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1.
Clin Exp Rheumatol ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31573481

RESUMO

OBJECTIVES: To investigate serum levels of a panel of angiogenic inducers (VEGF, FGF-2, Angiopoietin 1, -2, soluble VCAM-1) and inhibitors (angiostatin, endostatin, pentraxin-3) in patients with giant cell arteritis (GCA) and Takayasu's arteritis (TAK), in order to gain further insights into the molecular mechanisms driving angiogenesis dysregulation in large-vessel vasculitis (LVV). METHODS: Sera were obtained from 33 TAK patients and 14 GCA patients and from two groups of age-matched normal controls (NC). Disease activity was assessed using 18F-FDG PET/CT and clinical indices including NIH/Kerr criteria and ITAS. Angiogenic and anti-angiogenic factor serum levels were evaluated using commercial ELISA kits. Pentraxin 3 (PTX3) serum levels were evaluated by non-commercial ELISA, as already described. RESULTS: Among the angiogenic factors, only VEGF serum levels were significantly higher in TAK patients compared to NC. No difference was found between angiogenic factor levels in GCA patients compared to those detected in NC. Anti-angiogenic factor (Angiostatin, Endostatin, PTX3) serum levels were significantly higher in both GCA and TAK patients compared to NC. Significant associations were observed between VEGF and PTX3 levels and disease activity evaluated using PET scan and clinical indices. Cluster analysis based on PET scan scores in TAK patients showed significant ordered differences in VEGF and angiostatin serum levels. Indeed, we noted a progressive increase of VEGF and angiostatin from NC to the cluster including patients with the highest and more diffuse scan positivity. CONCLUSIONS: Our overall results demonstrate a circulating molecular profile characterised by a prevailing expression of anti-angiogenic soluble factors.

2.
J Rheumatol ; 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092713

RESUMO

OBJECTIVE: Neutrophil extracellular traps (NET) expose modified antigens for autoantibodies in vasculitis. Little is known about levels and removal pathways of NET in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN). We determined circulating levels and defined NET removal in large subsets of patients with incident SLE (iSLE), some of whom had new-onset nephritis. METHODS: Serum levels of NET (ELISA), DNase1/DNase1L3 (ELISA), and DNase activity (functional assay) were determined in 216 patients with iSLE [103 had incident LN (iLN)], in 50 patients with other primary glomerulonephritis, and in healthy controls. Ex vivo NET production by neutrophils purified from a random selection of patients was quantified as elastase/DNA release and by immunofluorescence techniques. RESULTS: Serum NET levels were very high in iSLE/iLN compared to all groups of controls and correlated with anti-dsDNA, C3-C4, and proteinuria; iLN had the highest levels. DNase activity was decreased in iLN compared to SLE (20% had one-half DNase activity) despite similar serum levels of DNase1/DNase1L3. In these cases, pretreatment of serum with protein A restored DNase efficiency; 1 patient was homozygous for a c.289_290delAC variant of DNASE1L3. Ex vivo NET production by neutrophils purified from LN, SLE, and normal controls was similar in all cases. CONCLUSION: Patients with iLN have increased circulating NET and reduced DNase activity, the latter being explained by the presence of inhibitory substances in circulation and/or by rare DNase1L3 mutations. Accumulation of NET derives from a multifactorial mechanism, and is associated and may contribute to disease severity in SLE, in particular to renal lesions. (Clinical trial registration: The Zeus study was registered at ClinicalTrials.gov, study number NCT02403115).

3.
Autoimmun Rev ; 18(2): 164-176, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30572134

RESUMO

Pregnancy requires a special management in women with inflammatory rheumatic diseases (RDs), with the aim of controlling maternal disease activity and avoiding fetal complications. Despite the heterogeneous course of RDs during pregnancy, their impact on pregnancy largely relates to the extent of active inflammation at the time of conception. Therefore, accurate evaluation of disease activity is crucial for the best management of pregnant patients. Nevertheless, there are limitations in using conventional measures of disease activity in pregnancy, as some items included in these instruments can be biased by symptoms or by physiological changes related to pregnancy and the pregnancy itself may influence laboratory parameters used to assess disease activity. This article aims to summarize the current literature about the available instruments to measure disease activity during pregnancy in RDs. Systemic lupus erythematosus is the only disease with instruments that have been modified to account for several adaptations which might interfere with the attribution of signs or symptoms to disease activity during pregnancy. No modified-pregnancy indices exist for women affected by other RDs, but standard indices have been applied to pregnant patients. The current body of knowledge shows that the physiologic changes that occur during pregnancy need to be either adapted from existing instruments or developed to improve the management of pregnant women with RDs. Standardized instruments to assess disease activity during pregnancy would be helpful not only for clinical practice but also for research purposes.


Assuntos
Complicações na Gravidez/fisiopatologia , Doenças Reumáticas/fisiopatologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/patologia , Doenças Reumáticas/patologia
4.
Joint Bone Spine ; 86(4): 475-481, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30579917

RESUMO

OBJECTIVE: The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age. METHODS: We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18-55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149). RESULTS: At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A "Disease Knowledge Index" (DKI) was created to investigate the degree of patients' information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning. CONCLUSION: Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30424972

RESUMO

OBJECTIVE: To evaluate aortic diameter and predictors of aortic dilatation using 18FDG-PET/CT in a longitudinally followed cohort of patients with large vessel vasculitis (LVV) compared with controls. METHODS: All consecutive patients with LVV who underwent at least 2 PET/CT scans between January 2008 and May 2015 were included. The first and last PET/CT study was evaluated by a radiologist and a nuclear medicine physician. Diameter and FDG uptake of the aorta was measured at 4 different levels: ascending, descending thoracic, suprarenal and infrarenal abdominal aorta. Twenty-nine age- and sex-matched patients with lymphoma who underwent at least 2 PET/CT scans in the same time interval were selected as controls. RESULTS: 93 patients with LVV were included in the study. In the time interval between first and last PET/CT study (median time 31 months), the diameter of the ascending, descending thoracic and suprarenal abdominal aorta significantly increased in LVV patients but not in controls. At last PET/CT, patients with LVV compared with controls had higher diameter of ascending [35.41 (5.54) vs 32.97 (4.11) mm, p = 0.029], descending thoracic [28.42 (4.82) vs 25.72 (3.55) mm, p = 0.007] and suprarenal abdominal aorta, mean [25.34 (7.01) vs 22.16 (3.26) mm, p = 0.005] and more frequently had aortic dilatation [19% vs 3%, p = 0.023]. Significant predictors of aortic dilatation were male sex [OR 7.27, p = 0.001] and, only for GCA, hypertension [OR 6.30, p = 0.031]. Finally, GCA patients with aortic FDG uptake grade 3 at first PET/CT, compared to those with aortic FDG uptake ≤2, had significantly higher aortic diameter. CONCLUSIONS: Patients with LVV are at increased risk of aortic dilatation compared with age- and sex-matched controls. Significant predictors of aortic dilatation are male sex and, only for GCA, hypertension. GCA patients with aortic FDG uptake grade 3 are at increased risk of aortic dilatation.

6.
Clin Exp Rheumatol ; 36 Suppl 111(2): 99-106, 2018 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29799393

RESUMO

OBJECTIVES: To compare patterns of vascular involvement using 18F-fluorodeoxyglucose-positron emission tomography computed tomography (FDG PET/CT) in patients with giant cell arteritis (GCA) and Takayasu's arteritis (TAK). METHODS: A total of 130 consecutive 18F-FDG PET/CT scans performed during the disease course for evaluating disease activity in 15 GCA and 13 TAK patients were retrospectively examined by two nuclear physicians blinded to clinical data. Standardised uptake values (SUVmax) in 14 vascular districts including all the aortic segments and the main tributaries were measured. The average SUVmax value for each vascular district was also calculated. Principal component analysis (PCA) and agglomerative hierarchical cluster analysis (CA) were used to explore distribution patterns of vascular FDG uptake. RESULTS: The aortic segments showed the highest SUV max values among the different districts in both GCA and TAK. SUV max values measured in the different districts were significantly higher in GCA compared to TAK, except for the axillary arteries. Regarding thoracic and abdominal aorta, ascending aorta and aortic arch had the highest correlation in both vasculitis (p<0.0001). CA confirmed that carotid, axillary, subclavian, iliac and femoral arteries clustered with their contralateral counterpart in both vasculitis. The 3 components of thoracic aorta clustered with abdominal aorta in TAK, while aortic arch clustered only with ascending aorta, and descending and abdominal aorta grouped together with iliac and femoral arteries in GCA. PCA analysis identified 3 different components for TAK and GCA explaining 72% and 71% of the total variance respectively in these two vasculitis. Confirming CA, a component including the entire aortic district was identified in TAK, but not in GCA. Similar results in PCA using averaged data were observed. CONCLUSIONS: Strong similarities, but also a subtle skewing in terms of distribution patterns of arterial involvement assessed by SUVmax values were observed between GCA and TAK.


Assuntos
Aortite/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Arterite de Células Gigantes/diagnóstico por imagem , Arterite de Takayasu/diagnóstico por imagem , Adulto , Idoso , Aorta Abdominal/diagnóstico por imagem , Aorta Torácica/diagnóstico por imagem , Aortite/etiologia , Artéria Axilar/diagnóstico por imagem , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/etiologia , Análise por Conglomerados , Feminino , Artéria Femoral/diagnóstico por imagem , Fluordesoxiglucose F18 , Humanos , Artéria Ilíaca/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Análise de Componente Principal , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Artéria Subclávia/diagnóstico por imagem
8.
J Autoimmun ; 86: 1-8, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28935492

RESUMO

OBJECTIVE: To investigate efficacy, safety and survival of belimumab and to identify predictors of drug response and drug discontinuation in patients with active SLE in clinical practice. PATIENTS AND METHODS: Data of SLE patients, treated with belimumab, from 11 Italian prospective cohorts were analyzed. SLEDAI-2K, anti-dsDNA, C3, C4, prednisone daily dose, DAS-28, 24-h proteinuria, CLASIa (Cutaneous LE Disease Area and Severity Index Activity) were recorded at baseline and every 6 months. SLE Responder Index-4 (SRI-4) was calculated at 12 and 24 months. Demographic and clinical features and comorbidities were included in the univariate and multivariate analysis. Adverse events were recorded at each visit. Statistics was performed using the SPSS software. RESULTS: We studied 188 SLE patients, mean follow-up 17.5 ± 10.6 months. The most frequent manifestations, which required the use of belimumab, were polyarthritis (45.2%) and skin rashes (25.5%). SRI-4 was achieved by 77.0% and 68.7% of patients at 12 and 24-months. Independent predictors of 12-month response were SLEDAI-2K ≥ 10 (OR 40.46, p = 0.001) and polyarthritis (OR 12.64, p = 0.001) and of 24-month response were SLEDAI-2K ≥ 10 (OR 15.97, p = 0.008), polyarthritis (OR 32.36, p = 0.006), and prednisone ≥7.5 mg/day (OR 9.94, p = 0.026). We observed a low rate of severe adverse events. Fifty-eight patients (30.8%) discontinued belimumab after a mean follow-up of 10.4 ± 7.5 months. The drug survival was 86.9%, 76.9%, 69.4%, 67.1%, and 61.9% at 6, 12, 18, 24, and 30 months, respectively. No factors associated with drug discontinuation were found. CONCLUSION: Belimumab is effective and safe when used in clinical practice setting.

