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1.
N Engl J Med ; 386(1): 11-23, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34986284

RESUMO

BACKGROUND: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia. METHODS: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months. RESULTS: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome. CONCLUSIONS: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).


Assuntos
Anemia Aplástica/terapia , Soro Antilinfocitário/uso terapêutico , Benzoatos/uso terapêutico , Ciclosporina/uso terapêutico , Hidrazinas/uso terapêutico , Imunossupressores/uso terapêutico , Pirazóis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/genética , Soro Antilinfocitário/efeitos adversos , Benzoatos/efeitos adversos , Ciclosporina/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Hidrazinas/efeitos adversos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Pirazóis/efeitos adversos , Receptores de Trombopoetina/agonistas , Indução de Remissão , Adulto Jovem
2.
Rev Med Suisse ; 18(764-5): 15-17, 2022 Jan 19.
Artigo em Francês | MEDLINE | ID: mdl-35048572

RESUMO

Glucocorticosteroids (GC) remain the mainstay of treatment in most systemic inflammatory diseases. GC have a broad anti-inflammatory action of rapid onset. The downsides of prolonged GC therapy are well established and include infections, osteoporosis and metabolic adverse effects, among others. In systemic sclerosis, GC are associated with an increased risk of scleroderma renal crisis and must be avoided. Adjunction of second-line immunosuppressive drugs may improve disease control and limit GC usage. We summarize here the findings of two studies published in 2021, one reporting the benefits of combining GC with mycophenolate mofetil in immune thrombocytopenia, the other suggesting that blockage of interleukin-6 may decrease disease progression in systemic sclerosis with lung involvement.


Les glucocorticoïdes (GC) demeurent le pilier du traitement de la plupart des maladies inflammatoires systémiques. Ils ont un effet anti-inflammatoire puissant et d'installation rapide. Les effets indésirables des GC sont bien connus : risque infectieux, ostéoporose, diabète et hypertension, entre autres. Dans la sclérose systémique, les GC sont à éviter, car associés à la survenue d'une crise rénale hypertensive. L'adjonction d'immunosuppresseurs comme deuxième ligne de traitement peut améliorer le contrôle de la maladie et limiter l'utilisation des GC. Nous résumons les résultats de deux études récentes, l'une rapportant les bénéfices de l'ajout de mycophénolate mofétil aux GC dans le purpura thrombopénique immun, l'autre suggérant que le blocage de l'interleukine 6 pourrait ralentir la progression de la sclérose systémique (ou sclérodermie) avec atteinte pulmonaire.


Assuntos
Doenças do Sistema Imunitário , Escleroderma Sistêmico , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores , Ácido Micofenólico , Escleroderma Sistêmico/tratamento farmacológico
3.
Artigo em Inglês | MEDLINE | ID: mdl-34759018

RESUMO

BACKGROUND AND OBJECTIVES: To investigate whether children receiving immunosuppressive therapies for neuroimmunologic disorders had (1) increased susceptibility to SARS-CoV2 infection or to develop more severe forms of COVID-19; (2) increased relapses or autoimmune complications if infected; and (3) changes in health care delivery during the pandemic. METHODS: Patients with and without immunosuppressive treatment were recruited to participate in a retrospective survey evaluating the period from March 14, 2020, to March 30, 2021. Demographics, clinical features, type of immunosuppressive treatment, suspected or confirmed COVID-19 in the patients or cohabitants, and changes in care delivery were recorded. RESULTS: One hundred fifty-three children were included: 84 (55%) female, median age 13 years (interquartile range [8-16] years), 79 (52%) on immunosuppressive treatment. COVID-19 was suspected or confirmed in 17 (11%) (all mild), with a frequency similar in patients with and without immunosuppressive treatment (11/79 [14%] vs 6/74 [8%], p = 0.3085). The frequency of neurologic relapses was similar in patients with (18%) and without (21%) COVID-19. Factors associated with COVID-19 included having cohabitants with COVID-19 (p < 0.001) and lower blood levels of vitamin D (p = 0.039). Return to face-to-face schooling or mask type did not influence the risk of infection, although 43(28%) children had contact with a classmate with COVID-19. Clinic visits changed from face to face to remote for 120 (79%) patients; 110 (92%) were satisfied with the change. DISCUSSION: In this cohort of children with neuroimmunologic disorders, the frequency of COVID-19 was low and not affected by immunosuppressive therapies. The main risk factors for developing COVID-19 were having cohabitants with COVID-19 and low vitamin D levels.


