Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 67
Filtrar
1.
Acta Neuropathol Commun ; 12(1): 64, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38650010

RESUMO

Glioblastoma (GBM) remains an untreatable malignant tumor with poor patient outcomes, characterized by palisading necrosis and microvascular proliferation. While single-cell technology made it possible to characterize different lineage of glioma cells into neural progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like) and mesenchymal like (MES-like) states, it does not capture the spatial localization of these tumor cell states. Spatial transcriptomics empowers the study of the spatial organization of different cell types and tumor cell states and allows for the selection of regions of interest to investigate region-specific and cell-type-specific pathways. Here, we obtained paired 10x Chromium single-nuclei RNA-sequencing (snRNA-seq) and 10x Visium spatial transcriptomics data from three GBM patients to interrogate the GBM microenvironment. Integration of the snRNA-seq and spatial transcriptomics data reveals patterns of segregation of tumor cell states. For instance, OPC-like tumor and NPC-like tumor significantly segregate in two of the three samples. Our differentially expressed gene and pathway analyses uncovered significant pathways in functionally relevant niches. Specifically, perinecrotic regions were more immunosuppressive than the endogenous GBM microenvironment, and perivascular regions were more pro-inflammatory. Our gradient analysis suggests that OPC-like tumor cells tend to reside in areas closer to the tumor vasculature compared to tumor necrosis, which may reflect increased oxygen requirements for OPC-like cells. In summary, we characterized the localization of cell types and tumor cell states, the gene expression patterns, and pathways in different niches within the GBM microenvironment. Our results provide further evidence of the segregation of tumor cell states and highlight the immunosuppressive nature of the necrotic and perinecrotic niches in GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Transcriptoma , Microambiente Tumoral , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
2.
Arthritis Res Ther ; 26(1): 74, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38509595

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFß1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients. METHODS: Fourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients' informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFß1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFß1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test. RESULTS: Cultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFß1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFß1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFß1 after 24 h of treatment (p < 0.05 vs. untreated cells). CONCLUSIONS: In cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFß1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.


Assuntos
Indóis , Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Humanos , Interleucina-10/metabolismo , c-Mer Tirosina Quinase/metabolismo , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Macrófagos/metabolismo , Pulmão , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/genética , Fibrose , Fenótipo , Proteínas Tirosina Quinases
3.
Brain Sci ; 14(2)2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38391718

RESUMO

Both glioblastoma (GBM) and dementia are devastating diseases with limited treatments that are usually not curative. Having clinically diagnosed dementia with an associated biopsy-proven etiology and a coexisting GBM diagnosis is a rare occurrence. The relationship between the development of neurodegenerative dementia and GBM is unclear, as there are conflicting reports in the literature. We present two cases of simultaneous biopsy-proven dementia, one with Alzheimer's disease (AD) and GBM, and one with cerebral amyloid angiopathy (CAA) and GBM. We discuss how these diseases may be associated. Whether one pathologic process begins first or develops concurrently is unknown, but certain molecular pathways of dementia and GBM appear directly related while others inversely related. Further investigations of these close molecular relationships between dementia and GBM could lead to development of improved diagnostic tools and therapeutic interventions for both diseases.

4.
CNS Oncol ; 13(1): CNS105, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-38380555

RESUMO

Atypical teratoid rhabdoid tumors (AT/RT) are rare and highly malignant CNS neoplasms primarily affecting children. Adult cases are extremely uncommon, with only approximately 92 reported. Spinal AT/RT in adults is particularly rare. Here, we present the case of a 50-year-old patient diagnosed with AT/RT of the spine. Initially, they were diagnosed and treated for a spinal ependymoma. However, after 10 years, a recurrence was detected through magnetic resonance imaging (MRI) and the tumor was reclassified as AT/RT. We discuss the significance of SMARCB1 gene mutations in diagnosing AT/RT and describe our unique treatment approach involving surgery, radiation and anti-PD1 therapy in this patient.


Atypical teratoid rhabdoid tumors (AT/RT) are rare and serious cancers that affect the brain and spine, and mostly occur in children. AT/RT are rare in adults, with only about 92 cases reported. Our article tells the story of a 50-year-old patient, who was diagnosed with a spinal tumor, initially classified as an ependymoma. Ten years later, the tumor recurred, and was found on routine surveillance imaging. After pathological examination of the recurrent tumor, it was diagnosed as AT/RT. The initial tissue was re-examined, and the original tumor was reclassified as an AT/RT. We explain why a gene called SMARCB1 is important for diagnosing AT/RT. Additionally, we share details about the treatments utilized: including surgery, radiation, and medicines that stimulate the immune system to kill cancer cells. This case highlights the challenges and treatments for this rare cancer in adults.


Assuntos
Neoplasias do Sistema Nervoso Central , Tumor Rabdoide , Teratoma , Humanos , Pessoa de Meia-Idade , Tumor Rabdoide/diagnóstico por imagem , Tumor Rabdoide/genética , Tumor Rabdoide/terapia , Proteína SMARCB1/genética , Teratoma/diagnóstico por imagem , Teratoma/genética , Teratoma/cirurgia
5.
Clin Rheumatol ; 43(2): 733-741, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38190091

RESUMO

INTRODUCTION: Juvenile Sjögren's disease (jSjD) is a rare autoimmune disease characterized by exocrine gland involvement and systemic manifestations, including small vessel vasculitis and Raynaud's phenomenon (RP). We aimed to investigate the microvascular status in jSjD patients by nailfold videocapillaroscopy (NVC) and the potential correlations with clinical and serological features. METHODS: Clinical data from thirteen consecutive jSjD patients (11 females and 2 males), with a mean age of 16 ± 4 years, diagnosed before 16 years of age (mean age at diagnosis 12 ± 3) according to the 2016 American College of Rheumatology/EULAR criteria for adult SjD, were collected including age- and sex-matched healthy controls (HCs). Clinical, laboratory, and instrumental data were collected, together with NVC examination. Non-specific and specific NVC parameters were investigated, such as capillary density, capillary dilations, giant capillaries, microhaemorrhages and abnormal shapes. Associations between NVC findings and clinical/serological features were explored and analysed using parametrical and non-parametrical tests. RESULTS: Capillary density reduction correlated significantly with articular involvement (arthralgias) (p = 0.024). Microhaemorrhages correlated with lower C3 levels (p = 0.034). No specific NVC pattern for jSjD was identified, whereas abnormal capillary shapes were significantly higher in jSjD patients than HCs (p = 0.005). NVC abnormalities were not associated with SjD-specific instrumental tests (biopsy, imaging, Schirmer's test). RP was present in 8% of jSjD patients. CONCLUSIONS: The reduction of capillary density, as well as microhaemorrhages at NVC analysis, are significantly associated with some clinical aspects like articular involvement and serum biomarkers (C3 reduction). The NVC is suggested as safe and further analysis in jSjD patients.


Assuntos
Doenças Autoimunes , Doença de Raynaud , Escleroderma Sistêmico , Síndrome de Sjogren , Masculino , Adulto , Feminino , Humanos , Criança , Adolescente , Adulto Jovem , Angioscopia Microscópica/métodos , Unhas/irrigação sanguínea , Capilares/diagnóstico por imagem , Capilares/patologia , Doenças Autoimunes/patologia , Síndrome de Sjogren/diagnóstico por imagem , Síndrome de Sjogren/patologia , Doença de Raynaud/patologia , Escleroderma Sistêmico/patologia
8.
Quant Imaging Med Surg ; 13(6): 3938-3947, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37284120