9.
Q J Nucl Med Mol Imaging ; 62(1): 34-39, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29166756

RESUMO

Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are large vessel vasculitis (LVV) primarily affecting the aorta and its major branches, mainly differentiated by the onset age (>50 years GCA and <40 years TA). In addition, temporal artery involvement and polymyalgia rheumatica are typical features of GCA, but not TA. Imaging techniques are required to secure the diagnosis of large-vessel vasculitides, and to monitor the disease course. Both morphological and metabolic imaging are involved. Morphological imaging is represented mainly by computerized tomography (CT), CT angiography, magnetic resonance (MR), MR angiography, color-Doppler sonography (CDS) and high-resolution CDS. Metabolic aspects of inflammatory process in LVV can be well studied by positron emission tomography/computed tomography with [18F]deoxyglucose ([18F]FDG PET/CT). It has an important increasing role in diagnosis, extent assessment and disease activity and therapy response evaluation. In the near future the concomitant development of increasingly powerful PET/CT scanners, of new radiopharmaceuticals more specific for inflammation, and of new PET/MRI hybrid scanners probably will lead to a further new step forward in the diagnosis and clinical management of LVV.


Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Diagnóstico por Imagem/métodos , Vasculite/diagnóstico por imagem , Vasos Sanguíneos/patologia , Fluordesoxiglucose F18 , Humanos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Vasculite/patologia
10.
Clin Rev Allergy Immunol ; 54(2): 244-260, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28895041

RESUMO

Despite the progress in the last years on the field of vasculitides, there are several unmet needs regarding classification, disease activity assessment, predictors of flares and complications, and type of treatment for the different forms. The 1990 American College of Rheumatology (ACR) classification criteria currently used to define giant cell arteritis and Takayasu arteritis were designed to discriminate between different types of vasculitides but not to differentiate vasculitis from other disorders. Recently, efforts have been made to overcome the shortcomings of the ACR criteria. The lack of an accepted definition of disease activity in large-vessel vasculitides presents a major challenge in creating useful and valid outcome tools for the assessment of disease course. Identification of predictors of flares can aid in optimizing therapeutic strategies, minimizing disease flares, and reducing treatment-related side effects. It is furthermore important to recognize and characterize the risk factor that might predict the manifestations associated with poor outcome and prognosis. Two RCTs have evidenced the efficacy of tocilizumab in addition to glucocorticoids (GCs) in the treatment of giant cell arteritis (GCA). However, the role of tocilizumab or other biological agents without GCs needs to be investigated. Recent observational studies have suggested that rituximab is also effective in patients with eosinophilic granulomatosis with polyangiitis and in antineutrophil cytoplasmic antibodies (ANCA)-negative patients with granulomatosis with polyangiitis and microscopic polyangiitis. Rituximab or anti-TNF alfa may represent a possible alternative therapy in case of refractory or difficult to treat polyarteritis nodosa (PAN) patients. The new International Criteria for Behçet's Disease have shown a better sensitivity and a better accuracy compared to the older International Study Group on Behçet's Disease criteria. The EULAR recommendations for the management of Behçet's disease (BD) have been recently updated. However, the treatment of refractory disease is still a real challenge.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Rituximab/uso terapêutico , Vasculite/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Progressão da Doença , Glucocorticoides/uso terapêutico , Humanos , Avaliação de Resultados (Cuidados de Saúde) , Fatores de Risco , Fator de Necrose Tumoral alfa/metabolismo , Vasculite/tratamento farmacológico
11.
Artigo em Inglês | MEDLINE | ID: mdl-28977672

RESUMO

Objectives: To assess the efficacy and safety of rituximab (RTX) in patients with Takayasu arteritis (TAK). Methods: We conducted a retrospective study on seven TAK patients treated with RTX. Six of the seven patients had a disease refractory to high dose glucocorticoids and conventional immunosuppressive and/or biologic agents. One newly diagnosed, treatment-naïve TAK patient refused glucocorticoids and received RTX alone. Clinical evaluation, laboratory tests and imaging modalities (CT or MR-angiography, and 18 F-fluorodeoxyglucose PET/CT) were performed at first RTX administration and every 6 months thereafter. Disease activity was assessed using the Kerr index. We also performed a literature review using PubMed, Ovid MEDLINE and Cochrane library. Results: Seven patients (6 females) were included in the study. Mean ( s . d .) age was 32.4 (17.3) years. At first RTX administration, all patients had active disease according to the Kerr index (⩾2), and had also evidence of active disease at PET/CT. Despite RTX treatment, four of the seven patients had evidence of persistent disease activity and/or radiographic disease progression during follow-up. Three out of seven patients in whom RTX was employed as rescue therapy achieved complete remission. In the literature review, we identified five papers describing nine patients treated with RTX with good results in eight cases, but short follow-up. Conclusion: Our data do not support a role for RTX as first line biologic therapy in TAK patients, but it may have a role in some patients as second or third line biologic therapy.