Assuntos
COVID-19/complicações , COVID-19/imunologia , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/imunologia , SARS-CoV-2/imunologia , Adolescente , COVID-19/prevenção & controle , COVID-19/virologia , Criança , Atenção à Saúde/organização & administração , Atenção à Saúde/estatística & dados numéricos , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Máscaras/estatística & dados numéricos , Máscaras/virologia , Doenças do Sistema Nervoso/virologia , Pandemias , Recidiva , Estudos Retrospectivos , Vitamina D/sangue
5.
J Oncol Pharm Pract ; 28(1): 31-38, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33349149

RESUMO

PURPOSE: Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) prodrug, is used to prevent graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). Although previous studies have reported that enterohepatic circulation (EHC) of MPA, which is usually observed in MMF-treated patients, does not occur in HSCT patients, it is unclear what happens in haploidentical-HSCT (haplo-HSCT) patients, who are using post-transplant cyclophosphamide. This study was conducted to investigate MPA pharmacokinetics in haplo-HSCT patients. METHODS: Seventeen haplo-HSCT patients, who received MMF for GVHD prophylaxis, were enrolled in this study. We collected blood samples on days 14 and 28, and plasma MPA concentrations were measured by high-performance liquid chromatography; pharmacokinetic parameters such as area under the curve (AUC), mean residence time (MRT), and apparent oral clearance (CL/F) were measured with moment analysis. We also evaluated EHC as AUC6-12h/AUC0-12h. RESULTS: There was no significant difference in MPA pharmacokinetic parameters between days 14 and 28. There was also no difference between the pharmacokinetic parameter changes and diarrhea. Additionally, varying plasma MPA concentrations suggested that MPA EHC did not occur. CONCLUSION: In this study, we revealed the pharmacokinetics of MMF in Japanese haplo-HSCT recipients. Additionally, our study demonstrated that MPA EHC might not occur in Japanese haplo-HSCT recipients.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Área Sob a Curva , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Japão , Ácido Micofenólico/uso terapêutico
7.
Bioorg Chem ; 118: 105482, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34801946

RESUMO

Podomycins A-L (1-12), 12 undescribed hypothemycin-type resorcylic acid lactones (RALs), were characterized from Podospora sp. G214, an endophyte harbored in the roots of Sanguisorba officinalis L. Their structures were addressed by spectroscopic data, X-ray crystallography, the modified Mosher's method, together with Mo2(OAc)4- and Rh2(OCOCF3)4-induced electronic circular dichroism (ICD) experiments. Podomycins A-C (1-3) represent the first class of natural RALs with a 13-membered macrolactone ring, while 4-12 are rearranged methoxycarbonyl substituted RALs. Biologically, compounds 2, 6, 8, 10, and 12 displayed immunosuppressive activities against T cell proliferation with IC50 values of 14.5-21.9 µM, and B cell proliferation with IC50 values of 22.3-36.5 µM, respectively. Further mechanism of action research demonstrated that podomycin F (6) distinctly induced apoptosis in activated T cells via MAPKs/AKT pathway.


