Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.078
Filtrar
1.
Rev Med Chil ; 147(6): 803-807, 2019 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-31859835

RESUMO

Pneumococcal meningitis produces several inflammatory disorders in susceptible subjects. A worsening of meningitis can occur on the fourth day of evolution in relation with the withdrawal of steroids. Other complications include the development of inflammatory signs in the post-acute stage of infection associated with disseminated vasculitis of the cerebral blood vessels and, even later, an autoimmune chronic meningitis. All these inflammatory complications are well controlled with the use of steroids. We report a 53-year-old woman with pneumococcal meningitis that had a good response to treatment with antibiotics and steroids. On the four day, after the steroids were discontinued, she complained of headache, became confused, and had an abnormal cerebrospinal fluid (CSF), report CT angiography showed signs of arteritis. She improved when the steroids were re-started. She was discharged in good condition but after slow tapering of the steroids over a four-month period she had a relapse of all her symptoms and had a gait disturbance. On readmission, she had an inflammatory CSF, there were no signs of infection and the cerebral MRI showed meningeal thickening with ventricular space enlargement. She improved again with steroids and she is now well on high-dose steroids but deteriorates each time the steroids are stopped. She experienced both acute and sub-acute inflammatory responses and finally developed a chronic meningitis responsive, and is dependent on steroids.


Assuntos
Doenças Autoimunes/microbiologia , Meningite Pneumocócica/complicações , Antibacterianos/uso terapêutico , Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/tratamento farmacológico , Líquido Cefalorraquidiano/microbiologia , Doença Crônica , Feminino , Humanos , Imagem por Ressonância Magnética , Meningite Pneumocócica/diagnóstico por imagem , Meningite Pneumocócica/tratamento farmacológico , Pessoa de Meia-Idade , Esteroides/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
2.
Expert Opin Ther Pat ; 29(12): 925-941, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31670985

RESUMO

Introduction: PI3Kδ is an important subtype of PI3K kinases, which is mainly expressed in leukocytes and plays an important role in the proliferation, differentiation, maturation and self-reaction of B cells. It is an effective target in the treatment of hematological malignancies and autoimmune diseases such as rheumatoid arthritis. Therefore, many pharmaceutical companies and research institutions have focused on the PI3Kδ subtype in an attempt to develop potent and selective PI3Kδ inhibitors.Areas covered: This review aims to provide an overview of the patented selective PI3Kδ inhibitors in treating cancer from 2015 to present.Expert opinion: Due to the importance of PI3Kδ, the development of selective PI3Kδ inhibitors for the treatment of hematoma and autoimmune diseases is expected. On 23 July 2014, the world's first selective PI3Kδ inhibitor, idelalisib, was approved by the FDA for the treatment of CLL, FL and SLL. Moreover, there are still many small molecule selective PI3Kδ inhibitors at different stages of development. The future research effort for development of PI3Kδ inhibitors is to manage the toxicity and lower the side-effects.


Assuntos
Antineoplásicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Doenças Autoimunes/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Desenvolvimento de Medicamentos , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Patentes como Assunto , Purinas/farmacologia , Quinazolinonas/farmacologia
3.
Rinsho Ketsueki ; 60(10): 1449-1454, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31695006

RESUMO

The clinical course of chronic lymphocytic leukemia (CLL) is often complicated by autoimmune cytopenia (AIC). Here we report a case of a 69-year-old woman with CLL complicated by monoclonal immunoglobulin deposition disease (MIDD) and AIC. The patient was diagnosed with CLL at the age of 63 years and treated with chemotherapy including rituximab and/or fludarabine owing to the development of anemia, multiple lymphadenopathy, and B symptoms at the age of 66 years. Furthermore, pancytopenia and renal failure developed at the age of 68 years. Consequently, the patient was admitted owing to dyspnea. Because of no apparent signs of CLL progression, we concluded that pancytopenia was due to AIC (autoimmune granulocytopenia and thrombocytopenia) and renal anemia. MIDD was diagnosed based on renal histology and detection of IgM and λ chain immunoglobulin deposits on glomeruli and tubules, which were presumed to be derived from CLL cells. The patient was treated with ibrutinib in order to reduce monoclonal protein levels. AIC improved concurrently with IgM reduction 1 month later. Supportive care, involving transfusion and granulocyte colony-stimulating factor, was not required approximately 3 months after initiating ibrutinib treatment. In contrast, MIDD did not improve and maintenance hemodialysis was required. Owing to its antitumor and immunomodulatory effects, ibrutinib may contribute to improve CLL-associated AIC.


