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1.
CNS Drugs ; 34(9): 879-896, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32780300

RESUMO

The coronavirus 2019 (COVID-19) pandemic is expected to linger. Decisions regarding initiation or continuation of disease-modifying therapy for multiple sclerosis have to consider the potential relevance to the pandemic. Understanding the mechanism of action and the possible idiosyncratic effects of each therapeutic agent on the immune system is imperative during this special time. The infectious side-effect profile as well as the route and frequency of administration of each therapeutic agent should be carefully considered when selecting a new treatment or deciding on risk mitigation strategies for existing therapy. More importantly, the impact of each agent on the future severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) vaccine should be carefully considered in treatment decisions. Moreover, some multiple sclerosis therapies may have beneficial antiviral effects against SARS-CoV-2 while others may have beneficial immune-modulating effects against the cytokine storm and hyperinflammatory phase of the disease. Conventional injectables have a favorable immune profile without an increased exposure risk and therefore may be suitable for mild multiple sclerosis during the pandemic. However, moderate and highly active multiple sclerosis will continue to require treatment with oral or intravenous high-potency agents but a number of risk mitigation strategies may have to be implemented. Immune-modulating therapies such as the fumerates, sphinogosine-1P modulators, and natalizumab may be anecdotally preferred over cell-depleting immunosuppressants during the pandemic from the immune profile standpoint. Within the cell-depleting agents, selective (ocrelizumab) or preferential (cladribine) depletion of B cells may be relatively safer than non-selective depletion of lymphocytes and innate immune cells (alemtuzumab). Patients who develop severe iatrogenic or idiosyncratic lymphopenia should be advised to maintain social distancing even in areas where lockdown has been removed or ameliorated. Patients with iatrogenic hypogammaglobulinemia may require prophylactic intravenous immunoglobulin therapy in certain situations. When the future SARS-CoV-2 vaccine becomes available, patients with multiple sclerosis should be advised that certain therapies may interfere with mounting a protective immune response to the vaccine and that serological confirmation of a response may be required after vaccination. They should also be aware that most multiple sclerosis therapies are incompatible with live vaccines if a live SARS-CoV-2 vaccine is developed. In this article, we review and compare disease-modifying therapies in terms of their effect on the immune system, published infection rates, potential impact on SARS-CoV-2 susceptibility, and vaccine-related implications. We propose risk mitigation strategies and practical approaches to disease-modifying therapy during the COVID-19 pandemic.


Assuntos
Antirreumáticos/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Sistema Imunitário/efeitos dos fármacos , Esclerose Múltipla , Pandemias , Pneumonia Viral , Vacinas Virais/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Risco Ajustado
2.
CNS Drugs ; 34(9): 879-896, 2020 09.
Artigo em Inglês | MEDLINE | ID: covidwho-709768

RESUMO

The coronavirus 2019 (COVID-19) pandemic is expected to linger. Decisions regarding initiation or continuation of disease-modifying therapy for multiple sclerosis have to consider the potential relevance to the pandemic. Understanding the mechanism of action and the possible idiosyncratic effects of each therapeutic agent on the immune system is imperative during this special time. The infectious side-effect profile as well as the route and frequency of administration of each therapeutic agent should be carefully considered when selecting a new treatment or deciding on risk mitigation strategies for existing therapy. More importantly, the impact of each agent on the future severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) vaccine should be carefully considered in treatment decisions. Moreover, some multiple sclerosis therapies may have beneficial antiviral effects against SARS-CoV-2 while others may have beneficial immune-modulating effects against the cytokine storm and hyperinflammatory phase of the disease. Conventional injectables have a favorable immune profile without an increased exposure risk and therefore may be suitable for mild multiple sclerosis during the pandemic. However, moderate and highly active multiple sclerosis will continue to require treatment with oral or intravenous high-potency agents but a number of risk mitigation strategies may have to be implemented. Immune-modulating therapies such as the fumerates, sphinogosine-1P modulators, and natalizumab may be anecdotally preferred over cell-depleting immunosuppressants during the pandemic from the immune profile standpoint. Within the cell-depleting agents, selective (ocrelizumab) or preferential (cladribine) depletion of B cells may be relatively safer than non-selective depletion of lymphocytes and innate immune cells (alemtuzumab). Patients who develop severe iatrogenic or idiosyncratic lymphopenia should be advised to maintain social distancing even in areas where lockdown has been removed or ameliorated. Patients with iatrogenic hypogammaglobulinemia may require prophylactic intravenous immunoglobulin therapy in certain situations. When the future SARS-CoV-2 vaccine becomes available, patients with multiple sclerosis should be advised that certain therapies may interfere with mounting a protective immune response to the vaccine and that serological confirmation of a response may be required after vaccination. They should also be aware that most multiple sclerosis therapies are incompatible with live vaccines if a live SARS-CoV-2 vaccine is developed. In this article, we review and compare disease-modifying therapies in terms of their effect on the immune system, published infection rates, potential impact on SARS-CoV-2 susceptibility, and vaccine-related implications. We propose risk mitigation strategies and practical approaches to disease-modifying therapy during the COVID-19 pandemic.


