RESUMO

As protein-losing enteropathy (PLE) can lead to hypogammaglobulinemia and lymphopenia, and since common variable immunodeficiency (CVID) is associated with digestive complications, we wondered if (1) PLE could occur during CVID and (2) specific features could help determine whether a patient with antibody deficiency has CVID, PLE, or both. Eligible patients were thus classified in 3 groups: CVID + PLE (n = 8), CVID-only (= 19), and PLE-only (n = 13). PLE was diagnosed using fecal clearance of α1-antitrypsin or 111In-labeled albumin. Immunoglobulin (Ig) A, G, and M, naive/memory B and T cell subsets were compared between each group. CVID + PLE patients had multiple causes of PLE: duodenal villous atrophy (5/8), nodular follicular hyperplasia (4/8), inflammatory bowel disease-like (4/8), portal hypertension (4/8), giardiasis (3/8), and pernicious anemia (1/8). Compared to the CVID-only group, CVID + PLE patients had similar serum Ig levels, B cell subset counts, but lower naive T cell proportion and IgG replacement efficiency index. Compared to the CVID-only group, PLE-only patients did not develop infections but had higher serum levels of IgG (p = 0.03), IgA (p < 0.0001), and switched memory B cells (p = 0.001); and decreased naive T cells (CD4+: p = 0.005; CD8+: p < 0.0001). Compared to the PLE-only group, CVID + PLE patients had higher infection rates (p = 0.0003), and lower serum Ig (especially IgA: p < 0.001) and switched memory B cells levels. In conclusion, PLE can occur during CVID and requires higher IgG replacement therapy dosage. PLE can also mimic CVID and is associated with milder immunological abnormalities, notably mildly decreased to normal serum IgA and switched memory B cell levels.


Assuntos
Imunodeficiência de Variável Comum , Enteropatias Perdedoras de Proteínas , Humanos , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/diagnóstico , Enteropatias Perdedoras de Proteínas/etiologia , Enteropatias Perdedoras de Proteínas/complicações , Diagnóstico Diferencial , Imunoglobulina A , Imunoglobulina G
15.
Allergy Asthma Proc ; 43(2): 155-162, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35317893

RESUMO

Background: A differential diagnosis between angiotensin-converting enzyme inhibitor (ACEi) angioedema (AE) and histaminergic AE (hAE) might be challenging. Follow-up data may help discriminate these conditions but are scarcely reported. Objective: To report on the follow-up of patients with suspected ACEi-AE and to describe the baseline characteristics of AE attacks in patients with a diagnosis of ACEi-AE after follow-up. Methods: Sixty-four patients with suspected ACEi-AE (i.e., with exposure to ACEi before the first attack, no urticaria associated, and normal C1-inhibitor levels) and at least one follow-up visit were included. Data were retrospectively collected at baseline and during the follow-up. Results: After the follow-up, the diagnosis of ACEi-AE was probable in only 30 patients. The remaining patients were reclassified as having probable hAE (21 patients) or undetermined-mechanism AE (13 patients). Patients with ACEi-AE were mostly men (61%), with a median age of 64 years (interquartile range [IQR] ±17 years), with a highly variable delay from ACEi introduction (median: 23 months; interquartile range: 103 months). Attacks preferentially involved lips (50%), tongue (47%), and throat (30%). Interestingly, patients with probable ACEi-AE after a follow-up also frequently presented with a history of allergy and atopic conditions (20%), attacks with preferential evening onset (25%), and spontaneous resolution in < 24 hours (26%), which are usually considered as suggestive of hAE. ACEi-AE attacks responded to icatibant in 79% of the patients. Conclusion: Patients with probable ACEi-AE were mostly men with facial involvement. A third of the patients with an initial suspected diagnosis of ACEi-AE had a final diagnosis of probable hAE. Although a follow-up of all patients should be a standard of care, it is critical to the correct diagnosis in the case of suspected bradykinin-associated AE, which may actually be due to histamine.


Assuntos
Angioedema , Urticária , Adolescente , Angioedema/induzido quimicamente , Angioedema/diagnóstico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bradicinina , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Urticária/induzido quimicamente
16.
J Clin Med ; 12(1)2022 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-36614946

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease associated with endothelial activation and fibrosis. Non-O blood group patients carry an increased risk of thrombosis, fibrosis and autoimmune diseases. The aim of our work was to evaluate the distribution of ABO groups in SSc patients and their association with the disease's characteristics. ABO groups were determined in 504 SSc patients (with 131 completed by a genotypic analysis). The distribution of ABO groups and their diplotypes in SSc patients was comparable to that of the general population, except for haplotypes O1 and B (65.6% vs. 61.6% and 8.8% vs. 5.8% in SSc patients vs. the general population, respectively, p = 0.01). The frequency of interstitial lung disease, pulmonary hypertension, calcinosis, digital ulcers, digestive diseases and venous thrombosis, and the Medsger score, were higher in non-O than in O-SSc patients, although they did not display statistical significance. Patients in the non-O group had higher levels of inflammation and endothelial activation biomarkers. In conclusion, the ABO blood group distribution of SSc patients did not differ significantly from that of the general population, but non-O blood groups were associated with inflammation and endothelial activation, and with a non-significant higher frequency of pulmonary and vascular complications in SSc.