Assuntos
Anticorpos Monoclonais , Doenças Autoimunes/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/complicações , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Feminino , Humanos , Rituximab
4.
BMC Neurol ; 19(1): 235, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31610799

RESUMO

BACKGROUND: Rhombencephalitis (RE) is a serious condition of the brain with multiple etiologies. We report a unique case of recurrent, postpartum RE that is associated with positive anti-centromere antibody (ACA). A discussion of the case, current literature on autoimmune RE and related autoantibodies are reviewed. CASE PRESENTATION: A healthy 33-year-old Caucasian patient (gravida 2, para 2) had two episodes of progressive focal neurological deficits during postpartum periods. Signs and symptoms included right-sided dysmetria, adiadochokinesia, weakness, ataxia, and photophobia. MRI revealed rhombencephalitis involving the mesencephalon of the brainstem. Extensive and comprehensive investigations using blood and cerebrospinal fluid (CSF) were consistently positive only for ACA. The first episode was successfully treated with empiric antimicrobial agents and steroid. Given the negative infectious work up with the prior episode and the nearly identical clinical presentations, the second episode was treated with corticosteroid only. This led to complete resolution of her symptoms and reversal of the brain magnetic resonance imaging (MRI) lesions. CONCLUSION: To the author's knowledge, this is the first report of a primary autoimmune RE during postpartum period that is associated with ACA. Immunologic causes should be considered early with any encephalitis. Given the risk of recurrence, relapse, and neurologic deterioration, regular monitoring is recommended, especially for female patients of child-bearing age. Consistent with the current literature on autoimmune RE, steroid seems to be an effective treatment for ACA-associated RE.


Assuntos
Anticorpos Antinucleares/imunologia , Doenças Autoimunes/imunologia , Encefalite/imunologia , Corticosteroides/uso terapêutico , Adulto , Autoantígenos/imunologia , Doenças Autoimunes/tratamento farmacológico , Centrômero/imunologia , Encefalite/diagnóstico , Encefalite/tratamento farmacológico , Feminino , Humanos , Imagem por Ressonância Magnética , Período Pós-Parto/imunologia
5.
Autoimmun Rev ; 18(11): 102390, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520803

RESUMO

Cytokines play a central role in the pathophysiology of autoimmune and inflammatory diseases. Several cytokines signal through the JAK-STAT pathway, which is now recognized as a major target to inhibit the effect of a wide array of cytokines. JAK inhibitors are increasingly used in the setting of inflammatory and autoimmune diseases. While the currently approved drugs are panJAK inhibitors, more selective small molecules are being developed and tested in various rheumatic disorders. In this extensive review, we present evidence- or hypothesis-based perspectives for these drugs in various rheumatologic conditions, such as rheumatoid arthritis, systemic lupus erythematosus, giant cell arteritis, and autoinflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Animais , Humanos
6.
Eur J Med Chem ; 182: 111646, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31521028

RESUMO

The immunoproteasome, a specialized form of proteasome, is mainly expressed in lymphocytes and monocytes of jawed vertebrates and responsible for the generation of antigenic peptides for cell-mediated immunity. Overexpression of immunoproteasome have been detected in a wide range of diseases including malignancies, autoimmune and inflammatory diseases. Following the successful approval of constitutive proteasome inhibitors bortezomib, carfilzomib and Ixazomib, and with the clarification of immunoproteasome crystal structure and functions, a variety of immunoproteasome inhibitors were discovered or rationally developed. Not only the inhibitory activities, the selectivities for immunoproteasome over constitutive proteasome are essential for the clinical potential of these analogues, which has been validated by the clinical evaluation of immunoproteasome-selective inhibitor KZR-616 for the treatment of systemic lupus erythematosus. In this review, structure, function as well as the current developments of various inhibitors against immunoproteasome are going to be summarized, which help to fully understand the target for drug discovery.