Assuntos
Antirreumáticos/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Sistema Imunitário/efeitos dos fármacos , Esclerose Múltipla , Pandemias , Pneumonia Viral , Vacinas Virais/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Risco Ajustado
3.
PLoS One ; 15(8): e0237143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760165

RESUMO

OBJECTIVES: Abatacept acts as a competitive inhibitor of the CD28/(CD80/86) costimulation signal required for T cell activation. Mechanisms of action of abatacept have not been fully investigated. The objective of this study was to provide detailed insight into the mode of action of Abatacept based on gene expression data. METHODS: In this ancillary study from the APPRAISE trial, we investigated the global molecular effects of Abatacept in whole blood samples collected prospectively in biologic naive rheumatoid arthritis patients (n = 19) at baseline and 6 months after the initiation of Abatacept therapy concomitant with methotrexate. Whole human genome microarrays (4x44K) were performed on both baseline and 6-month samples from responders and non-responders patients categorized according to EULAR criteria. T-test with Benjamini-Hochberg correction was performed to identify significant gene expression changes. Gene Ontology and Single Experiment Analysis tools allowed us to highlight specific biological mechanisms involved in methotrexate/Abatacept. RESULTS: In methotrexate/Abatacept responders, 672 genes were significantly (q<0.05) dysregulated at 6 months compared to baseline. Correlation analysis highlighted 19 genes whose dysregulations were significantly associated with disease activity variation (p<0.05) and whose functions were associated with proliferation, apoptosis of cells and mitochondrial metabolism, suggesting a restoration of oxidative signaling. The other 653 gene expression changes were relative to direct or indirect effects of methotrexate/Abatacept treatment and were significantly (p<0.005) involved in pathways relative to mRNA processing, proteasome, angiogenesis, apoptosis and TCR signaling. This study highlights new mechanisms of action of methotrexate/Abatacept and may provide new therapeutic targets to prevent autoimmunity in rheumatoid arthritis.


Assuntos
Abatacepte/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Metotrexato/farmacologia , Transcriptoma/efeitos dos fármacos , Abatacepte/administração & dosagem , Abatacepte/uso terapêutico , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade
4.
BMC Infect Dis ; 20(1): 464, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32615992

RESUMO

BACKGROUND: Despite successful clinical outcomes of biologic medications in patients with chronic rheumatic diseases, some considerable adverse effects such as infections remain a major concern. Possibility of tuberculosis (TB) reactivation over treatment with anti-tumor necrotizing factor (TNF) alpha agents has necessitated a screening test before initiation of treatment. However, screening over the course of treatment is not recommended in those patients with negative baseline screening tests. This study aimed to evaluate the efficacy of tuberculin skin test (TST) before treatment in patients with chronic rheumatologic diseases who were indicated to receive anti-TNF-alpha therapy and the necessity of repeating this test over the course of treatment. METHODS: In this prospective study, patients with chronic rheumatologic diseases receiving anti-TNF-alpha agents were studied in a two-year period. TST was performed before treatment and those with positive results were excluded from the study. Thereafter, treatment with anti-TNF-alpha agents was initiated with the indicated dose. TST was repeated before administration of biologic treatment until TST became positive or 16 weeks after the initiation of treatment with anti-TNF-alpha. RESULTS: A total of 51 cases were studied, of whom one patient (1.9%) was excluded due to positive TST before treatment. All participants received infliximab and the TST test became positive in one patient (2%) 2 weeks after receiving the first dose. Also, the results of further tests at weeks 6, 10, and 14 were all negative for the remaining patients. CONCLUSION: Due to the possibility of TST conversion after administration of anti-TNF-alpha therapy, it is important to consider TB monitoring in patients under treatment with these agents using available methods such as TST.