12.
Clin Exp Rheumatol ; 35 Suppl 103(1): 102-110, 2017 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28466804

RESUMO

OBJECTIVES: To investigate serum levels of IL- 6 and soluble IL-6 receptor (sIL-6R) in patients with large-vessel vasculitis and their relationship with disease activity. METHODS: Sera were obtained from 33 Takayasu's arteritis (TAK) patients and 14 giant cell arteritis (GCA) patients, and from 60 age-matched normal controls (NCs). Disease activity was assessed using 18F-FDG PET/CT and clinical indices including NIH/Kerr criteria and ITAS. Among TAK patients with active disease at baseline, clinical records and serum samples from 11 TAK patients were available for the longitudinal study. IL-6 and sIL-6R serum levels were evaluated using commercial ELISA kits. RESULTS: IL-6 and sIL-6R serum levels were significantly higher in both GCA and TAK patients compared to NCs. IL-6 levels in TAK patients were significantly increased irrespective of disease phase, while a significant increase in sIL-6R concentrations was only found in TAK patients with active disease. Conversely, in GCA, IL-6 levels were significantly raised only in patients with active diseases, whereas sIL-6R levels appeared to be significantly higher irrespective of disease activity. Longitudinal analysis showed that levels of sIL-6R in TAK patients were significantly higher only at baseline, compared to NCs, whereas IL-6 levels were found to be significantly increased at each follow-up time point. CONCLUSIONS: These overall results might suggest a role for sIL-6R as a potential biomarker for disease activity in TAK patients, whereas in GCA, modifications of IL-6 might better identify patients with active disease.


Assuntos
Arterite de Células Gigantes/sangue , Interleucina-6/sangue , Receptores de Interleucina-6/sangue , Arterite de Takayasu/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Análise por Conglomerados , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Fluordesoxiglucose F18/administração & dosagem , Arterite de Células Gigantes/diagnóstico por imagem , Arterite de Células Gigantes/imunologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Prognóstico , Compostos Radiofarmacêuticos/administração & dosagem , Índice de Gravidade de Doença , Arterite de Takayasu/diagnóstico por imagem , Arterite de Takayasu/imunologia , Fatores de Tempo , Regulação para Cima
13.
Expert Rev Clin Immunol ; 12(10): 1037-45, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27079756

RESUMO

INTRODUCTION: Polymyalgia rheumatica is one of the most common rheumatic inflammatory disorders in people older than 50 years characterized by aching and prolonged morning stiffness in the shoulder and pelvic girdle and neck.. AREAS COVERED: In this review, we will focus on recent advances on the diagnosis and management of PMR. Expert commentary: Controversy exist whether PMR represent a single entity disease or is an umbrella term that comprises a clinical presentation common to a range of related conditions (polymyalgic syndrome). To date there are no specific diagnostic tests, and the diagnosis remains clinical, although ultrasonography, positron emission tomography scan and the recent ACR/EULAR classification criteria may help to confirm the clinical diagnosis. A step-wise process for the diagnosis of PMR has been proposed. Low-dose steroids are highly effective in the majority of patients and remain the mainstay of treatment, but relapses occur in about 50% of patients and glucocorticoid related adverse event are common. The steroid sparing effects of the immunosuppressive treatment evaluated to date are unclear.