Assuntos
Antineoplásicos/farmacologia , Doenças Autoimunes/tratamento farmacológico , Neoplasias Hematológicas/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Animais , Antineoplásicos/química , Doenças Autoimunes/metabolismo , Compostos de Boro/química , Compostos de Boro/farmacologia , Bortezomib/química , Bortezomib/farmacologia , Glicina/análogos & derivados , Glicina/química , Glicina/farmacologia , Neoplasias Hematológicas/metabolismo , Humanos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Inibidores de Proteassoma/química
7.
Brain Nerve ; 71(9): 1003-1012, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31506402

RESUMO

We present a case of a 73-year-old female who developed subacute memory disturbance, reduced consciousness and quadriparesis following pernicious anemia. Brain magnetic resonance imagings (MRI) in diffusion weighted, T2 weighted and fluid attenuated inversion recovery (FLAIR) images revealed hyperintensities in bilateral frontal, parietal, temporal and occipital cortices, left thalamus, bilateral splenium of corpus callosum, and bilateral subcortical white matters. Brain gadolinium enhanced T1 weighted MRI revealed very slight post-contrast enhancement lesions in the right posterior temporal region and bilateral parietal regions. Serum was negative for anti- aquaporin (AQP) 4 antibody, anti-glutamic acid decarboxylase (GAD) antibody and anti-voltage-gated potassium channel (VGKC) antibody, and cerebrospinal fluid (CSF) was negative for anti- N-methyl-D-aspartate (NMDA) receptor antibody. CSF analysis showed slight protein elevation with normal cellular content. No evidence of neoplasm was observed using whole-body 18 F -fluorodeoxyglucose- positron emission tomography/computed tomography. Pathological findings of the left frontal lesion revealed perivascular and scattered parechymal T-lymphocytic infiltration, and astrogliosis without vascular hyalinization. Patient achieved partial recovery during two intraveneous pulse methylprednisolone treatments, and exacerbation afterwards. After the third intraveneous pulse methylprednisolone treatment, remission is sustained for six years. This case can be regarded as autoantibody-negative but probable autoimmune encephalitis with the features of nonparaneoplastic panencephalitis and treatable dementia. Nonparaneoplastic autoimmune panencephalitis with widespread multifocal brain lesions on brain MRI is extremely rare, with exception of anti- NMDA receptor antibody encephalitis.


Assuntos
Anemia Perniciosa/complicações , Doenças Autoimunes/etiologia , Demência/etiologia , Encefalite/etiologia , Idoso , Doenças Autoimunes/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Demência/tratamento farmacológico , Encefalite/tratamento farmacológico , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética
8.
N Engl J Med ; 381(10): 923-932, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483963

RESUMO

BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 µg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).


Assuntos
Doenças Autoimunes/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Administração por Inalação , Adulto , Idoso , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico por imagem , Método Duplo-Cego , Esquema de Medicação , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Proteinose Alveolar Pulmonar/diagnóstico por imagem , Proteinose Alveolar Pulmonar/imunologia , Capacidade de Difusão Pulmonar , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Fumar/efeitos adversos , Tomografia Computadorizada por Raios X , Teste de Caminhada
9.
Expert Opin Ther Pat ; 29(9): 663-674, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31403347

RESUMO

Introduction: RORγt is critical for the differentiation of Th17 cells and the production of IL-17. Inhibition of RORγt is considered as a promising strategy to treat Th17-mediated autoimmune diseases. Quite a number of RORγt inhibitors have been progressed into clinical trials, besides much biological interests in this attractive target. Areas covered: This article reviews the progress of RORγt inhibitors (antagonists and inverse agonists) that are active in clinical development based on an analysis of the related patents published by the corresponding companies in the period of January 2016 through May 2019. Expert opinion: The development of RORγt inhibitors has gone through a boom period in the past three years. However, with a little bit frustration, some of the frontrunner clinical compounds were either discontinued or suspended for further development possibly due to some safety concerns or lack of efficacy in humans. There is a need to probe deeply into these concerns in the on-going pre-clinical and clinical studies. Given the effectiveness of a few recently FDA-approved anti-IL-17(R) antibodies on psoriasis, the discovery of RORγt inhibitors continues to be an exciting field for the development of novel treatment approaches.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Animais , Doenças Autoimunes/imunologia , Descoberta de Drogas , Humanos , Interleucina-17/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Patentes como Assunto , Células Th17/imunologia
10.
Transfus Apher Sci ; 58(4): 449-452, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31395426

RESUMO

Ghosal hematodiaphyseal dysplasia (GHDD) is an autosomal recessive inherited disorder associated with biallelic mutations in the TBXAS1 gene located on the chromosome 7q33-34, which encodes thromboxane-A-synthase. GHDD is characterized by defective hematopoiesis due to bone marrow fibrosis and metadiaphyseal dysplasia of long bones. The accurate diagnosis of this rare syndrome is critical since it reduces the need of blood transfusions by corticosteroid therapy, leading to a significant improvement in anemia and bone changes. The aim of this study is to report two adult siblings diagnosed as GHDD, who admitted with pancytopenia and treated with steroids treatment in adult hematology clinic.


Assuntos
Anemia Refratária , Anemia , Doenças Autoimunes , Cromossomos Humanos Par 7/genética , Mutação , Osteocondrodisplasias , Irmãos , Adulto , Anemia/diagnóstico por imagem , Anemia/tratamento farmacológico , Anemia/genética , Anemia Refratária/diagnóstico por imagem , Anemia Refratária/tratamento farmacológico , Anemia Refratária/genética , Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Humanos , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/tratamento farmacológico , Osteocondrodisplasias/genética
11.
EBioMedicine ; 46: 381-386, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31371192

RESUMO

BACKGROUND: Alemtuzumab is approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab-related secondary autoimmune disorders (sAID) are common, with thyroid sAID being the most frequent, and fundamentally affect the risk-benefit ratio. Therefore, biomarkers indicating the development of sAID are urgently needed to instruct clinical decisions. METHODS: We evaluated whether the anti-thyroid autoantibodies (ThyAb) anti-thyroglobulin (anti-TG) and anti-thyroid-peroxidase (anti-TPO) detected at baseline by standard testing are able to indicate increased risk for thyroid sAID following alemtuzumab treatment in a multicentre prospective cohort of 106 alemtuzumab-treated RRMS patients. We here present an interim-analysis with a median follow-up of 36 months. FINDINGS: Baseline characteristics demonstrated no significant differences between patients with or without thyroid sAID. 29/106 (27·4%) patients developed thyroid sAID between 5 and 51 months following alemtuzumab treatment initiation. 14/29 patients (48·3%) were positive for ThyAb at baseline and developed thyroid sAID. Hazard ratio for time to thyroid autoimmunity was 12.15 (95% CI 4.73-31.2) indicating a highly increased risk for ThyAb positive patients. Baseline ThyAb were associated with shorter time to sAID, but not with a specific disease entity of thyroid sAID. Hazard ratios for age, sex, previous treatment, disease duration, disability and smoking status demonstrated no significant association with thyroid autoimmunity. INTERPRETATION: Standard ThyAb-testing for anti-TPO and anti-TG antibodies at baseline was able to indicate increased risk for clinically manifest thyroid sAID and should therefore be used in clinical decisions concerning alemtuzumab treatment initiation. FUND: German Ministry of Education, Science, Research and Technology and the German Research foundation.


Assuntos
Alemtuzumab/efeitos adversos , Autoanticorpos/farmacologia , Autoimunidade/efeitos dos fármacos , Glândula Tireoide/imunologia , Adulto , Antineoplásicos Imunológicos/efeitos adversos , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais
12.
Eur J Med Chem ; 182: 111591, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419779

RESUMO

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) - stimulator of interferon genes (STING) signaling pathway plays the critical role in the immune response to DNA. Pharmacological modulation of the STING pathway has been well characterized both from structural and functional perspectives, which paves the way for the drug design of small modulators by medicinal chemists. Here, we outline recent progress in studies on the STING pathway, the structure and biological function of STING, the STING related disease, as well as the rationale and progress in the development of STING modulators. Our review demonstrates that STING is a promising drug target, and providing clues for the discovery of novel STING agonists and antagonists for the potential treatment of various disease including microbial infectious diseases, cancer, and autoimmune disease.


Assuntos
Descoberta de Drogas , Proteínas de Membrana , Neoplasias/tratamento farmacológico , Nucleotídeos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Xantonas/farmacologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/metabolismo , Humanos , Proteínas de Membrana/agonistas , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Crit Rev Oncol Hematol ; 142: 51-57, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31376677

RESUMO

The biological milieu and clinical picture of myelodysplastic syndromes (MDS) is characterised by a variety of immune mechanisms and manifestations, including an increased frequency of autoimmune disorders. The present review will try to shed some light on the potential clinical and pathogenetic implications of these immune processes in MDS by focusing on the beneficial effects exerted by some MDS-modifying therapies on autoimmune manifestations.


Assuntos
Doenças Autoimunes/terapia , Autoimunidade , Síndromes Mielodisplásicas/terapia , Doenças Autoimunes/tratamento farmacológico , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/imunologia
14.
BMJ Case Rep ; 12(8)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31377716

RESUMO

Thymoma-associated multiorgan autoimmunity is a relatively new term to describe the rare paraneoplastic syndrome that complicates thymoma, which can involve the thyroid, liver and intestine in addition to the skin. The pathology often indicates a graft-versus-host-like pattern commonly observed in recipients of an allogeneic haematopoietic cell transplant. We report a case of type B2 and B3 thymoma with invasion to the lung and pleura in a patient who presented with oral lichen planus and graft-versus-host-like erythroderma. The cutaneous lesions improved after complete resection of the thymoma in combination with systemic glucocorticoids, which was subsequently complicated by cytomegalovirus pneumonitis.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Glucocorticoides/uso terapêutico , Timoma/cirurgia , Neoplasias do Timo/cirurgia , Doenças Autoimunes/etiologia , Terapia Combinada , Glucocorticoides/efeitos adversos , Humanos , Biópsia Guiada por Imagem , Líquen Plano Bucal/etiologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Pleura/patologia , Timoma/complicações , Timoma/patologia , Neoplasias do Timo/complicações , Neoplasias do Timo/patologia
15.
Mini Rev Med Chem ; 19(18): 1531-1543, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31288716

RESUMO

The search for inhibitors of the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) has been ongoing for several decades and has resulted in a number of JAK inhibitors being approved for use in patients, such as tofacitinib for the treatment of autoimmune diseases such as Rheumatoid Arthritis (RA). Although initially thought to be a JAK3 selective inhibitor, tofacitinib was subsequently found to possess significant activity to inhibit JAK1 and JAK2 which has contributed to some adverse side effects. A selective JAK3 inhibitor should only have an effect within the immune system since JAK3 is solely expressed in lymphoid tissue; this makes JAK3 a target of interest in the search for treatments of autoimmune diseases. A method to obtain selectivity for JAK3 over the other JAK family members, which has attracted more scientific attention recently, is the targeting of the active site cysteine residue, unique in JAK3 within the JAK family, with compounds containing electrophilic warheads which can form a covalent bond with the nucleophilic thiol of the cysteine residue. This review encompasses the historical search for a covalent JAK3 inhibitor and the most recently published research which hasn't been reviewed to date. The most important compounds from the publications reviewed the activity and selectivity of these compounds together with some of the more important biological results are condensed in to an easily digested form that should prove useful for those interested in the field.


Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Amidas/química , Amidas/metabolismo , Amidas/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Derivados de Benzeno/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Janus Quinase 3/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico
16.
Expert Opin Drug Saf ; 18(8): 733-744, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173698

RESUMO

Objectives: To examine agreement between the FDA Adverse Event Reporting System (FAERS) and observational studies in common infections for tumor necrosis factor inhibitors (TNFi's). Methods: Using MedDRA® preferred terms, all infection cases in FAERS with each TNFi were retrieved using EvidexTM. Observational studies reporting TNFi-related infections were identified from PubMed (OS-PM) and ClinicalTrials.gov (OS-CT). Infections with a reporting rate of ≥2% (based on percentage of total number of infections) from each data source were compiled. Fleiss's kappa and Cohen's kappa (κ) were calculated to determine agreement across all three sources and between each two sources. Results: A total of 163,789 FAERS infection cases, 53 OS-PM studies and 52 OS-CT studies were identified. The Fleiss' kappa that comparing all 3 data sources demonstrated lack of agreement. Significant moderate agreements were found between FAERS and OS-CT for etanercept and adalimumab, respectively (κ = 0.53, p = 0.02; κ = 0.56, p = 0.02), but no agreements (κ < 0) when comparing FAERS vs. OS-PM or OS-CT vs. OS-PM. Conclusion: For common TNFi-related infections, passive (FAERS) and active (observational studies) pharmacovigilance results are similar between FAERS vs. OS-CT for etanercept and adalimumab but dissimilar across the 3 sources. Our findings suggest incorporating both active and passive pharmacovigilance methods in post-marketing drug safety assessment.


Assuntos
Fatores Imunológicos/efeitos adversos , Farmacovigilância , Vigilância de Produtos Comercializados/métodos , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Doenças Autoimunes/tratamento farmacológico , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Humanos , Fatores Imunológicos/administração & dosagem , Vigilância de Produtos Comercializados/estatística & dados numéricos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Estados Unidos , United States Food and Drug Administration
17.
MAbs ; 11(6): 1175-1190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31181988

RESUMO

We describe a bispecific dual-antagonist antibody against human B cell activating factor (BAFF) and interleukin 17A (IL-17). An anti-IL-17 single-chain variable fragment (scFv) derived from ixekizumab (Taltz®) was fused via a glycine-rich linker to anti-BAFF tabalumab. The IgG-scFv bound both BAFF and IL-17 simultaneously with identical stoichiometry as the parental mAbs. Stability studies of the initial IgG-scFv revealed chemical degradation and aggregation not observed in either parental antibody. The anti-IL-17 scFv showed a high melting temperature (Tm) by differential scanning calorimetry (73.1°C), but also concentration-dependent, initially reversible, protein self-association. To engineer scFv stability, three parallel approaches were taken: labile complementary-determining region (CDR) residues were replaced by stable, affinity-neutral amino acids, CDR charge distribution was balanced, and a H44-L100 interface disulfide bond was introduced. The Tm of the disulfide-stabilized scFv was largely unperturbed, yet it remained monodispersed at high protein concentration. Fluorescent dye binding titrations indicated reduced solvent exposure of hydrophobic residues and decreased proteolytic susceptibility was observed, both indicative of enhanced conformational stability. Superimposition of the H44-L100 scFv (PDB id: 6NOU) and ixekizumab antigen-binding fragment (PDB id: 6NOV) crystal structures revealed nearly identical orientation of the frameworks and CDR loops. The stabilized bispecific molecule LY3090106 (tibulizumab) potently antagonized both BAFF and IL-17 in cell-based and in vivo mouse models. In cynomolgus monkey, it suppressed B cell development and survival and remained functionally intact in circulation, with a prolonged half-life. In summary, we engineered a potent bispecific antibody targeting two key cytokines involved in human autoimmunity amenable to clinical development.


Assuntos
Anticorpos Biespecíficos , Doenças Autoimunes/tratamento farmacológico , Fator Ativador de Células B/antagonistas & inibidores , Interleucina-17/antagonistas & inibidores , Anticorpos de Cadeia Única , Animais , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Fator Ativador de Células B/imunologia , Feminino , Células HEK293 , Células HT29 , Humanos , Interleucina-17/imunologia , Macaca fascicularis , Camundongos , Camundongos Transgênicos , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacologia
18.
Med. clín (Ed. impr.) ; 152(12): 502-507, jun. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-183322

RESUMO

Pneumocystis jirovecii (P. jirovecii) causes a potentially fatal pneumonia in immunocompromised individuals (Pneumocystis pneumonia or PcP), particularly in HIV-infected patients and those treated with immunosuppressive drugs, such as transplant patients and those with systemic autoimmune diseases. P. jirovecii colonization can be found in almost a third of patients with systemic autoimmune diseases. Although the incidence of PcP in such patients is usually low, mortality is quite high, ranging between 30% and 50% in the majority of autoimmune diseases. PcP development is almost always observed in patients not receiving prophylaxis for the infection. Despite the above, there are no clinical guidelines established for PcP prophylaxis in patients with autoimmune diseases treated with glucocorticoids, cytotoxic drugs, or more recently, biological agents. The objective of this review is to analyze the available data on the incidence of PcP and the effect of PcP prophylaxis in patients with autoimmune diseases that may be useful in clinical practice


El hongo Pneumocystis jirovecii (P. jirovecii) es la causa de una neumonía (Pneumocystis pneumonia o PcP) potencialmente mortal en individuos inmunodeprimidos, sobre todo en pacientes infectados por el VIH, y en aquellos tratados con fármacos inmunodepresores, como los sometidos a trasplantes y los afectos de enfermedades autoinmunes sistémicas. En estos últimos, alrededor de un tercio de los casos puede estar colonizado por P. jirovecii y, aunque la incidencia de la PcP suele ser baja, la mortalidad de la misma es considerablemente alta, y oscila entre el 30 y el 50% en la mayoría de las enfermedades autoinmunes. El desarrollo de la PcP se observa casi siempre en pacientes que no reciben profilaxis para la infección. Aun así, no existen guías clínicas establecidas para la profilaxis de la PcP en pacientes afectos de enfermedades autoinmunes que son tratados con glucocorticoides, fármacos citotóxicos o más recientemente, con agentes biológicos. El objetivo de esta revisión es analizar los datos disponibles sobre la incidencia de la PcP y el efecto de la profilaxis para infección por P. jirovecii en los pacientes afectos de enfermedades autoinmunes que puedan ser útiles en la práctica clínica


Assuntos
Humanos , Pneumonia por Pneumocystis/diagnóstico , Pneumocystis carinii/isolamento & purificação , Doenças Autoimunes/epidemiologia , Pneumocystis carinii/efeitos dos fármacos , Doenças Autoimunes/tratamento farmacológico , Glucocorticoides/administração & dosagem , Ciclofosfamida/administração & dosagem , Rituximab/administração & dosagem
19.
Pediatr Rheumatol Online J ; 17(1): 19, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046790

RESUMO

BACKGROUND: CANDLE syndrome (an acronym for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) is a recently described rare autosomal recessive disorder charaterized by systemic autoinflammation. Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive. This syndrome is caused by loss of function mutations and malfunction of the immunoproteasome complex. Most patients have biallelic mutations in the PSMB8 gene that encodes the ß5i catalytic subunit of the immunoproteasome. Examples of digenic inheritance have been also described in CANDLE. CANDLE patients have strong type I interferon gene expression signature and they are responsive to treatment with JAK inhibitors. However, possible serious side-effects remain a concern. Here, we report another patient with CANDLE whose disease activity was well controlled by the treatment with baricitinib. CASE PRESENTATION: We report a Bulgarian patient of the Turkish ancestry who carries biallelic mutations in the PSMB8 gene: p.Ala92Val and p.Lys105Gln. The pathogenic variant p.Ala92Val has not been previously described in patients with CANDLE. We also comment on the unusual feature in this patient, nephrolithiasis, that has not been described in other patients, however it might be related to the positive family history for kidney stones. We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth. The treatment with glucocorticoids (GC) was completely discontinued. No side effects have been observed, however they remain in consideration for a life-long therapy of this disease. CONCLUSIONS: CANDLE should be suspected in patients with early-onset systemic inflammatory disease and prominent skin manifestations. Molecular testing can confirm the clinical diagnosis and is very important in guiding therapies. Treatment with JAK inhibitors is highly efficacious and appears to be safe in children with CANDLE and other intereforonopathies.


Assuntos
Azetidinas/uso terapêutico , Dermatite/tratamento farmacológico , Febre/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Lipodistrofia/tratamento farmacológico , Neutropenia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Criança , Doença Crônica , Dermatite/complicações , Febre/complicações , Humanos , Lipodistrofia/complicações , Masculino , Neutropenia/complicações , Complexo de Endopeptidases do Proteassoma/imunologia , Síndrome , Resultado do Tratamento
20.
Nutrients ; 11(5)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052496

RESUMO

Over recent decades, many clinical trials on curcumin supplementation have been conducted on various autoimmune diseases including osteoarthritis, type 2 diabetes, and ulcerative colitis patients. This review attempts to summarize the highlights from these clinical trials. The efficacy of curcumin either alone or in conjunction with existing treatment was evaluated. Sixteen clinical trials have been conducted in osteoarthritis, 14 of which yielded significant improvements in multiple disease parameters. Eight trials have been conducted in type 2 diabetes, all yielding significant improvement in clinical or laboratory outcomes. Three trials were in ulcerative colitis, two of which yielded significant improvement in at least one clinical outcome. Additionally, two clinical trials on rheumatoid arthritis, one clinical trial on lupus nephritis, and two clinical trials on multiple sclerosis resulted in inconclusive results. Longer duration, larger cohort size, and multiple dosage arm trials are warranted to establish the long term benefits of curcumin supplementation. Multiple mechanisms of action of curcumin on these diseases have been researched, including the modulation of the eicosanoid pathway towards a more anti-inflammatory pathway, and the modulation of serum lipid levels towards a favorable profile. Overall, curcumin supplementation emerges as an effective therapeutic agent with minimal-to-no side effects, which can be added in conjunction to current standard of care.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Curcumina/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Nefrite Lúpica/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA