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1.
J Med Virol ; 94(1): 291-297, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34491575

RESUMO

Due to current advances and growing experience in the management of coronavirus Disease 2019 (COVID-19), the outcome of COVID-19 patients with severe/critical illness would be expected to be better in the second wave compared with the first wave. As our hospitalization criteria changed in the second wave, we aimed to investigate whether a favorable outcome occurred in hospitalized COVID-19 patients with only severe/critical illness. Among 642 laboratory-confirmed hospitalized COVID-19 patients in the first wave and 1121 in the second wave, those who met World Health Organization (WHO) definitions for severe or critical illness on admission or during follow-up were surveyed. Data on demographics, comorbidities, C-reactive protein (CRP) levels on admission, and outcomes were obtained from an electronic hospital database. Univariate analysis was performed to compare the characteristics of patients in the first and second waves. There were 228 (35.5%) patients with severe/critical illness in the first wave and 681 (60.7%) in the second wave. Both groups were similar in terms of age, gender, and comorbidities, other than chronic kidney disease. Median serum CRP levels were significantly higher in patients in the second wave compared with those in the first wave [109 mg/L (interquartile range [IQR]: 65-157) vs. 87 mg/L (IQR: 39-140); p < 0.001]. However, intensive care unit admission and mortality rates were similar among the waves. Even though a lower mortality rate in the second wave has been reported in previous studies, including all hospitalized COVID-19 patients, we found similar demographics and outcomes among hospitalized COVID-19 patients with severe/critical illness in the first and second wave.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/mortalidade , Cuidados Críticos/estatística & dados numéricos , Índice de Gravidade de Doença , Idoso , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Azitromicina/uso terapêutico , Proteína C-Reativa/análise , COVID-19/epidemiologia , COVID-19/patologia , Comorbidade , Combinação de Medicamentos , Enoxaparina/uso terapêutico , Feminino , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Hidroxicloroquina/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Lopinavir/uso terapêutico , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Pirazinas/uso terapêutico , Estudos Retrospectivos , Ritonavir/uso terapêutico , SARS-CoV-2 , Resultado do Tratamento , Turquia/epidemiologia
3.
Nat Commun ; 12(1): 5981, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645812

RESUMO

The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape.


Assuntos
Inibidores de Adenilil Ciclases/farmacologia , Adenilil Ciclases/genética , Antineoplásicos/farmacologia , AMP Cíclico/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Inibidores de Adenilil Ciclases/síntese química , Adenilil Ciclases/imunologia , Animais , Antineoplásicos/síntese química , Compostos de Benzil/química , AMP Cíclico/imunologia , AMP Cíclico/metabolismo , Ésteres , Feminino , Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Injeções Intralesionais , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Micelas , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Células Mieloides/patologia , Peptídeos/química , Ácido Poliglutâmico/química , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Sarcosina/análogos & derivados , Sarcosina/química , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Carga Tumoral/efeitos dos fármacos , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
4.
Curr Cardiol Rep ; 23(11): 170, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34633515

RESUMO

PURPOSE OF REVIEW: Aim of the review is to discuss the results of major clinical trials and how they can have impact on clinical practice. RECENT FINDINGS: Pericardial diseases have been the Cinderella of cardiovascular diseases for many years, but improvements in the knowledge of etiology and the pathophysiology especially of recurrent pericarditis have led to first clinical trials that have demonstrated the efficacy and safety of colchicine on top of standard anti-inflammatory therapies and of anti-IL-1 agents (anakinra and rilonacept) in corticosteroid-dependent and colchicine-resistant pericarditis. Current pooled data suggest that anti-IL-1 agents should be a first option for corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation by means of elevated C-reactive protein. This could translate into an upgraded recommendation for these agents in future guidelines. Treatment of pericardial diseases is improving moving towards a more personalized therapy according to the presentation and etiology, and new or old drugs could be important to expand the therapeutic spectrum.


Assuntos
Pericardite , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Colchicina/uso terapêutico , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Pericardite/tratamento farmacológico
8.
Women Health ; 61(9): 872-879, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34551674

RESUMO

Anakinra, which is an Interleukin-1 (IL-1) receptor antagonist with the advancing disease process, has started to be considered as an alternative treatment for Covid-19 patients with cytokine storms. We evaluated the effect of corticosteroids and IL-1 receptor blockage with anakinra on pregnant patients with Covid-19 at high risk for respiratory distress, ongoing fever, deterioration in their general condition and consequently maternal and fetal complications. Fourteen pregnant women who received anakinra (median dosage: 400 mg) and corticosteroid (methylprednisolone-median dosage: 80 mg) treatment were evaluated retrospectively. Patients were assessed according to the World Health Organization (WHO) scale. The mortality rate of the cohort was 7.1%, the median hospitalization period of the patients was 15 days and 2 patients had premature births. Covid-19 was found to have a similar spectrum of symptoms in pregnant and non-pregnant women, such as dyspnea, cough and fever. Our study was the first to analyze the combined treatment of corticosteroid and anakinra in pregnant patients with pneumonia from Covid-19 based on the WHO scoring system. Due to the obscurity in the treatment process in pregnant patients, studies are ongoing on managing Covid-19 infection in these patients. We presume that the early use of anakinra and corticosteroid treatments in patients severely infected with Covid-19 may have positive effects on disease progression and survival.


Assuntos
COVID-19 , Proteína Antagonista do Receptor de Interleucina 1 , Corticosteroides , Feminino , Humanos , Gravidez , Gestantes , Estudos Retrospectivos , SARS-CoV-2
9.
Nat Med ; 27(10): 1752-1760, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34480127

RESUMO

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/ß inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.


Assuntos
COVID-19/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Idoso , COVID-19/virologia , Método Duplo-Cego , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos , SARS-CoV-2/isolamento & purificação
11.
J Dermatol ; 48(11): 1789-1792, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34435697

RESUMO

Schnitzler syndrome is characterized by chronic urticarial rash, neutrophilic dermal infiltrate, recurrent fever, bone pain, elevated C-reactive protein, and neutrophilic leukocytosis. The pathophysiology of Schnitzler syndrome is unknown, but it is considered to be an acquired form of an autoinflammatory disease because of the resemblance to clinical phenotypes of cryopyrin-associated periodic syndrome, in which a gain-of-function mutation in NLRP3 causes overexpression of interleukin (IL)-1ß. Schnitzler syndrome is generally accompanied by a monoclonal immunoglobulin (Ig)M gammopathy with a long-term risk of lymphoproliferation that is possibly associated with an MYD88 mutation. Herein, we present the following four patients with Schnitzler syndrome: a 63-year-old woman; a 65-year-old man; a 43-year-old woman; and a 63-year-old woman. Each patient fulfilled the Strasbourg diagnostic criteria, but none of the patients had any mutation in NLRP3 or MYD88 detected in their peripheral blood. Although approved treatment options for Schnitzler syndrome are lacking, our patients were treated with IL-1-targeted therapy (anakinra or canakinumab) or anti-IL-6 (tocilizumab). The acute inflammatory clinical manifestations improved completely with canakinumab and partially with anakinra and tocilizumab, but the serum IgM levels were gradually increased in all patients, even during treatment. To determine whether treatment with anti-IL-1ß or IL-6 prevents conversion to a hematopoietic disorder, further collection of cases and long-term follow-up will be needed.


Assuntos
Interleucina-6 , Síndrome de Schnitzler , Adulto , Idoso , Anticorpos Monoclonais , Feminino , Humanos , Imunoglobulina M , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Síndrome de Schnitzler/diagnóstico , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/genética
13.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343136

RESUMO

IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-1beta/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diferenciação Celular/imunologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/imunologia , Ligante RANK/imunologia , Linfócitos T Reguladores/metabolismo
14.
Clin Exp Rheumatol ; 39 Suppl 132(5): 75-79, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34369359

RESUMO

OBJECTIVES: To evaluate the efficacy of IL-1 blockers in a cohort of patients with colchicine-resistant familial Mediterranean fever (crFMF) treated consecutively with anakinra and canakinumab. METHODS: Patients with crFMF treated with anakinra and canakinumab in any order were identified using the computerised database of Sheba Medical Centre. Background characteristics of the patients, reason for switching IL-1 inhibitor, and frequency of attacks under colchicine only, anakinra, and canakinumab were extracted from the computerised patient files. Patients were then interviewed for patient-reported outcomes. RESULTS: A total of 46 patients in our clinic were prescribed canakinumab for crFMF after previous anakinra treatment, whereas no patients who switched treatment from canakinumab to anakinra were identified. Of those, 23/46 patients (50%) discontinued anakinra due to inadequate response (11 of them with secondary failure after a good initial response). Frequency of flares was significantly decreased following switch to canakinumab from anakinra treatment (p<0.01). After the switch to canakinumab, the median duration of flares, the severity of pain during a flare, and the patient's global assessment of disease activity were all significantly decreased (p≤0.01), according to the reports from the patients. CONCLUSIONS: Canakinumab is an effective treatment for FMF after failure of anakinra due to any cause.


Assuntos
Febre Familiar do Mediterrâneo , Anticorpos Monoclonais Humanizados , Colchicina , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1 , Resultado do Tratamento
15.
J Trop Pediatr ; 67(3)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34363079

RESUMO

BACKGROUND: The severity of Helicobacter pylori infection is determined by the interplay between bacterial virulence, host genetic and environmental factors. This study aimed to identify interleukin-1 beta (IL-1ß) and interleukin receptor antagonist (IL-1RN) gene polymorphisms and their associations with H. pylori infection, and severity of chronic gastritis in Egyptian children. METHODS: A case control study was conducted on 100 children (50 H. pylori positive and 50 controls). Genotyping of IL-1ß-31 gene was done by PCR-CTPP (confronting two-pair primers), of IL-1ß-511 was performed using allele specific PCR, and investigation of the variable number tandem repeat polymorphism of the IL-1RN gene was done by PCR. RESULTS: The genotype C/T of IL1ß-511 was the predominant genotype (36/50; 72%) among H. pylori positive cases (p ≤ 0.001). The presence of C/T genotype at position 511 of IL1ß was associated with increased risk of infection with H. pylori (p ≤ 0.001, odds ratio = 6.612) and with more severe disease (p = 0.004, odds ratio = 8.333). No association of IL-1ß-31 or IL-1RN gene polymorphisms with H. pylori infection or with risk of severe gastric diseases was found. Children who carry two polymorphisms are almost four times at risk for development of H. pylori infection (p = 0.026, odds ratio = 3.937). CONCLUSIONS: Polymorphism at position -511 of IL1ß gene is associated with increased risk of H. pylori infection as well as of severe corpus gastric disease in Egyptian children. This population should be considered a high-risk group, which needs regular gastric endoscopic surveillance, and should be target for H. pylori eradication. Lay summaryThe genotype C/T of IL1ß-511 gene was the predominant genotype (36/50; 72%) among H. pylori positive children. Polymorphism at position -511 of IL1ß gene is associated with increased risk of Helicobacter pylori infection as well as of severe corpus gastric disease in Egyptian children. No association of IL-1ß-31 or IL-1RN gene polymorphisms with H. pylori infection or with risk of severe gastric diseases in Egyptian children.


Assuntos
Gastrite , Infecções por Helicobacter , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta , Estudos de Casos e Controles , Criança , Gastrite/genética , Gastrite/microbiologia , Predisposição Genética para Doença , Genótipo , Infecções por Helicobacter/epidemiologia , Helicobacter pylori , Humanos , Interleucina-1beta/genética , Polimorfismo Genético
16.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360845

RESUMO

Psoriasis (PS) is a skin disease with autoimmune features mediated by immune cells, which typically presents inflammatory erythematous plaques, and is associated with many comorbidities. PS exhibits excessive keratinocyte proliferation, and a high number of immune cells, including macrophages, neutrophils, Th1 and Th17 lymphocytes, and mast cells (MCs). MCs are of hematopoietic origin, derived from bone marrow cells, which migrate, mature, and reside in vascularized tissues. They can be activated by antigen-provoking overexpression of proinflammatory cytokines, and release a number of mediators including interleukin (IL)-1 and IL-33. IL-1, released by activated keratinocytes and MCs, stimulates skin macrophages to release IL-36-a powerful proinflammatory IL-1 family member. IL-36 mediates both innate and adaptive immunity, including chronic proinflammatory diseases such as psoriasis. Suppression of IL-36 could result in a dramatic improvement in the treatment of psoriasis. IL-36 is inhibited by IL-36Ra, which binds to IL-36 receptor ligands, but suppression can also occur by binding IL-38 to the IL-36 receptor (IL-36R). IL-38 specifically binds only to IL-36R, and inhibits human mononuclear cells stimulated with IL-36 in vitro, sharing the effect with IL-36Ra. Here, we report that inflammation in psoriasis is mediated by IL-1 generated by MCs-a process that activates macrophages to secrete proinflammatory IL-36 inhibited by IL-38. IL-37 belongs to the IL-1 family, and broadly suppresses innate inflammation via IL-1 inhibition. IL-37, in murine models of inflammatory arthritis, causes the suppression of joint inflammation through the inhibition of IL-1. Therefore, it is pertinent to think that IL-37 can play an inhibitory role in inflammatory psoriasis. In this article, we confirm that IL-38 and IL-37 cytokines emerge as inhibitors of inflammation in psoriasis, and hold promise as an innovative therapeutic tool.


Assuntos
Interleucina-1/imunologia , Interleucinas/uso terapêutico , Psoríase/imunologia , Animais , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/uso terapêutico , Interleucina-33/imunologia , Interleucinas/imunologia , Mastócitos/imunologia , Mastócitos/metabolismo , Psoríase/tratamento farmacológico , Pele
17.
Arthritis Res Ther ; 23(1): 216, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412663

RESUMO

BACKGROUND: Excessive osteoclast activity, which is strongly stimulated by pro-inflammatory mediators, results in bone and cartilage degeneration as central features of many arthritides. Levels of the alarmin S100A8/A9 and interleukin (IL)-1ß are both increased in arthritis patients and correlate with disease activity and progression of tissue erosion. We previously presented S100A8/A9 as a good biomarker for joint inflammation and arthritis pathology under circumstances of high IL-1 signaling in mice that lack the gene encoding IL-1 receptor antagonist (Il1rn-/- mice). Here, we investigated whether S100A8/A9 is also actively involved in the development of joint inflammation and both cartilage and bone pathology under these conditions by comparing Il1rn-/- mice with mice that have an additional deficiency for S100a9 (Il1rn-/-XS100a9-/-). METHODS: Il1rn-/-XS100a9-/- on a BALB/c background were obtained by crossing S100a9-/- mice and Il1rn-/- mice. Arthritis incidence and severity were macroscopically scored. Myeloid cell populations in the bone marrow and spleen were determined using flow cytometry. In vitro osteoclastogenesis of bone marrow cells was evaluated with TRAP staining. Microscopic joint inflammation, cartilage degeneration, and bone destruction were evaluated using histology of ankle joints of 12- and 20-week-old mice. RESULTS: Macroscopically scored arthritis severity was comparable between Il1rn-/- and Il1rn-/-XS100a9-/- mice. Inflammation, cartilage erosion, and bone erosion were clearly present in 12-week-old mice of both strains lacking Il1rn-/-, but not significantly different between Il1rn-/-XS100a9-/- and Il1rn-/-. Moreover, we observed that the numbers of neutrophils and monocytes were increased by the absence of Il1rn, which was affected by the absence of S100a9 only in the spleen but not in the bone marrow. In line with our other findings, the absence of S100a9 did not affect the osteoclastogenic potential of osteoclast precursors in the absence of Il1rn. Finally, in agreement with the findings in early arthritis development in 12-week-old mice, cartilage and bone erosion in 20-week-old mice was significantly higher in both Il1rn-/- strains, but the additional absence of S100a9 did not further affect tissue pathology. CONCLUSION: S100A8/A9 deficiency does not significantly affect inflammation and joint destruction in mice with high IL1ß signaling suggesting that S100A8/A9 is not essential for the development of arthritis under these conditions.


Assuntos
Artrite Experimental , Calgranulina A , Calgranulina B , Proteína Antagonista do Receptor de Interleucina 1 , Animais , Artrite Experimental/genética , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Humanos , Inflamação/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
18.
Nat Immunol ; 22(9): 1118-1126, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34326534

RESUMO

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.


Assuntos
Proteínas de Ligação a DNA/genética , Doenças Hereditárias Autoinflamatórias/genética , Doenças Inflamatórias Intestinais/genética , Macrófagos/imunologia , Fatores de Transcrição/genética , Animais , Calgranulina A/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Lipocalina-2/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th17/imunologia , Transcrição Genética/genética , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo
19.
Clin Exp Rheumatol ; 39 Suppl 132(5): 30-36, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34251317

RESUMO

OBJECTIVES: Anakinra and canakinumab are the most commonly used agents in colchicine resistant/intolerant patients. In this study we investigated long-term efficacy and safety of anakinra and canakinumab. METHODS: In this retrospective study, we enrolled 101 adult patients with familial Mediterranean fever (FMF). Clinical and laboratory parameters before and after treatment with anakinra/canakinumab and the side effects observed during the treatment were recorded. All patients received anakinra initially and switched to canakinumab, in case of inadequate response/intolerance. RESULTS: The median (IQR) duration of treatment with anti-IL-1 agents was 35 (24-47.5) months. 101 patients were treated with anakinra and 27 patients with canakinumab. The autoinflammatory diseases activity and attacks decreased with both anakinra and canakinumab. Anakinra was effective in decreasing proteinuria and canakinumab was not effective in decreasing proteinuria in anakinra unresponsive patients. The modified FMF score was achieved in 76.2% of anakinra and 88.9% of canakinumab group. Injection site reactions (ISRs, n:15) was the most common reason of discontinuation of anakinra and most of ISRs developed in first 3 months of treatment. One severe skin rash, two anaphylactic reactions and one severe neutropenia were observed with anakinra; in the first, eighth, twelfth and fiftieth months, respectively. No severe side effects or side effect-related discontinuation of canakinumab were observed. CONCLUSIONS: Anakinra and canakinumab seem to be effective in long-term management of FMF patients. Canakinumab had a favourable safety/tolerability profile. Anakinra is also generally safe, but the serious side effects that may be observed in the short and long-term use should be taken into account.


Assuntos
Febre Familiar do Mediterrâneo , Proteína Antagonista do Receptor de Interleucina 1 , Adulto , Anticorpos Monoclonais Humanizados , Colchicina , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
20.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207085

RESUMO

Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.


Assuntos
Inflamassomos/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteínas Recombinantes/farmacologia , Superóxido Dismutase/metabolismo , Animais , Células Cultivadas , Fibrose Cística/etiologia , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Modelos Animais de Doenças , Doença Granulomatosa Crônica/etiologia , Doença Granulomatosa Crônica/metabolismo , Doença Granulomatosa Crônica/patologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Oxirredução , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo
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