17.
Proteomics ; 22(3): e2100116, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34665929

RESUMO

Fibroblasts (Fb) are key effector cells in systemic sclerosis (SSc). Fb stimulation with transforming growth factor beta 1 (TGF-ß1) is considered as a positive control in studies assessing fibrogenesis. The lack of standardization of TGF-ß1 stimulation might be responsible for discrepancies in experiments performed in different conditions. Using quantitative proteomics analysis, we evaluated the impact of changes in experimental conditions on proteomic profiles of primary Fb. Principal component analysis (PCA) identified several groups of differentially expressed proteins influenced by cell passage, culture medium, and both concentration and duration of exposure to TGF-ß1 stimulation. Bioinformatics analysis revealed that late passages expressed proteins involved in senescence. TGF-ß1 concentration and time of stimulation were correlated with the expression of proteins involved in the fibrogenesis and inflammatory processes. These data underline the need for standardization of culture conditions to allow inter-data comparisons in future in vitro studies, especially when using "omics" approaches.


Assuntos
Proteômica , Escleroderma Sistêmico , Células Cultivadas , Biologia Computacional , Fibroblastos/metabolismo , Humanos , Escleroderma Sistêmico/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
19.
Diagnostics (Basel) ; 11(6)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207757

RESUMO

BACKGROUND: The detection of additional autoantibodies is of great concern in systemic sclerosis (SSc) when those included in the ACR/EULAR classification are negative. In this context, the interest of antifibrillarin (anti-U3RNP) autoantibodies (AFAs) in the routine evaluation of SSc remains unclear. We aimed to assess the relevance of AFAs and their clinical association in SSc patients. METHODS: In a multicenter observational retrospective study, we collected immunological and clinical data associated with AFA positivity in SSc (n = 42) and non-SSc patients (n = 13). Patients with SSc negative for AFAs (n = 83) were considered as a control group. AFAs were detected by indirect immunofluorescence (IIF) using HEp-2 cells, EliA or immunoblot techniques. RESULTS: We confirmed a typical nuclear IIF pattern and showed that AFAs are mostly exclusive towards SSc conventional autoantibodies. Although also observed in non-SSc patients, high levels of AFAs with the ELiA technique allowed the diagnosis of SSc. Compared to AFA-negative SSc patients, AFA-positive SSc patients more frequently exhibited visceral involvements. They more frequently suffered from the diffuse cutaneous form and had a higher global severity of the disease. CONCLUSIONS: We demonstrate the usefulness of quantifying AFAs in the immunological exploration of SSc, especially when patients are seronegative for SSc conventional autoantibodies and display a typical IIF pattern. AFAs might constitute an interesting marker of SSc severity.

20.
Eur J Intern Med ; 91: 45-52, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33972152

RESUMO

OBJECTIVES: Clinical significance of anti-Ro52 antibodies in connective tissue diseases (CTD) is controversial. Anti-Ro52 antibodies might be associated with a more severe CTD phenotype, especially interstitial lung disease (ILD). The aims of this study were to evaluate ILD prevalence and severity, the prevalence of micro- or macroangiopathy and CTD-associated cancers in CTD with anti-Ro52 antibodies. METHODS: CTD patients with anti-Ro52 antibody screening by immunoblot at diagnosis were enrolled. Two groups were retrospectively formed according to the presence of anti-Ro52 antibodies with an unbiased 1:1 matching on CTD types. Unsupervised multiple correspondence analysis and hierarchical clustering analysis were used to aggregate anti-Ro52 positive patients in subgroups. RESULTS: 408 CTD patients were included. Anti-Ro52 antibodies were detected in 33 % of CTD patients. Anti-Ro52 antibodies were associated with ILD at CTD diagnosis (47.8% vs. 23.0%, OR 3.3 95% IC 1.4 to 8.0, p = 0.008), even after adjusting for the presence of anti-Ro60 antibodies, especially in patients with antisynthetase syndrome, primary Sjögren syndrome and systemic sclerosis. Micro- or macroangiopathy was more frequent in anti-Ro52 positive CTD patients (18.6% vs. 9.7%, p = 0.02) and CTD patients with anti-Ro52 antibodies experienced more frequent relapses and required more immunosuppressive drugs. Clusters 4 and 5 identified anti-Ro52 positive CTD patients with severe ILD and with clinical features of systemic sclerosis or antisynthetase syndrome respectively. CONCLUSIONS: We found that anti-Ro52 antibodies were independently associated with ILD in CTD patients irrespective of CTD type. Anti-Ro52 antibodies could be associated with severity and a more relapsing disease course in CTD patients.


Assuntos
Doenças do Tecido Conjuntivo , Miosite , Adulto , Autoanticorpos , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/epidemiologia , Humanos , Miosite/complicações , Miosite/epidemiologia , Estudos Retrospectivos , Ribonucleoproteínas
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