Assuntos
Imunoterapia/métodos , Polimialgia Reumática/diagnóstico , Tomografia por Emissão de Pósitrons , Ultrassonografia , Algoritmos , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/metabolismo , Diagnóstico Diferencial , Humanos , Interleucina-6/imunologia , Polimialgia Reumática/imunologia , Polimialgia Reumática/terapia , Esteroides/uso terapêutico
14.
Ann Rheum Dis ; 75(8): 1527-33, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26342092

RESUMO

OBJECTIVES: There is increasing evidence that microRNAs (miRNAs) are deregulated in autoimmune and cardiovascular diseases. The present study aimed to identify if miRNAs are deregulated in giant cell arteritis (GCA), a vasculitis affecting large-sized and medium-sized arteries, and to determine if miRNA levels might allow to discriminate between patients with GCA and those without. METHODS: 58 patients who had temporal artery biopsy (TAB) for suspected GCA were included in the study and divided into three groups: patients with TAB-positive GCA showing a transmural inflammation (n=27), patients with TAB-negative GCA (n=8) and TAB-negative non-GCA patients with a final diagnosis different from GCA (n=23). To identify candidate miRNAs deregulated in GCA, we profiled the expression of 1209 miRNAs in inflamed TABs and normal TABs. Selected miRNAs were then validated by real-time PCRs and in situ hybridisation (ISH). RESULTS: MiR-146b-5p, -146a, -155, -150, -21 and -299-5p were significantly more expressed in inflamed TABs from patients with GCA. miRNAs were mainly deregulated at the tissue level because peripheral blood mononuclear cells and polymorphonuclear cells from the three groups of patients and age-matched healthy controls had similar levels of miRNAs. ISH showed that miR-21 was mainly expressed by cells in the medial and intimal layers of inflamed TABs. Patients with TAB-negative GCA had a miRNA profile similar to TAB-negative non-GCA patients. CONCLUSIONS: MiR-146b-5p, -146a, -21, -150, -155, -299-5p are overexpressed in the presence of inflammation in TABs from patients with GCA.


Assuntos
Arterite de Células Gigantes/genética , MicroRNAs/genética , Artérias Temporais/patologia , Remodelação Vascular/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/patologia , Glucocorticoides/farmacologia , Humanos , Hibridização In Situ , Masculino , MicroRNAs/metabolismo , Artérias Temporais/metabolismo , Transcriptoma
15.
Clin Exp Rheumatol ; 33(6 Suppl 94): S60-6, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26394376

RESUMO

OBJECTIVES: Behçet's disease is a multifactorial vasculitis that shows its highest prevalence in geographical areas historically involved in the Silk Road, suggesting that it might have originated somewhere along these ancient trade routes. This study aims to provide a first clue towards genetic evidence for this hypothesis by testing it via an anthropological evolutionary genetics approach. METHODS: Behçet's disease variation at ancestry informative mitochondrial DNA control region and haplogroup diagnostic sites was characterised in 185 disease subjects of Italian descent and set into the Eurasian mitochondrial landscape by comparison with nearly 9,000 sequences representative of diversity observable in Italy and along the main Silk Road routes. RESULTS: Dissection of the actual genetic ancestry of disease individuals by means of population structure, spatial autocorrelation and haplogroup analyses revealed their closer relationships with some Middle Eastern and Central Asian groups settled along the Silk Road than with healthy Italians. CONCLUSIONS: These findings support the hypothesis that the Behçet's disease genetic risk has migrated to western Eurasia in parallel with ancestry components typical of Silk Road-related groups. This provided new insights that are useful to improve the understanding of disease origins and diffusion, as well as to inform future association studies aimed at properly accounting for the actual genetic ancestry of the examined Behçet's disease samples in order to minimise the detection of spurious associations and to improve the identification of genetic variants with actual clinical relevance.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Síndrome de Behçet/genética , Comércio , DNA Mitocondrial/genética , Grupo com Ancestrais do Continente Europeu/genética , Evolução Molecular , Marcadores Genéticos , Seda , Ásia/etnologia , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiologia , Análise por Conglomerados , Predisposição Genética para Doença , Genética Populacional , Haplótipos , Humanos , Itália/epidemiologia , Linhagem , Fenótipo , Fatores de Risco , Análise de Sequência de DNA , Seda/economia , Topografia Médica
16.
Presse Med ; 44(6 Pt 2): e231-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26024760

RESUMO

Biological agents represent a valid therapeutic option in patients with severe and/or relapsing vasculitis. Over the last years, some of these agents have become an established therapy (such as RTX in AAV or IFX for ocular BD), and some appear to hold promise to become so. In addition, there are a number of drugs in the pipeline that may contribute to further improve the prognosis of vasculitis. As the range of medications available for vasculitis widens, the need will also increase to define the best treatment schemes as well as to identify those patients that may benefit most from biological agents.


Assuntos
Produtos Biológicos/uso terapêutico , Vasculite/tratamento farmacológico , Abatacepte , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Etanercepte , Previsões , Arterite de Células Gigantes/tratamento farmacológico , Humanos , Imunoconjugados/uso terapêutico , Imunoglobulina G/uso terapêutico , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores do Fator de Necrose Tumoral/uso terapêutico , Arterite de Takayasu/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
17.
Am J Hum Genet ; 96(4): 565-80, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25817017

RESUMO

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRß1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRß1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.


Assuntos
Genes MHC da Classe II/genética , Arterite de Células Gigantes/genética , Herança Multifatorial/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Genótipo , Humanos , Análise Multivariada , Razão de Chances
18.
Curr Rheumatol Rep ; 17(2): 7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25618573

RESUMO

Antiphospholipid antibody-positive patients can develop bleeding due to capillaritis, microthrombosis, antiprothrombin antibodies, thrombocytopenia, and/or excessive antithrombotic therapy. Clinical characteristics of patients, e.g., renal impairment, elderly, or concomitant medications, are closely related to the risk of bleeding. The management of bleeding in antiphospholipid antibody (aPL)-positive patients is challenging due to the baseline increased risk of thrombosis. If anticoagulation is stopped, it should be restarted as soon as possible once the acute bleeding is controlled; the continuation of anticoagulation despite active bleeding may be required in selected cases. High-dose corticosteroid is the mainstay treatment for diffuse alveolar hemorrhage, lupus anticoagulant-hypoprothrombinemia syndrome, and severe thrombocytopenia; immunosuppressive drugs are also required to improve the long-term outcomes. Hydrocortisone is critical in adrenal hemorrhage patients due to concomitant adrenal insufficiency; despite bleeding, anticoagulation should be maintained as much as possible. Plasma exchange should be considered in catastrophic antiphospholipid syndrome patients with concurrent bleeding. This article will review the causes of bleeding in aPL-positive patients as well as the management strategies.


Assuntos
Síndrome Antifosfolipídica/complicações , Hemorragia/etiologia , Doenças das Glândulas Suprarrenais/diagnóstico , Doenças das Glândulas Suprarrenais/tratamento farmacológico , Doenças das Glândulas Suprarrenais/etiologia , Hemorragia/diagnóstico , Hemorragia/tratamento farmacológico , Humanos , Hipoprotrombinemias/diagnóstico , Hipoprotrombinemias/tratamento farmacológico , Hipoprotrombinemias/etiologia , Pneumopatias/diagnóstico , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Alvéolos Pulmonares
19.
Semin Arthritis Rheum ; 44(4): 472-5, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25260843