RESUMO

Background: Nailfold video capillaroscopy (NVC) is a simple, non-invasive diagnostic tool but studies with normal values for capillary density in healthy children are rare. Ethnic background seems to play a role in capillary density; however, this is not well substantiated yet. In this work, we set out to evaluate influence of ethnic background/skin pigmentation and age on capillary density reading in healthy children. Secondary aim was to investigate whether there is a significant difference in density between different fingers within the same patient. Methods: Between 2016 and 2021, healthy children from schools around AUMC were approached, by convenience sampling. In this cross-sectional study, capillaroscopic images were obtained in a one-time videocapillaroscopy (×200 magnification) addressing the capillary density (i.e., number of capillaries per linear millimetre in the distal row). This parameter was compared to age, sex, ethnicity, skin pigment grade (I-III) and between eight different fingers, excluding the thumbs. Density differences were compared by ANOVAs. Correlations between capillary density and age were calculated with Pearson correlations. Results: We investigated 145 healthy children with mean age of 11.03 years (SD 3.51). The range of capillary density was 4-11 capillaries per millimetre. We observed a lower capillary density in the 'grade II' (6.4±0.5 cap/mm, P<0.001) and 'grade III' (5.9±0.8 cap/mm, P<0.001) pigmented-classified groups compared to the 'grade I' group (7.0±0.7 cap/mm). We did not find a significant correlation between age and density in the overall group. The fifth fingers on both sides had a significantly lower density compared to the other fingers. Conclusions: Healthy children <18 years with higher degree of skin pigmentation show a significantly lower nailfold capillary density. In subjects with an African/Afro-Caribbean and North-African/Middle-Eastern ethnicity, a significantly lower mean capillary density was observed compared to subjects with the Caucasian ethnicity (P<0.001, and P<0.05, respectively. There were no significant differences between other ethnicities. No correlation was found between age and capillary density. The fifth fingers on both hands displayed lower capillary density compared to the other fingers. This needs to be taken into account when describing lower density in paediatric patients with connective tissue diseases.

9.
Diagnostics (Basel) ; 13(9)2023 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-37174957

RESUMO

OBJECTIVE: To investigate in an unselected, systemic sclerosis (SSc) cohort if baseline laser speckle contrast analysis (LASCA) peripheral blood perfusion (PBP) measurements differ between 'early' SSc (without skin involvement, or 'limited' SSc-LSSc) and 'clinically overt' SSc (with skin involvement, limited cutaneous SSc-LcSSc and diffuse cutaneous SSc-DcSSc) in routine setting. METHODS: A group of twenty consecutive 'early' SSc patients and forty consecutive 'clinically overt' SSc patients (twenty LcSSc and twenty DcSSc) underwent clinical and LASCA examinations (to assess the peripheral blood perfusion [PBP] of both hands volar). RESULTS: No statistically significant difference in adjusted PBP was found in the 'early' versus the 'clinically overt' group (p = 0.77) when adjusted for possible confounding factors (e.g., vasoactive medication, active smoking, history of DTL and disease duration). A wide variability was noted when observing the individual datapoints of each subset. CONCLUSION: This study with an unselected SSc population in daily routine, non-research setting, showed there was no difference in adjusted PBP at baseline between 'early' SSc and 'clinically overt' SSc when corrected for possible confounding factors. Interestingly a wide variation of individual datapoints were observed in each subset, which emphasizes the heterogeneity of SSc.

10.
Arthritis Rheumatol ; 75(8): 1434-1444, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36787101

RESUMO

OBJECTIVE: We undertook this study to explore the efficacy, safety, and tolerability of ziritaxestat, a selective autotaxin inhibitor, in patients with early diffuse cutaneous systemic sclerosis (dcSSc). METHODS: NOVESA was a 24-week, multicenter, phase IIa, double-blind, placebo-controlled study. Adults with dcSSc were randomized to oral ziritaxestat 600 mg once daily or matching placebo. The primary efficacy end point was change from baseline in modified Rodnan skin score (MRSS) at week 24. Secondary end points assessed safety and tolerability; other end points included assessment of skin and blood biomarkers. Patients in NOVESA could enter a 104-week open-label extension (OLE). RESULTS: Patients were randomized to ziritaxestat (n = 21) or placebo (n = 12). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (-8.9 versus -6.0 units, respectively; P = 0.0411). Placebo patients switching to ziritaxestat in the OLE showed similar reductions in MRSS to those observed for ziritaxestat patients in the parent study. Ziritaxestat was well tolerated; the most frequent treatment-related treatment-emergent adverse events were headache and diarrhea. Circulating lysophosphatidic acid (LPA) C18:2 was significantly reduced, demonstrating ziritaxestat target engagement, and levels of fibrosis biomarkers were reduced in the blood. No differentially expressed genes were identified in skin biopsies. Significant changes in 109 genes were identified in blood samples. CONCLUSION: Ziritaxestat resulted in significantly greater reduction in MRSS at week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is provided in the Supplementary Material, available on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42477.