Assuntos
Antirreumáticos/uso terapêutico , Infliximab/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Teste Tuberculínico/métodos , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Antirreumáticos/farmacologia , Doença Crônica , Feminino , Humanos , Infliximab/farmacologia , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
5.
Int J Nanomedicine ; 15: 3497-3509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547009

RESUMO

Purpose: The existing treatment modalities for rheumatoid arthritis are less effective and safe, therefore it is essential to develop new treatments that particularly target the inflamed joints with decreased off-target side-effects. The current study proposes a nanoparticle-based therapeutic approach to target the anti-oxidant defense system of arthritic Balb/c mice. Methods: Biogenic selenium nanoparticles (SeNPs) were synthesized by using Trachyspermum ammi seed extract and were evaluated for their toxicological, as well as their therapeutic potential in collagen-induced arthritic mice. Results: The tested doses of SeNPs had no significant toxic effects on liver, kidney, spleen, and serum biochemical parameters in comparison to healthy mice. The SeNPs treatment reduced the disease severity, as demonstrated by decreased paw edema along with reduced lymphocytic cellular infiltration in the histopathological findings. SeNPs also revealed dose-independent improvement in the redox state of inflamed synovium by significantly improving the activity of antioxidant enzymes in comparison to the arthritic controls. Conclusion: It is therefore concluded that nano-selenium in combination with TAE extract showed enhanced therapeutic efficacy as compared to their individual effects.


Assuntos
Antirreumáticos/uso terapêutico , Apiaceae/química , Artrite Reumatoide/tratamento farmacológico , Nanopartículas/química , Selênio/toxicidade , Selênio/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antirreumáticos/farmacologia , Artrite Reumatoide/patologia , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Bovinos , Edema/patologia , Feminino , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Oxirredução , Extratos Vegetais/química , Selênio/administração & dosagem , Selênio/farmacologia , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Baço/efeitos dos fármacos , Baço/patologia
6.
Clin Rheumatol ; 39(7): 2085-2094, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32474885

RESUMO

COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.


Assuntos
Antirreumáticos , Infecções por Coronavirus , Síndrome da Liberação de Citocina , Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Pandemias , Pneumonia Viral , Antirreumáticos/classificação , Antirreumáticos/imunologia , Antirreumáticos/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Humanos , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Síndrome de Ativação Macrofágica/etiologia , Síndrome de Ativação Macrofágica/imunologia , Síndrome de Ativação Macrofágica/terapia , Seleção de Pacientes , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Tempo para o Tratamento
7.
Clin Rheumatol ; 39(7): 2085-2094, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-436778

RESUMO

COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.


Assuntos
Antirreumáticos , Infecções por Coronavirus , Síndrome da Liberação de Citocina , Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Pandemias , Pneumonia Viral , Antirreumáticos/classificação , Antirreumáticos/imunologia , Antirreumáticos/farmacologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Humanos , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Síndrome de Ativação Macrofágica/etiologia , Síndrome de Ativação Macrofágica/imunologia , Síndrome de Ativação Macrofágica/terapia , Seleção de Pacientes , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Tempo para o Tratamento
8.
Int J Exp Pathol ; 101(1-2): 55-64, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32459025

RESUMO

Rheumatoid arthritis is a disabling autoimmune disease with a high global prevalence. Treatment with disease-modifying anti-arthritic drugs (DIMARDs) has been routinely used with beneficial effects but with adverse long-term consequences; novel targeted biologics and small-molecule inhibitors are promising options. In this study, we investigated whether purified omega unsaturated fatty acids (ω-UFAs) and dialysable leukocyte extracts (DLEs) prevented the development of arthritis in a model of collagen-induced arthritis (CIA) in mice. We also investigated whether the transcription factor NF-κB and the NLRP3 inflammasome were involved in the process and whether their activity was modulated by treatment. The development of arthritis was evaluated for 84 days following treatment with nothing, dexamethasone, DLEs, docosahexaenoic acid, arachidonic acid, and oleic acid. Progression of CIA was monitored by evaluating clinical manifestations, inflammatory changes, and histological alterations in the pads' articular tissues. Both DLEs and ω-UFAs led to an almost complete inhibition of the inflammatory histopathology of CIA and this was concomitant with the inhibition of NF-kB and the inhibition of the activation of NLRP3. These data suggest that ω-UFAs and DLEs might have NF-κB as a common target and that they might be used as ancillary medicines in the treatment of arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/prevenção & controle , Cartilagem Articular/efeitos dos fármacos , Extratos Celulares/farmacologia , Ácidos Graxos Insaturados/farmacologia , Leucócitos , Animais , Ácido Araquidônico/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Colágeno Tipo II , Diálise , Ácidos Docosa-Hexaenoicos/farmacologia , Feminino , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ácido Oleico/farmacologia
9.
Clin Rheumatol ; 39(7): 2069-2075, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32472461