RESUMO

OBJECTIVES: To describe the response to IL-6 blockade [tocilizumab (TCZ)] in three patients affected by highly refractory neuro-Behçet disease (NBD). METHODS: Three patients who had failed synthetic immunosuppressants and TNF-α antagonists combined with glucocorticoids received TCZ after obtaining their informed consent. Two patients underwent TCZ infusions at 8mg/kg every 4 weeks for a mean period of 24 months, while in one patient, the frequency of TCZ infusions was increased to every other week after 21 months due to a disease flare. Concomitant therapy with synthetic agents and low-to-medium dose glucocorticoids was continued. Clinical and imaging findings were assessed before and after the onset of TCZ therapy. RESULTS: In all our patients, a very short time lag between the onset of treatment with TCZ and the clinical response was observed. A partial response occurred in two patients and a nearly complete response in one. Some loss of efficacy occurred after 18 months in one patient, but there was again a significant improvement when the interval between the infusions was shortened. TCZ was overall well tolerated and no serious adverse events occurred. In two patients, the prednisone dose could successfully be tapered to about 20mg/day, while in another patient glucocorticoids could safely be withdrawn. Brain MRI remained virtually unchanged in all patients. CONCLUSIONS: Although TCZ has not yet been included among the medications recommended for the treatment of NBD, our data suggest that it may be considered for patients with refractory NBD.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Índice de Gravidade de Doença , Adulto , Síndrome de Behçet/patologia , Encéfalo/patologia , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Resultado do Tratamento
20.
Am J Surg Pathol ; 38(10): 1360-70, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25216320

RESUMO

We reviewed 888 temporal artery biopsies (TAB) performed in 871 patients in a single institution from January 1986 to December 2013. Forty-four biopsies (4.9%) were inadequate, 490 (55.2%) were devoid of inflammation and were considered negative, and 354 (39.9%) showed inflammation and were considered positive. On the basis of the localization of the inflammation, positive TABs were further classified into 4 categories: small vessel vasculitis (SVV), in which inflammation was limited to small periadventitial vessels devoid of muscular coat, with sparing of the temporal artery (32 cases, 9% of the positive biopsies); vasa vasorum vasculitis (VVV), in which inflammation was limited to the adventitial vasa vasorum (23 cases, 6.5% of the positive biopsies); inflammation limited to adventitia (ILA), in which inflammation extended from a strictly perivascular localization to the surrounding adventitia, without medial involvement (25 cases, 7% of the positive biopsies); and transmural inflammation (TMI), in which inflammation crossed the external elastic lamina and extended to the media (274 cases, 77.5% of the positive biopsies). In TMI, inflammation was generally more prominent between media and adventitia and mostly consisted of T lymphocytes and macrophages, with occasionally a significant number of plasma cells. Numerous eosinophils or neutrophils (with or without leucocytoclasia and suppurative necrosis), fibrinoid necrosis (limited to small branches of the temporal artery), and acute thrombosis were unusual, being present in 8%, 1.8%, 0.7%, and 9.5% of our biopsies with TMI, respectively. Giant cells, laminar necrosis, and calcifications prevailed along the internal elastic lamina and were present in 74.8%, 25.2%, and 20% of the biopsies with TMI, respectively. Among the 322 patients with positive TAB on whom we obtained clinical information, 317 had giant cell arteritis and 5 had a different disease: 3 (with SVV at histology) had ANCA-associated vasculitis, 1 (with SVV with amyloid deposits) had primary systemic amyloidosis, and 1 (with TMI limited to a small branch) had polyarteritis nodosa. In none of these cases the biopsy showed fibrinoid necrosis or significant numbers of eosinophils or neutrophils. Considering the 317 patients with giant cell arteritis, those with SVV and VVV compared with those with TMI had a significantly lower frequency of cranial manifestation (including headache, jaw claudication, and abnormalities of temporal arteries), lower serum levels of acute-phase reactants, and a reduced frequency of prednisone therapy at the time of TAB, of the "halo sign" at color duplex sonography of temporal arteries, and of systemic symptoms (for VVV). Polymyalgia rheumatica and blindness were equally represented in all patients groups, whereas there was a higher frequency of male sex and peripheral arthritis in patients with SVV. Patients with ILA were more similar to those with TMI, having a lower frequency of headache, of abnormalities of temporal arteries, and of a positive "halo sign" at color duplex sonography of temporal arteries. In conclusion, the histologic spectrum of inflammatory lesions that can be found in TAB is broad, and the differences have clinical implications.


Assuntos
Arterite de Células Gigantes/patologia , Artérias Temporais/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Arterite de Células Gigantes/imunologia , Humanos , Itália , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Artérias Temporais/imunologia
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