Assuntos
Esclerodermia Difusa , Adulto , Humanos , Esclerodermia Difusa/patologia , Resultado do Tratamento , Pele/patologia , Biópsia , Método Duplo-Cego , Fibrose
11.
J Hand Surg Glob Online ; 4(6): 394-398, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36425372

RESUMO

Purpose: Wide-awake local anesthesia with no tourniquet has dramatically changed hand surgery practice. Using lidocaine with epinephrine and no tourniquet has allowed many procedures to be moved from the main operating room to an in-office procedure room. Previous studies have shown that using local anesthesia is safe and cost effective, with high patient satisfaction. This study evaluated patient satisfaction and complications for the first 1,011 elective hand surgeries performed using wide-awake anesthesia in an in-office procedure room. Methods: The first 1,011 patients who underwent elective hand surgery in an in-office procedure room were surveyed regarding their satisfaction. The patients were monitored for postoperative complications. Patient survey results and complications were logged in a database and analyzed. Results: Single-digit trigger finger release was the most common procedure performed (n = 582), followed by mass excision (n = 158), multiple-digit trigger finger releases (n = 109), and carpal tunnel release (n = 41). There were 43 (4.3%) superficial skin infections, with the majority seen in single-digit trigger finger releases (n = 27). There were no deep wound infections. All infections were managed nonsurgically with oral antibiotics and local wound care. Ninety-nine percent of the patients rated the in-office procedure room experience as the same as or better than a dental visit, would recommend wide-awake anesthesia to a friend or family member, and would undergo the procedure again. Using "lean and green" hand packs saved our institution more than $65,000 and saved 18.4 tons of waste during this study period. Conclusions: Surgical procedures performed with wide-awake local anesthesia with no tourniquet in an in-office procedure room can be performed safely with a low infection rate, are cost effective, and have high patient satisfaction. Clinical relevance: Minor hand surgery done in an in-office procedure room is safe, is cost effective, and has high patient satisfaction.

13.
J Hand Surg Glob Online ; 4(4): 249-253, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35880151

RESUMO

Information regarding the management of intra-articular base fractures of the index metacarpal is scarce. Fractures of the base of the index metacarpal are rare because of the inherent stability of the joint. Of the handful of case reports on this injury, there appear to be 2 main patterns: fractures of the dorsal radial condyle and fractures of the volar ulnar condyle, which are attached to the extensor carpi radialis longus and flexor carpi radialis tendons, respectively. Although majority of previously reported volar fragment fractures were treated with Kirschner wire stabilization, we reported a case that was managed nonsurgically. The case presented is of a 70-year-old man with a fracture of the volar ulnar condyle of the base of the index metacarpal. Although he initially struggled with swelling of the hand and mobility of the fingers, he did well with nonsurgical management and regained full strength in his hand.

14.
S D Med ; 75(4): 166-169, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35709348

RESUMO

Acute calcific tendinitis (ACT) is a relatively uncommon disorder that can involve the hand and wrist. ACT is frequently misdiagnosed due to a lack of familiarity with the condition and the clinical presentation that can be confused with other conditions. We report a case of acute calcific tendinitis of the flexor carpi ulnaris (FCU) tendon in a 68-year-old woman. She presented with acute left volar wrist pain, erythema, swelling, and restricted range of motion. Due to her inability to take nonsteroidal anti-inflammatory drugs (NSAIDs) and oral prednisone, she was treated with lavage and steroid injection of the calcified mass. Following the injection, there was dramatic improvement in her symptoms. Cortisone injection with lavage is an accepted treatment for rotator cuff calcific tendinitis and is another treatment option for ACT involving the hand and wrist.


Assuntos
Calcinose , Tendinopatia , Idoso , Calcinose/complicações , Calcinose/diagnóstico por imagem , Calcinose/terapia , Feminino , Humanos , Esteroides , Tendinopatia/complicações , Tendinopatia/diagnóstico por imagem , Tendinopatia/tratamento farmacológico , Tendões , Irrigação Terapêutica
15.
Clin Exp Rheumatol ; 40(2): 274-283, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35200123

RESUMO

OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.