Assuntos
Apoptose/efeitos dos fármacos , Imunossupressores/farmacologia , Lactonas/farmacologia , Podospora/química , Linfócitos T/efeitos dos fármacos , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Imunossupressores/química , Imunossupressores/isolamento & purificação , Lactonas/química , Lactonas/isolamento & purificação , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Proteínas Proto-Oncogênicas c-akt , Relação Estrutura-Atividade , Linfócitos T/metabolismo
9.
Gene ; 809: 146007, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34688813

RESUMO

AIM: The purpose of this study was to investigate the effect of CYP3A7, CYP3A4, and CYP3A5 genetic polymorphisms in liver transplant recipients and donors on tacrolimus concentrations in the early stages after liver transplantation. METHODS: One hundred and thirty-eight liver transplant recipients and matched donors were genotyped for CYP3A7 (rs10211 and rs2257401), CYP3A4 (rs4646437 and rs2242480), and CYP3A5*3 (rs776746) polymorphisms. The relationships between dose-adjusted trough concentrations (C0/D) of tacrolimus and corresponding genotypes were investigated. RESULTS: Recipient CYP3A polymorphisms were associated with tacrolimus concentrations. The CYP3A7 rs10211 AA carriers (186.2 vs 90.5, p < 0.001), CYP3A4 rs4646437 CC carriers (184.0 vs 88.8, p < 0.001), CYP3A4*1G rs2242480 CC carriers (189.8 vs 99.7, p < 0.001), and CYP3A5*3 rs776746 GG carriers (197.3 vs 86.0, p < 0.001) had an almost twofold increase in the tacrolimus C0/D compared to that of the non-carriers. We further investigated the effect of the combination of recipient (intestinal) and donor (hepatic) genotypes on tacrolimus concentrations. Regardless of the genotype of the matched donor, CYP3A7 rs10211, CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746) polymorphisms of recipients could affect tacrolimus concentrations. For the CYP3A4 rs4646437 polymorphisms, when the donor carried CYP3A4 rs4646437 CC, the recipient CYP3A4 rs4646437 polymorphism was associated with the C0/D of tacrolimus, and when the donor carried CYP3A4 rs4646437 CT/TT genotype, the recipient CYP3A4 rs4646437 polymorphism also affected on tacrolimus C0/D, although the effect was not significant. CONCLUSION: The large inter-individual variation in tacrolimus concentrations in the early stages after liver transplantation is influenced by genetic polymorphisms of CYP3A7, CYP3A4, and CYP3A5. Recipient (intestinal) CYP3A7, CYP3A4, and CYP3A5 polymorphisms seem to contribute more to such variation than donors. Therefore, the detection of CYP3A polymorphisms in recipients could help to predict the tacrolimus starting dose in the early stages after liver transplantation.


Assuntos
Citocromo P-450 CYP3A/genética , Transplante de Fígado , Tacrolimo/sangue , Adulto , Feminino , Frequência do Gene , Humanos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tacrolimo/uso terapêutico , Doadores de Tecidos
10.
J Pharm Biomed Anal ; 208: 114443, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34735994

RESUMO

Therapeutic drug monitoring (TDM) of immunosuppressants is essential to avoid either rejection or toxicity after solid organ transplantations. Capillary microsampling approaches are an outstanding alternative to conventional venous sampling for TDM (easy and non-invasive collection, enabling self-sampling, and cost-saving shipment, processing and storage). Volumetric absorptive microsampling (VAMS) has gained importance in the last years, as it was meant to overcome the hematocrit (Hct) related issues commonly associated to DBS analysis. Despite all the benefits, microsampling techniques performance (including a thorough clinical validation) should be set up before their implementation in clinical practice. The aim of this study was to perform a clinical validation for both tacrolimus (TAC) and mycophenolic acid (MPA) in both DBS and Mitra™ VAMS. For the clinical validations, two different requirements were set up: analytical (following EMA and FDA guidelines) and clinical (following the Royal College of Pathologists of Australasia -RCPA- recommendations) acceptance criteria. For DBS, both analytical and clinical acceptance criteria were fulfilled for TAC, with 98.7% and 95% of the paired samples within the preset limits, respectively. For MPA, the analytical criterion was met (70.6% of paired specimens), although only half of the pairs were within the clinical limits. For VAMS, the clinical validation for both TAC and MPA showed good correlations but significant lower concentrations in VAMS compared to the routine matrices. After VAMS concentrations correction, the analytical requirement was fulfilled for both analytes (71.1% for TAC, 75% for MPA), although the more restrictive criteria recommended by the RCPA were not met for any analyte (half of the samples fell within the acceptance area). In addition, no significant Hct impact on the quantification was found in any case. Also, a preliminary home-sampling trial was set up, showing promising results. Moreover, a comparison between VAMS vs. DBS analytical and clinical performances was carried out, including a home-sampling trial, sample quality results and costs. Although the analytical performance for both VAMS and DBS was similar, DBS were superior regarding clinical criteria, sampling quality and cost.


Assuntos
Ácido Micofenólico , Tacrolimo , Coleta de Amostras Sanguíneas , Teste em Amostras de Sangue Seco , Humanos , Imunossupressores
11.
Gut ; 71(1): 34-42, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33384335

RESUMO

OBJECTIVE: In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. DESIGN: In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis. RESULTS: 100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004). CONCLUSIONS: FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02517684).


Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infliximab/uso terapêutico , Adolescente , Anti-Inflamatórios/uso terapêutico , Azatioprina/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Prednisolona/uso terapêutico , Indução de Remissão , Índice de Gravidade de Doença
12.
Pediatr Infect Dis J ; 41(1): e10-e15, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34711782

RESUMO

BACKGROUND: Osteomyelitis with proliferative periostitis is a relatively uncommon inflammatory condition of the jaws, mainly characterized by periosteal formation of reactive bone. It primarily affects children and adolescences, also referred to as Garre's osteomyelitis, more frequently involving the molar region of the mandible. Cases lacking an obvious source of infection may have an immunologically mediated etiopathogenesis, falling under the spectrum of primary chronic osteomyelitis or chronic recurrent multifocal osteomyelitis (CRMO). CASE REPORT: Herein, we present a case of chronic osteomyelitis in a 6.5-year-old girl, who suffered from recurrent painful episodes of swelling of the mandible for the last 2 years, previously requiring hospitalization and administration of intravenous (IV) antibiotics and NSAIDs with limited responsiveness. The biopsy showed features consistent with osteomyelitis with proliferative periostitis. The patient was initially managed with an IV combination antibiotic regimen with only partial improvement. The possibility of an autoimmune mechanism in the context of primary chronic osteomyelitis or CRMO was considered, and immunosuppressive therapy (TNF inhibitor etanercept along with corticosteroids and methotrexate) was administered, resulting in clinical resolution. CONCLUSIONS: Osteomyelitis and its childhood variants are relatively rare and their management presents several challenges. Although typically treated with administration of antibiotics, possibly along with surgical intervention, other treatment modalities may be necessary for resilient and persistent cases. In a subset of cases, especially in the absence of local infectious factors, immunologically mediated mechanisms may play an important role and appropriate immunosuppressive therapy may be effective.


Assuntos
Imunossupressores/uso terapêutico , Mandíbula/patologia , Osteomielite/complicações , Osteomielite/tratamento farmacológico , Periostite/tratamento farmacológico , Antibacterianos/uso terapêutico , Biópsia , Criança , Diagnóstico Diferencial , Gerenciamento Clínico , Feminino , Humanos , Osteomielite/diagnóstico , Periostite/diagnóstico
13.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(11): 1267-1275, 2021 Nov 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34911862

RESUMO

Systemic lupus erythematosus (SLE) is a chronic and autoimmunity-mediated diffuse connective tissue disease. The mainstay of treatments for SLE mainly relies on corticosteroids and immunosuppressants, which have a series of unavoidable side effects. Therefore, it is of fundamental importance to search novel therapeutic targets for better treatment with favorable efficacy and minor side effects. Recent studies shed light on potential therapeutic targets for SLE, mainly covering the followings: B-cell/plasmocyte-related targets [B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), CD20, CD22, CD19/FcγRIIb, Bruton tyrosine kinase (Btk), and proteasome], T cell-related targets [calcineurin, mammalian target of rapamycin (mTOR), regulatory factor X1 (RFX1), and Rho kinase], macrophage-related targets (macrophage migration inhibitory factor), intracellular signaling molecules, cytokines (cereblon, histone deacetylase 6, Janus activated kinase/signal transducer and activator of transcription), co-stimulating factors (CD28/B7, CD40/CD154), IgE autoantibody, and gut microbiome. Among them, belimumab (a humanized monoclonal antibody against B-lymphocyte stimulator) and telitacicept (a recombinant human B-lymphocyte stimulator receptor-antibody fusion protein) have been sequentially approved for the clinical treatment of SLE in China. A variety of new targeted-therapy drugs are in the Phase 2 or Phase 3 clinical trials,among which anifrolumab (a human monoclonal antibody against type I interferon receptor subunit 1) has completed a Phase 3 clinical trial with good responses achieved, although its incidence of herpes zoster is higher than that in the control group. The research progress in both molecular mechanisms and new drug development for different therapeutic targets have greatly promoted our better and in-depth understanding of the pathogenesis of SLE, and have also reflected the complexity and heterogeneity of the disease. Successful development and clinical application of more novel therapies would no doubt usher in a new era of individualized treatment for SLE in the future.


Assuntos
Doença Enxerto-Hospedeiro , Lúpus Eritematoso Sistêmico , Anticorpos Monoclonais/uso terapêutico , Linfócitos B , Humanos , Imunossupressores , Lúpus Eritematoso Sistêmico/tratamento farmacológico
14.
Ital J Pediatr ; 47(1): 237, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911536

RESUMO

BACKGROUND: A retrospective study was conducted in order to investigate and describe the characteristics of Immunoglobulin A vasculitis (IgAV), previously known as Henoch-SchÓ§nlein purpura, in the paediatric population of a community-based healthcare delivery system in the Italian region of Abruzzo. METHODS: This is a population-based retrospective chart review of the diagnosis of IgAV in children ages 0 to 18, admitted to the Department of Paediatrics of Chieti and Pescara between 1 January 2000 and 31 December 2016. All children enrolled presented with clinical symptoms and laboratory findings and met the EULAR/PRINTO/PRES 2008 criteria. RESULTS: Two-hundred-eight children met the criteria for IgAV, with the highest incidence reported among children below 7-years of age. A correlation with recent infections was found in 64% of the cohort; the onset was more frequently during the winter and fall. Purpura had a diffuse distribution in the majority of patients; joint impairment was the second most frequent symptom (43%), whereas the gastrointestinal tract was involved in 28% of patients. CONCLUSIONS: Hereby, we confirm the relative benignity of IgAV in a cohort of Italian children; with regards to renal involvement, we report a better outcome compared to other studies. However, despite the low rate of renal disease, we observed a wide use of corticosteroids, especially for the treatment of persistent purpura.


Assuntos
/epidemiologia , Dor Abdominal/epidemiologia , Adolescente , Distribuição por Idade , Anemia/epidemiologia , Artralgia/epidemiologia , Artrite/epidemiologia , Sedimentação Sanguínea , Proteína C-Reativa/análise , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Glucocorticoides/uso terapêutico , Hospitalização , Humanos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Infecções/epidemiologia , Itália/epidemiologia , Nefropatias/epidemiologia , Nefropatias/etiologia , Leucocitose/epidemiologia , Masculino , Púrpura/epidemiologia , Estudos Retrospectivos , Estações do Ano , Distribuição por Sexo , Trombocitose/epidemiologia
15.
Int J Mol Sci ; 22(24)2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34948358

RESUMO

Membranous nephropathy (MN) is an important cause of nephrotic syndrome and chronic kidney disease (CKD) in adults. The pathogenic significance of B cells in MN is increasingly recognized, especially following the discovery of various autoantibodies that target specific podocytic antigens and the promising treatment responses seen with B cell depleting therapies. The presence of autoreactive B cells and autoantibodies that bind to antigens on podocyte surfaces are characteristic features of MN, and are the result of breaches in central and peripheral tolerance of B lymphocytes. These perturbations in B cell tolerance include altered B lymphocyte subsets, dysregulation of genes that govern immunoglobulin production, aberrant somatic hypermutation and co-stimulatory signalling, abnormal expression of B cell-related cytokines, and increased B cell infiltrates and organized tertiary lymphoid structures within the kidneys. An understanding of the role of B cell tolerance and homeostasis may have important implications for patient management in MN, as conventional immunosuppressive treatments and novel B cell-targeted therapies show distinct effects on proliferation, differentiation and reconstitution in different B cell subsets. Circulating B lymphocytes and related cytokines may serve as potential biomarkers for treatment selection, monitoring of therapeutic response and prediction of disease relapse. These recent advances in the understanding of B cell tolerance in MN have provided greater insight into its immunopathogenesis and potential novel strategies for disease monitoring and treatment.


Assuntos
Linfócitos B/patologia , Glomerulonefrite Membranosa/patologia , Tolerância Imunológica , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Citocinas/análise , Citocinas/imunologia , Gerenciamento Clínico , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/terapia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Imunossupressores/uso terapêutico , Terapia de Alvo Molecular
16.
Int J Mol Sci ; 22(24)2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34948375

RESUMO

Pediatric autoimmune liver disorders include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is an idiopathic disease characterized by immune-mediated hepatocyte injury associated with the destruction of liver cells, causing inflammation, liver failure, and fibrosis, typically associated with autoantibodies. The etiology of AIH is not entirely unraveled, but evidence supports an intricate interaction among genetic variants, environmental factors, and epigenetic modifications. The pathogenesis of AIH comprises the interaction between specific genetic traits and molecular mimicry for disease development, impaired immunoregulatory mechanisms, including CD4+ T cell population and Treg cells, alongside other contributory roles played by CD8+ cytotoxicity and autoantibody production by B cells. These findings delineate an intricate pathway that includes gene to gene and gene to environment interactions with various drugs, viral infections, and the complex microbiome. Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. The current first-line therapy comprises prednisolone plus azathioprine to induce clinical and biochemical remission. Further understanding of the cellular and molecular mechanisms encountered in AIH may depict their impact on clinical aspects, detect biomarkers, and guide toward novel, effective, and better-targeted therapies with fewer side effects.


Assuntos
Hepatite Autoimune/patologia , Fígado/patologia , Animais , Azatioprina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Glucocorticoides/uso terapêutico , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/genética , Hepatite Autoimune/imunologia , Humanos , Imunossupressores/uso terapêutico , Fígado/imunologia , Fígado/metabolismo , Prednisolona/uso terapêutico , RNA não Traduzido/genética , RNA não Traduzido/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
17.
Int J Mol Sci ; 22(24)2021 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-34948117

RESUMO

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recent studies have demonstrated that the hallmark of AOSD is a cytokine storm, which is characterized by the excessive production of interleukin (IL)-1, IL-6, IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), suggesting how pro-inflammatory cytokines play an important role in the pathogenesis of this disease. Actually, a certain proportion of patients (around 17-32%) with severe clinical symptoms achieves only partial remission or is resistant to both first-line corticosteroids and second-line DMARDs. These patients are defined as refractory AOSD patients, requiring higher dosage glucocorticoids, longer treatment duration, or the simultaneous introduction of immunosuppressive drugs, further leading to AOSD relapses. In this narrative review, we will analyze the latest literature data to unravel potential pathogenetic factors associated with specific patterns of AOSD disease or relapses in order to identify biomarkers that may guide clinical decisions, eventually leading to new therapeutic options.


Assuntos
Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Doença de Still de Início Tardio , Biomarcadores/metabolismo , Citocinas/metabolismo , Resistência a Medicamentos , Humanos , Doença de Still de Início Tardio/tratamento farmacológico , Doença de Still de Início Tardio/metabolismo , Doença de Still de Início Tardio/patologia
18.
Acta Vet Scand ; 63(1): 54, 2021 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-34961516

RESUMO

Primary immune thrombocytopenia (ITP) is a cause of severe thrombocytopenia in dogs. Immunosuppressive corticosteroid drugs are frequently used in the management of ITP, but treatment failure may occur. Immunomodulatory and non-corticosteroid immunosuppressive drugs might improve outcomes from therapy either alone or in combination with corticosteroids. The objectives of this scoping review were (1) to evaluate the current evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP, and (2) to answer the clinical question, whether or not therapy with immunomodulatory or non-corticosteroid immunosuppressive drugs alone or in combination with corticosteroids could improve outcome, compared to therapy with corticosteroids alone. A literature search was performed in the electronic databases of Agricola, CAB Abstracts, Embase, Medline and Web of Science for publications in November 2019 and again February 1, 2021. Selection criteria were relatively strict and included peer-reviewed research papers reporting outcome measures from immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP with a pre-therapeutic mean or median platelet count < 50,000/µL as a strict criterion for inclusion. Studies were evaluated if they had an appropriate diagnostic work up to exclude underlying conditions. Outcome measures and adverse events were compared between drug protocols both within studies and between studies. The search identified 456 studies, with six studies being eligible for inclusion. The studies were mostly case series while two were randomized controlled trials. Level of evidence varied with an overall uncertain subject enrollment, small groups, inadequate description and variable use of drug protocols or outcome measures. For outcomes such as platelet recovery time and duration of hospitalization, an improvement was observed using adjunctive therapy (human intravenous immunoglobulin) compared to therapy with corticosteroids alone. For outcomes of complete platelet recovery time, survival (6-month), mortality and relapse, no improvement was observed using adjunctive drugs compared to corticosteroids alone. Specifically, therapy with mycophenolate mofetil alone and adjunctive azathioprine were associated with more severe adverse events compared to other drug protocols. Evidence relating to immunomodulatory and immunosuppressive drug protocols in the treatment of canine ITP was of variable quality. Future larger case-controlled trials are required for determination of optimal treatment protocols in canine ITP.


Assuntos
Doenças do Cão , Preparações Farmacêuticas , Púrpura Trombocitopênica Idiopática , Animais , Plaquetas , Doenças do Cão/tratamento farmacológico , Cães , Imunossupressores/uso terapêutico , Contagem de Plaquetas/veterinária , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/veterinária
19.
BMC Gastroenterol ; 21(1): 494, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34949172

RESUMO

BACKGROUND: Intravenous corticosteroid is the mainstay for managing acute severe ulcerative colitis, but one-third of patients do not respond to intravenous corticosteroid. Tacrolimus, a salvage therapy before colectomy, is usually orally administered, though its bioavailability is low compared intravenous administration. The efficacy of intravenous tacrolimus has not been widely studied. AIM: To determine the efficacy and safety of intravenous tacrolimus for the treatment of acute severe ulcerative colitis. METHODS: Eighty-seven hospitalized acute severe ulcerative colitis patients were enrolled for a prospective cohort study between 2009 and 2017. Sixty-five patients received intravenous tacrolimus and 22 received oral tacrolimus. The primary outcome was the achievement of clinical remission within 2 weeks. Relapse and colectomy incidence and adverse events were assessed at 24 weeks. RESULTS: Response rates of both treatments exceeded 50% but were not significantly different. The remission rate was higher in intravenous tacrolimus compared with oral tacrolimus. At 24 weeks, oral and intravenous tacrolimus showed similar relapse-free survival rates; however, colectomy-free survival rates were higher in intravenous tacrolimus compared with oral tacrolimus. CONCLUSIONS: Patients receiving intravenous tacrolimus achieved superior remission and colectomy-free survival rates compared with patients receiving oral tacrolimus. Safety was similar between the two treatments.


Assuntos
Administração Intravenosa , Colite Ulcerativa , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Humanos , Quimioterapia de Indução , Estudos Prospectivos , Indução de Remissão , Índice de Gravidade de Doença , Resultado do Tratamento
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