RESUMO

Since December 2019, the pandemic caused by coronavirus disease 2019 (COVID-19) raises a real public health problem. COVID-19 appeared in Wuhan (Hubei province) in China. Drugs that have been used in rheumatology for decades seem to be effective in this infection and are for the most part being studied. The rational use of these anti-rheumatic drugs is based on the cytokinic storm (hyperproduction of IL1, IL6, TNF α) in the body by COVID-19 in its severe form. In this review, the authors make the difference between the infectious and auto-inflammatory part of COVID-19; the disease does not seem to be a risk factor for admission to the intensive care unit for patients suffering from inflammatory rheumatism; however, the poverty of studies on this subject should be noted. The authors also review anti-rheumatic drugs while studying COVID-19 treatment.


Assuntos
Antirreumáticos/farmacologia , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Doenças Reumáticas , Betacoronavirus/isolamento & purificação , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/imunologia
10.
Clin Rheumatol ; 39(7): 2069-2075, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-430171

RESUMO

Since December 2019, the pandemic caused by coronavirus disease 2019 (COVID-19) raises a real public health problem. COVID-19 appeared in Wuhan (Hubei province) in China. Drugs that have been used in rheumatology for decades seem to be effective in this infection and are for the most part being studied. The rational use of these anti-rheumatic drugs is based on the cytokinic storm (hyperproduction of IL1, IL6, TNF α) in the body by COVID-19 in its severe form. In this review, the authors make the difference between the infectious and auto-inflammatory part of COVID-19; the disease does not seem to be a risk factor for admission to the intensive care unit for patients suffering from inflammatory rheumatism; however, the poverty of studies on this subject should be noted. The authors also review anti-rheumatic drugs while studying COVID-19 treatment.


Assuntos
Antirreumáticos/farmacologia , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Doenças Reumáticas , Betacoronavirus/isolamento & purificação , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/imunologia
11.
Expert Opin Pharmacother ; 21(9): 1015-1025, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32345068

RESUMO

INTRODUCTION: The treatment of rheumatoid arthritis (RA), a chronic, systemic, autoimmune disease, has been greatly advanced by the introduction of biologic disease-modifying antirheumatic drugs (DMARDs); however, many patients still fail to achieve disease remission. Peficitinib, an orally bioavailable inhibitor of the Janus kinase (JAK) receptor family, was approved in Japan in 2019 and Korea in 2020 for the treatment of RA. AREAS COVERED: This review provides an overview of JAK inhibitors currently marketed or in development; the pharmacodynamics and pharmacokinetics of peficitinib; and the efficacy and safety data for peficitinib from Phase 2b and 3 trials. EXPERT OPINION: Peficitinib has proven clinical efficacy in Asian patients (Japan, Korea, and Taiwan) with RA who have an inadequate response to conventional DMARDs. In Phase 3 trials, clinical improvements and prevention of joint destruction were demonstrated for both 100 mg and 150 mg once-daily peficitinib versus placebo, and treatment for up to 52 weeks was well tolerated. Safety signals, in particular the increased incidence of herpes zoster-related disease, appeared in line with other JAK inhibitors. Post-launch monitoring will establish the long-term safety and effectiveness of this drug, and further studies are necessary to determine its potential use in non-Asian populations.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunossupressores/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/farmacologia , Adamantano/uso terapêutico , Antirreumáticos/farmacologia , Humanos , Niacinamida/farmacologia , Niacinamida/uso terapêutico
12.
Clin Rheumatol ; 39(7): 2055-2062, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32277367