Assuntos
Dermatomiosite , Doenças Pulmonares Intersticiais , Autoanticorpos , Dermatomiosite/complicações , Feminino , Humanos , Helicase IFIH1 Induzida por Interferon , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
16.
Lancet Rheumatol ; 4(10): e679-e687, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38265966

RESUMO

BACKGROUND: Nintedanib is a tyrosine kinase inhibitor used in the treatment of progressive fibrosing interstitial lung diseases (ILDs). We assessed the safety and tolerability of nintedanib in patients with autoimmune disease-related ILDs and with other ILDs in subgroups by sex. METHODS: In this post-hoc analysis, we pooled data from the two INPULSIS trials in patients with idiopathic pulmonary fibrosis (IPF), the SENSCIS trial in patients with fibrosing ILDs associated with systemic sclerosis, and the INBUILD trial in patients with progressive fibrosing ILDs other than IPF. In each trial, patients were randomly assigned to receive oral nintedanib 150 mg twice daily or matched placebo. We assessed adverse events reported over 52 weeks in patients with autoimmune disease-related ILDs and other ILDs in subgroups by sex. FINDINGS: In these analyses, we included 746 patients with autoimmune disease-related ILDs (523 [70%] were female, 223 [30%] were male; 615 [82%] had systemic sclerosis), of whom 370 (50%) received nintedanib (268 [72%] female and 102 [28%] male patients) and 376 (50%) received placebo (255 [68%] female and 121 [32%] male patients); and 1554 patients with other ILDs (437 [28%] female, 1117 [72%] male; 1061 [68%] with IPF), of whom 888 (57%) received nintedanib (237 [27%] female and 651 [73%] male patients) and 666 (43%) received placebo (200 [30%] female and 466 [70%] male patients). Of 102 male and 268 female patients with autoimmune disease-related ILDs treated with nintedanib, nausea was reported in 21 (21%) male and 92 (34%) female patients, vomiting in 12 (12%) male and 73 (27%) female patients, alanine aminotransferase increase in four (4%) male and 31 (12%) female patients, aspartate aminotransferase increase in three (3%) male and 23 (9%) female patients, and adverse events leading to dose reduction in 18 (18%) male and 101 (38%) female patients; 28 (27%) male and 107 (40%) female patients had at least one treatment interruption. Of 651 male and 237 female nintedanib-treated patients with other ILDs, nausea was reported in 135 (21%) male and 95 (40%) female patients, vomiting in 51 (8%) male and 70 (30%) female patients, alanine aminotransferase increase in 19 (3%) male and 31 (13%) female patients, aspartate aminotransferase increase in 17 (3%) male and 26 (11%) female patients, and adverse events leading to dose reduction in 106 (16%) male and 84 (35%) female patients; 155 (24%) male and 82 (35%) female patients had at least one treatment interruption. The proportions of patients with adverse events leading to discontinuation of nintedanib were similar between female and male patients with autoimmune disease-related ILDs (44 [16%] of 268 vs 17 [17%] of 102), but were greater among female than male patients with other ILDs (62 [26%] of 237 vs 112 [17%] of 651). Across subgroups by diagnosis and sex, diarrhoea was the most frequent adverse event associated with nintedanib (autoimmune-related ILDs: 198 [74%] of 268 female and 73 [72%] of 102 male patients; other ILDs: 155 [65%] of 237 female and 408 [63%] of 651 male patients), and was the event that most frequently led to treatment discontinuation (autoimmune-related ILDs: 20 [7%] female and five [5%] male patients; other ILDs: 16 [7%] female and 27 [4%] male patients). INTERPRETATION: The adverse event profile of nintedanib was generally similar between male and female patients with autoimmune disease-related ILDs, and between male and female patients with other ILDs, but nausea, vomiting, liver enzyme elevations, dose reductions, and treatment interruptions were more frequent in female patients than in male patients. Sex should be considered in the monitoring and management of adverse events that might be associated with nintedanib. FUNDING: Boehringer Ingelheim.