RESUMO

The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern. Environmental factors such as air pollution and smoking and comorbid conditions (hypertension, diabetes mellitus and underlying cardio-respiratory illness) likely increase the severity of COVID-19. Rheumatic manifestations such as arthralgias and arthritis may be prevalent in about a seventh of individuals. COVID-19 can result in acute interstitial pneumonia, myocarditis, leucopenia (with lymphopenia) and thrombocytopenia, also seen in rheumatic diseases like lupus and Sjogren's syndrome. Severe disease in a subset of patients may be driven by cytokine storm, possibly due to secondary hemophagocytic lymphohistiocytosis (HLH), akin to that in systemic onset juvenile idiopathic arthritis or adult-onset Still's disease. In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2 (ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored. Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation may be considered during infection episodes as per standard practices. Development of a vaccine may be the only effective long-term protection against this disease.Key Points• Patients with coronavirus disease 19 (COVID-19) may have features mimicking rheumatic diseases, such as arthralgias, acute interstitial pneumonia, myocarditis, leucopenia, lymphopenia, thrombocytopenia and cytokine storm with features akin to secondary hemophagocytic lymphohistiocytosis.• Although preliminary results may be encouraging, high-quality clinical trials are needed to better understand the role of drugs commonly used in rheumatology like hydroxychloroquine and tocilizumab in COVID-19.• Until further evidence emerges, it may be cautiously recommended to continue glucocorticoids and other disease-modifying antirheumatic drugs (DMARDs) in patients receiving these therapies, with discontinuation of DMARDs during infections as per standard practice.


Assuntos
Infecções por Coronavirus , Imunidade/efeitos dos fármacos , Conduta do Tratamento Medicamentoso , Pandemias , Pneumonia Viral , Doenças Reumáticas , Antirreumáticos/farmacologia , Betacoronavirus/isolamento & purificação , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Humanos , Seleção de Pacientes , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/epidemiologia , Índice de Gravidade de Doença
13.
Clin Rheumatol ; 39(7): 2055-2062, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-46545

RESUMO

The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern. Environmental factors such as air pollution and smoking and comorbid conditions (hypertension, diabetes mellitus and underlying cardio-respiratory illness) likely increase the severity of COVID-19. Rheumatic manifestations such as arthralgias and arthritis may be prevalent in about a seventh of individuals. COVID-19 can result in acute interstitial pneumonia, myocarditis, leucopenia (with lymphopenia) and thrombocytopenia, also seen in rheumatic diseases like lupus and Sjogren's syndrome. Severe disease in a subset of patients may be driven by cytokine storm, possibly due to secondary hemophagocytic lymphohistiocytosis (HLH), akin to that in systemic onset juvenile idiopathic arthritis or adult-onset Still's disease. In the absence of high-quality evidence in this emerging disease, understanding of pathogenesis may help postulate potential therapies. Angiotensin converting enzyme 2 (ACE2) appears important for viral entry into pneumocytes; dysbalance in ACE2 as caused by ACE inhibitors or ibuprofen may predispose to severe disease. Preliminary evidence suggests potential benefit with chloroquine or hydroxychloroquine. Antiviral drugs like lopinavir/ritonavir, favipiravir and remdesivir are also being explored. Cytokine storm and secondary HLH might require heightened immunosuppressive regimens. Current international society recommendations suggest that patients with rheumatic diseases on immunosuppressive therapy should not stop glucocorticoids during COVID-19 infection, although minimum possible doses may be used. Disease-modifying drugs should be continued; cessation may be considered during infection episodes as per standard practices. Development of a vaccine may be the only effective long-term protection against this disease.Key Points• Patients with coronavirus disease 19 (COVID-19) may have features mimicking rheumatic diseases, such as arthralgias, acute interstitial pneumonia, myocarditis, leucopenia, lymphopenia, thrombocytopenia and cytokine storm with features akin to secondary hemophagocytic lymphohistiocytosis.• Although preliminary results may be encouraging, high-quality clinical trials are needed to better understand the role of drugs commonly used in rheumatology like hydroxychloroquine and tocilizumab in COVID-19.• Until further evidence emerges, it may be cautiously recommended to continue glucocorticoids and other disease-modifying antirheumatic drugs (DMARDs) in patients receiving these therapies, with discontinuation of DMARDs during infections as per standard practice.


Assuntos
Infecções por Coronavirus , Imunidade/efeitos dos fármacos , Conduta do Tratamento Medicamentoso , Pandemias , Pneumonia Viral , Doenças Reumáticas , Antirreumáticos/farmacologia , Betacoronavirus/isolamento & purificação , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Humanos , Seleção de Pacientes , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/epidemiologia , Índice de Gravidade de Doença
14.
J Virol ; 94(11)2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188727

RESUMO

Brain-resident microglia and myeloid cells (perivascular macrophages) are important HIV reservoirs in vivo, especially in the central nervous system (CNS). Despite antiretroviral therapy (ART), low-level persistent HIV replication in these reservoirs remains detectable, which contributes to neuroinflammation and neurological disorders in HIV-infected patients. New approaches complementary to ART to repress residual HIV replication in CNS reservoirs are needed. Our group has recently identified a BRD4-selective small molecule modulator (ZL0580) that induces the epigenetic suppression of HIV. Here, we examined the effects of this compound on HIV in human myeloid cells. We found that ZL0580 induces potent and durable suppression of both induced and basal HIV transcription in microglial cells (HC69) and monocytic cell lines (U1 and OM10.1). Pretreatment of microglia with ZL0580 renders them more refractory to latent HIV reactivation, indicating an epigenetic reprogramming effect of ZL0580 on HIV long terminal repeat (LTR) in microglia. We also demonstrate that ZL0580 induces repressive effect on HIV in human primary monocyte-derived macrophages (MDMs) by promoting HIV suppression during ART treatment. Mechanistically, ZL0580 inhibits Tat transactivation in microglia by disrupting binding of Tat to CDK9, a process key to HIV transcription elongation. High-resolution micrococcal nuclease mapping showed that ZL0580 induces a repressive chromatin structure at the HIV LTR. Taken together, our data suggest that ZL0580 represents a potential approach that could be used in combination with ART to suppress residual HIV replication and/or latent HIV reactivation in CNS reservoirs, thereby reducing HIV-associated neuroinflammation.IMPORTANCE Brain-resident microglia and perivascular macrophages are important HIV reservoirs in the CNS. Persistent viral replication and latent HIV reactivation in the CNS, even under ART, are believed to occur, causing neuroinflammation and neurological disorders in HIV-infected patients. It is critical to identify new approaches that can control residual HIV replication and/or latent HIV reactivation in these reservoirs. We here report that the BRD4-selective small molecule modulator, ZL0580, induces potent and durable suppression of HIV in human microglial and monocytic cell lines. Using an in vitro HIV-infected, ART-treated MDM model, we show that ZL0580 also induces suppressive effect on HIV in human primary macrophages. The significance of our research is that it suggests a potential new approach that has utility in combination with ART to suppress residual HIV replication and/or HIV reactivation in CNS reservoirs, thereby reducing neuroinflammation and neurological disorders in HIV-infected individuals.


Assuntos
Antirreumáticos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Epigênese Genética/efeitos dos fármacos , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Infecções por HIV/metabolismo , HIV-1/fisiologia , Microglia , Monócitos , Fatores de Transcrição/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Antirreumáticos/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Microglia/metabolismo , Microglia/patologia , Microglia/virologia , Monócitos/metabolismo , Monócitos/patologia , Monócitos/virologia , Fatores de Transcrição/metabolismo
15.
Pharm Biol ; 58(1): 157-164, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32037930

RESUMO

Context: Er Miao San (EMS) is a traditional Chinese medicine composed of Atractylodis Rhizoma and Phellodendri Cortex in a 1:1 weight ratio. EMS has been used to treat rheumatism in China for many years.Objective: To evaluate the anti-arthritic activity of EMS extract on adjuvant-induced arthritis (AA) in Sprague-Dawley rats and to clarify its mechanisms of action.Materials and methods: EMS (0.75, 1.5 and 3 g/kg, once daily) was orally administered from day 18 after immunization to day 31. The effects of EMS on AA rats were evaluated by histopathological examination, paw swelling and polyarthritis index. The proliferation of fibroblast-like synoviocyte (FLS) and T cells was detected by CCK-8. The percentages of Th17 cells and Treg cells in splenocytes were determined by flow cytometry. Levels of cytokines in serum were detected by ELISA.Results: EMS treatment significantly decreased the paw volume (from 1.20 to 0.81), polyarthritis index (from 9.56 to 4.46) and alleviated ankle joint histopathology in AA rats. EMS inhibited the proliferation of FLS and T cells. Furthermore, EMS treatment decreased Th17 cells (from 4.62 to 2.08%) and increased Treg cells (from 2.77 to 4.75%) in splenocytes. The levels of IL-17A, TNF-α and IL-6 were remarkably decreased in the serum of EMS-treated rats, whereas the levels of IL-10 and TGF-ß1 were significantly increased.Conclusions: EMS exhibits anti-arthritic activity in the AA model by regulating the balance of cytokines and the ratio of Th17 and Treg cells. These insights may provide an experimental basis for the clinical treatment of RA.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Animais , Antirreumáticos/administração & dosagem , Artrite Experimental/patologia , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Adjuvante de Freund , Masculino , Ratos , Ratos Sprague-Dawley , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo
16.
Curr Atheroscler Rep ; 22(1): 4, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932973

RESUMO

PURPOSE OF REVIEW: Despite major advances in terms of prevention, diagnosis, risk-stratification, management and rehabilitation, atherosclerosis and atherothrombosis continue to have major morbidity and mortality implications worldwide. Since the unraveling of the pivotal role of inflammation in atherothrombosis pathophysiology, several focused treatments have been proposed with the ultimate goal of preventing or treating myocardial infarction, stroke, and peripheral artery disease. In particular, given the centrality of interleukin-1 (IL-1), targeted anti-IL-1 agents have attracted substantial attention and efforts. Yet, uncertainty persists on the real risk-benefit and cost-benefit balance of anti-IL-1 agents in patients with or at risk of atherothrombosis. RECENT FINDINGS: Several trials have been recently completed on atherothrombosis prevention and treatment with anti-IL-1 agents, ranging, for instance, from the large Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial to the series of translational studies conducted within the Virginia Commonwealth University-Anakinra Remodeling Trial (VCU-ART) platform. In light of the present scoping umbrella review, it appears evident that anti-IL-1 agents can reduce systemic inflammation and improve surrogate markers of cardiac and vascular function, with potential benefits on the risk of new/worsening heart failure. One trial suggested an increased risk of major adverse events with anti-interleukin-1 agents, possibly due to a rebound phenomenon, but this was based on a post-hoc analysis of a small number of events, and it was not supported by all other pertinent trials. The CANTOS study showed a potential hazard due to an increased risk of fatal infections, but the effect size was rather small. In addition, cost issues limit the foreseeable scope of these treatment strategies in unselected patients, calling instead for more refined prescribing. The evidence base on the risk-benefit and cost-benefit profile of anti-IL-1 agents for atherothrombosis prevention and treatment has expanded substantially in the last decade. While largely dominated by the landmark CANTOS trial, effect estimates also including the VCU-ART trials suggest complex short- and long-term effects which may prove favorable in carefully selected patients with acute or chronically sustained inflammation. Conversely, more liberal use appears less promising, and further studies with currently available agents or novel ones are eagerly needed to better define their role in the era of precision molecular medicine.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Trombose/tratamento farmacológico , Trombose/prevenção & controle , Anticorpos Monoclonais Humanizados/farmacologia , Antirreumáticos/farmacologia , Biomarcadores , Humanos , Inflamação/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Infarto do Miocárdio/prevenção & controle , Medição de Risco , Acidente Vascular Cerebral/prevenção & controle
17.
Arthritis Rheumatol ; 72(1): 57-66, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350812

RESUMO

OBJECTIVE: To evaluate the antiinflammatory and analgesic effects of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease, and to determine whether urinary sepiapterin levels, as measured in mice and healthy human volunteers, could be useful as a noninvasive, translational biomarker of SPR inhibition/target engagement. METHODS: The collagen antibody-induced arthritis (CAIA) model was used to induce joint inflammation in mice. The effects of pharmacologic inhibition of SPR on thresholds of heat-, cold-, and mechanical-evoked pain sensitivity and on signs of inflammation were tested in mice with CAIA. In addition, mice and healthy human volunteers were treated with SPR inhibitors, and changes in urinary sepiapterin levels were analyzed by high-performance liquid chromatography. RESULTS: CAIA in mice was characterized by 2 phases: in the acute inflammation (early) phase, joint inflammation and heat-, mechanical-, and cold-induced pain hypersensitivity were present, while in the postinflammation (late) phase, no joint inflammation was observed but heat- and mechanical-induced hypersensitivity, but not cold hypersensitivity, were present. Inhibition of SPR in mice with CAIA significantly attenuated the heat-induced hyperalgesia in both phases, and the mechanical allodynia in the late phase. Signs of inflammation were unaffected by SPR inhibition. Urinary tetrahydrobiopterin levels, as a marker of inflammatory pain, were increased during inflammation in mice with CAIA (2-fold increase over controls; P < 0.05) and significantly reduced by SPR inhibition (P < 0.05 versus vehicle-treated mice). Increased urinary sepiapterin levels in the presence of SPR inhibition in both mice and healthy human volunteers were associated with high sensitivity (70-85%) and high specificity (82-88%) for the prediction of SPR inhibition/target engagement. CONCLUSION: SPR inhibition reduces the pain associated with joint inflammation, thus showing its potential utility as an analgesic strategy for inflammatory joint pain. In addition, SPR inhibition increases urinary sepiapterin levels, indicating the potential of this measurement as a noninvasive biomarker of target engagement of SPR inhibitors, such as sulfasalazine, a disease-modifying antirheumatic drug that is currently used as a first-line treatment for rheumatoid arthritis.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antirreumáticos/farmacologia , Artrite Experimental/fisiopatologia , Hiperestesia/fisiopatologia , Articulações/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Pterinas/urina , Sulfassalazina/farmacologia , Adulto , Animais , Artrite Experimental/patologia , Biomarcadores/urina , Biopterina/análogos & derivados , Biopterina/urina , Cromatografia Líquida de Alta Pressão , Temperatura Baixa , Feminino , Membro Posterior , Temperatura Alta , Humanos , Articulações/patologia , Masculino , Camundongos
18.
Int J Antimicrob Agents ; 55(3): 105828, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31669742