Assuntos
Doenças Autoimunes , Fibrose Pulmonar Idiopática , Indóis , Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Humanos , Feminino , Masculino , Alanina Transaminase , Doenças Pulmonares Intersticiais/tratamento farmacológico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Aspartato Aminotransferases , Náusea , Escleroderma Sistêmico/tratamento farmacológico , Vômito , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Arthritis Res Ther ; 23(1): 306, 2021 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-34952630

RESUMO

BACKGROUND: In rheumatoid arthritis (RA), macrophages play an important role in modulating the immunoinflammatory response through their polarisation into "classically" (M1) or "alternatively activated" (M2) phenotypes. In RA, CTLA4-Ig (abatacept) reduces the inflammatory activity of macrophages by interacting with the costimulatory molecule CD86. The study aimed to investigate the efficacy of CTLA4-Ig treatment to induce an M2 phenotype both in M1-polarised monocyte-derived macrophages (MDMs) obtained from healthy subjects (HS) and in cultured MDMs obtained from active RA patients. METHODS: Cultured MDMs were obtained from peripheral blood mononuclear cells of 7 active RA patients and from 10 HS after stimulation with phorbol myristate acetate (5 ng/mL) for 24 h. HS-MDMs were then stimulated with lipopolysaccharide (LPS, 1 mg/mL) for 4 h to induce M1-MDMs. M1-MDMs and RA-MDMs were treated with CTLA4-Ig (100 µM and 500 µM) for 3, 12, 24, and 48 h. The gene expression of CD80, CD86, and TLR4 (M1 markers); CD163, CD204, and CD206 (surface M2 markers); and MerTK (functional M2 marker) was evaluated by qRT-PCR. The protein synthesis of surface M2 markers was investigated by Western blotting. The statistical analysis was performed by the Wilcoxon t-test. RESULTS: In LPS-induced HS-M1-MDMs, CTLA4-Ig 100 µM and 500 µM significantly downregulated the gene expression of M1 markers (3 h p<0.01 for all molecules; 12 h p<0.05 for TLR4 and CD86) and significantly upregulated that of M2 markers, primarily after 12 h of treatment (CD163: p < 0.01 and p < 0.05; CD206: p < 0.05 and p < 0.01; CD204: p < 0.05 by 100 mg/mL). Moreover, in these cells, CTLA4-Ig 500 µM increased the protein synthesis of surface M2 markers (p < 0.05). Similarly, in RA-MDMs, the CTLA4-Ig treatment significantly downregulated the gene expression of M1 markers at both concentrations primarily after 12 h (p < 0.05). Furthermore, both concentrations of CTLA4-Ig significantly upregulated the gene expression of CD206 (after 3 h of treatment; p < 0.05), CD163, and MerTK (after 12 h of treatment, p < 0.05), whereas CD204 gene expression was significantly upregulated by the high concentration of CTLA4-Ig (p < 0.05). The protein synthesis of all surface markers was increased primarily by CTLA4-Ig 500 µM, significantly for CD204 and CD206 after 24 h of treatment (p < 0.05). CONCLUSIONS: CTLA4-Ig treatment seems to induce the in vitro shift from M1 to M2 macrophages, of both HS-M1-MDMs and RA-MDMs, as observed by the significant downregulation exerted on selected M1 markers and the upregulation of selected M2 markers suggesting an additional mechanism for its modulation of the RA inflammatory process.


Assuntos
Artrite Reumatoide , Leucócitos Mononucleares , Abatacepte/metabolismo , Abatacepte/farmacologia , Abatacepte/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Antígeno CTLA-4 , Células Cultivadas , Voluntários Saudáveis , Humanos , Macrófagos/metabolismo
18.
Eur J Clin Invest ; 51(8): e13572, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33851422