RESUMO

INTRODUCTION: Vancomycin-resistant enterococci (VRE) are a leading cause of nosocomial infections because of the limited number of effective therapeutic options. In an effort to repurpose FDA-approved drugs against antibiotic-resistant bacteria, auranofin has been identified as a potent drug against VRE. METHODS AND RESULTS: The present study determined that auranofin's antibacterial activity was not affected when evaluated against a higher inoculum size of VRE (~107 CFU/mL), and auranofin successfully reduced the burden of stationary phase VRE cells via a time-kill assay. In addition, auranofin reduced VRE production of key virulence factors, including proteases, lipase and haemagglutinin. The promising features of auranofin prompted evaluation of its in vivo efficacy in a lethal mouse model of VRE septicaemia. All mice receiving auranofin at 0.125 mg/kg orally, 0.125 mg/kg subcutaneously (SC) or 0.0625 mg/kg (SC) survived the lethal VRE challenge. Additionally, auranofin was superior to linezolid, the current drug of choice, in reducing VRE burden in the liver, kidneys and spleen of mice. Remarkably, auranofin successfully reduced VRE below the limit of detection in murine internal organs after 4 days of oral or subcutaneous treatment. CONCLUSION: These results indicate that auranofin warrants further investigation as a new treatment for systemic VRE infections.


Assuntos
Antibacterianos/farmacologia , Auranofina/farmacologia , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Animais , Antirreumáticos/farmacologia , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Linezolida/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Enterococos Resistentes à Vancomicina/patogenicidade
20.
J Immunol Res ; 2019: 6929286, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828173

RESUMO

Objective: Iguratimod, a novel disease-modifying anti-rheumatic drug for the treatment of rheumatoid arthritis, has been approved in China and Japan. Here, we aimed to find whether iguratimod can inhibit the aggressive behavior and promote apoptosis of rheumatoid fibroblast-like synoviocytes (RA-FLSs). Methods: The proliferation of RA-FLSs was assessed by 5-ethynyl-2'-deoxyuridine test and Cell Counting Kit-8. Migration and invasion were determined by the wound test and a transwell assay. Apoptosis was tested by flow cytometry. The mRNA expression of matrix metalloproteinases (MMPs) and proinflammatory cytokines in RA-FLSs were measured by quantitative PCR and ELISA. To gain insight into the molecular signaling mechanisms, we determined the effect of iguratimod on the activation of mitogen-activated protein kinases (MAPK) signaling pathways by the cellular thermal shift assay (CETSA) and western blot. Results: Iguratimod treatment significantly reduced the proliferation, migration, and invasive capacities of RA-FLSs in a dose-dependent manner in vitro. MMP-1, MMP-3, MMP-9, Interleukin-6 (IL-6), and monocyte chemoattractant protein-1 mRNA and protein levels were all decreased after treatment with iguratimod. Furthermore, tumor necrosis factor-alpha- (TNF-α-) induced expression of phosphorylated c-Jun N-terminal kinases (JNK) and P38 MAPK were inhibited by iguratimod. Additionally, iguratimod promoted the apoptosis of RA-FLSs. Most importantly, iguratimod was shown to directly interact with JNK and P38 protein by CETSA assay. Moreover, activating transcription factor 2 (ATF-2), a substrate of both JNK and P38, was suppressed by iguratimod. Conclusions: Our findings suggested that the therapeutic effects of iguratimod on RA might be, in part, due to targeting the aggressive behavior and apoptosis of RA-FLSs.


Assuntos
Antirreumáticos/farmacologia , Cromonas/farmacologia , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Imunossupressores/farmacologia , Sulfonamidas/farmacologia , Sinoviócitos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/cirurgia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/imunologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Cultura Primária de Células , Transdução de Sinais , Sinovectomia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinoviócitos/imunologia , Sinoviócitos/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
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