RESUMO

BACKGROUND: Uveitis is one of the most frequent ophthalmologic manifestations in rheumatology. Uveal inflammation can underlie a systemic inflammatory rheumatic disease (SIRD) in approximately 30% of cases with a significant burden on the quality of life since it represents a cause of blindness in up to 20% of cases in Western countries. METHODS: In this review, we provide a comprehensive overview of the pathophysiology of uveitis associated with SIRDs. According to our literature survey on the epidemiology of uveitis among SIRDs, spondyloarthritides, Behçet's disease and sarcoidosis get the major impact. RESULTS: In Behçet's uveitis, the key players are highly polarized Th1 and Th17 lymphocytes, natural killer T cells and γδ T cells. All contribute to a great destructive inflammatory environment with the most serious visual damage resulting from the involvement of the posterior segment of the eye. In contrast, spondyloarthritides-related uveitis derives from a complex interaction between genetic background and extra-ocular inflammatory mediators originating from enthesitis, arthritis, psoriatic lesions and microbiome pro-inflammatory alterations. In such conditions, the immune infiltration of CD4+ T cells, Th17 and natural killer cells along with pro-inflammatory cytokines, TNF-α among all, leads to intraocular inflammation. Lastly, granuloma formation represents the primary hallmark lesion in sarcoid uveitis. This suggests a profound link between the innate system that mainly recruits activated macrophages and adaptive system involving by Th1, Th17 and Th17.1 cells. CONCLUSIONS: Awareness among rheumatologists of a potential severe ocular involvement generates new insights into targeted therapeutic approaches and personalized treatments for each patient.


Assuntos
Doenças Reumáticas/complicações , Uveíte/fisiopatologia , Animais , Síndrome de Behçet/complicações , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Sarcoidose/complicações , Espondiloartropatias/complicações , Linfócitos T/imunologia , Uveíte/complicações
19.
BMJ Open ; 11(3): e044483, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737437

RESUMO

INTRODUCTION: Systemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease associated with high morbidity and mortality, especially in diffuse cutaneous SSc (dcSSc). Currently, there are several treatments available in early dcSSc that aim to change the disease course, including immunosuppressive agents and autologous haematopoietic stem cell transplantation (HSCT). HSCT has been adopted in international guidelines and is offered in current clinical care. However, optimal timing and patient selection for HSCT are still unclear. In particular, it is unclear whether HSCT should be positioned as upfront therapy or rescue treatment for patients refractory to immunosuppressive therapy. We hypothesise that upfront HSCT is superior and results in lower toxicity and lower long-term medical costs. Therefore, we propose this randomised trial aiming to determine the optimal treatment strategy for early dcSSc by comparing two strategies used in standard care: (1) upfront autologous HSCT versus (2) immunosuppressive therapy (intravenous cyclophosphamide pulse therapy followed by mycophenolate mofetil) with rescue HSCT in case of treatment failure. METHODS AND ANALYSIS: The UPSIDE (UPfront autologous hematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) study is a multicentre, randomised, open-label, controlled trial. In total, 120 patients with early dcSSc will be randomised. The primary outcome is event-free survival at 2 years after randomisation. Secondary outcomes include serious adverse events, functional status and health-related quality of life. We will also evaluate changes in nailfold capillaroscopy pattern, pulmonary function, cardiac MR and high-resolution CT of the chest. Follow-up visits will be scheduled 3-monthly for 2 years and annually in the following 3 years. ETHICS AND DISSEMINATION: The study was approved by the Dutch Central Committee on Research Concerning Human Subjects (NL72607.041.20). The results will be disseminated through patient associations and conventional scientific channels. TRIAL REGISTRATION NUMBERS: NCT04464434; NL 8720.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Esclerodermia Difusa , Ciclofosfamida/uso terapêutico , Humanos , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Esclerodermia Difusa/tratamento farmacológico , Transplante Autólogo
20.
Rheumatology (Oxford) ; 60(11): 5028-5041, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33580257

RESUMO

OBJECTIVE: To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD). METHODS: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared with 7202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc patients (85 from the EUSTAR registry) and compared with 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration and age at SSc onset. RESULTS: Patients with isolated anti-PM/Scl+, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of DM, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls. In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed. CONCLUSION: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous DM, calcinosis and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome.


Assuntos
Exorribonucleases/imunologia , Complexo Multienzimático de Ribonucleases do Exossomo/imunologia , Sistema de Registros , Escleroderma Sistêmico/imunologia , Adulto , Autoanticorpos , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA